Introducing New Vaccines into the South African Guest Editors:

30 / S3
Volume 30, Supplement 3, 7 September 2012
ISSN 0264-410X
Vaccine Vol. 30 / S3 ( 2012 ) S3/C1–C86
Introducing New Vaccines into the South African
National Immunisation Programme - A Case Study
Guest Editors: M. Jeffrey Mphahlele, Ntombenhle J. Ngcobo,
André Meheus, Anwar A. Hoosen and Barry D. Schoub
Introducing New Vaccines into the South African National Immunisation Programme - A Case Study
ELSEVIER
Available online at www.sciencedirect.com
The Official Journal of the Edward Jenner Society
The Official Journal of the International Society for Vaccines
The Official Journal of the Japanese Society for Vaccinology
Editor-in-Chief
G.A. Poland, Rochester, MN, USA
Associate Editors
A.W. Artenstein, Pawtucket, RI, USA
A. Barrett, Galveston, TX, USA
B.M. Buddle, Palmerston North, New Zealand
B. Chen, Atlanta, GA, USA
T. Fooks, Addlestone, Surrey, UK
S.J. Jacobsen, Pasadena, CA, USA
H. Kiyono, Tokyo, Japan
J. McElhaney, Vancouver, BC, Canada
A. Oberg, Rochester, MN, USA
A. Osterhaus, Rotterdam, The Netherlands
D. Weiner, Philadelphia, PA, USA
B. Weniger, Atlanta, GA, USA
Vaccine Series Editor-in-Chief
R.E. Spier, Guildford, Surrey, UK
International Editorial Board
F.E. Andre Rixensart, Belgium
R. Arnon Rehovot, Israel
L. Babiuk Saskatoon, Canada
N. Barrett Vienna, Austria
H. Bogaerts Rixensart, Belgium
J.D. Cherry Los Angeles, CA, USA
M. Corbel Herts, UK
R. Dagan Beer-Sheva, Israel
K. Dalsgaard Copenhagen, Denmark
P. van Damme Antwerp, Belgium
B. Dodet Lyon, France
R. Edelman Baltimore, MD, USA
F. Ennis Worcester, MA, USA
G. Hewinson London, UK
J. Holmgren Goteborg, Sweden
T. Jefferson Rome, Italy
D. Katz Atlanta, GA, USA
Y. Kawaoka Tokyo, Japan
T. Lehner London, UK
R.A. Lerner La Jolla, CA, USA
M. Levin London, UK
M.M. Levine Baltimore, MD, USA
M.A. Liu Emeryville, CA, USA
S. Lu Massachusetts, MA, USA
J. Melling Swiftwater, PA, USA
E. Miller London, UK
G.H. Mitchell London, UK
W.J.W. Morrow Washington, WA, USA
P. Nara Frederick, MD, USA
J. van Oirschot Lelystad, Netherlands
S.A. Plotkin Doylestown, PA, USA
R. Rappuoli Siena, Italy
C. Sasakawa Tokyo, Japan
W. Schaffner Nashville, TN, USA
G. Schild Herts, UK
K. Takeda Osaka, Japan
R. Titball Exeter, UK
P. Valenzuela Emeryville, CA, USA
F. Wild INSERM, Lyon, France
B.N. Wilkie Ontario, Canada
K. Yamanishi Osaka, Japan
Aims and Scope
VACCINE is the pre-eminent journal for those interested in vaccines and vaccination. It serves as an interface between
academics, those in research and development, and workers in the field. Relevant topics range from basic research
through to applications, safety and legislation.
Key aspects include
• human vaccines – infectious diseases
• immunology/animal models
• regulation/societal/legislation
• human vaccines – non-infectious diseases
• delivery systems/vectors/adjuvants
• review articles
• veterinary vaccines
• production/manufacturing/safety
Please bookmark this URL: http://www.elsevier.com/locate/vaccine
The Official Journal of the Edward Jenner Society
The Official Journal of the International Society for Vaccines
The Official Journal of the Japanese Society for Vaccinology
Introducing New Vaccines into the South African
National Immunisation Programme - A Case Study
Guest Editors:
M. Jeffrey Mphahlele
HIV and Hepatitis Research Unit, University of Limpopo and
National Health Laboratory Service (NHLS), Dr. George Mukhari Tertiary Hospital,
Medunsa Campus, P.O. Box 173, Medunsa 0204, Pretoria, South Africa
Ntombenhle J. Ngcobo
National EPI Unit, Cluster: Maternal, Child, Women’s Health and Nutrition,
National Department of Health, Private Bag X828, Pretoria 001, South Africa
André Meheus
Network for Education and Support in Immunisation (NESI),
Department of Epidemiology and Social Medicine, University of Antwerp,
Universiteitsplein 1, 2610 Antwerp, Belgium
Anwar A. Hoosen
Department of Medical Microbiology, University of Pretoria and
Tshwane Academic Division of the National Health Laboratory Service (NHLS),
Private Bag X323, Riviera 0007, Pretoria, South Africa
Barry D. Schoub
National Institute for Communicable Diseases/National Health Laboratory Service,
University of the Witwatersrand, Private Bag X4, Sandringham 2131, South Africa
This supplement was developed as a collaborative effort between the South African Vaccination and
Immunisation Centre - SAVIC (at the University of Limpopo, South Africa) and the Network for Education and
Support in Immunisation - NESI (at the University of Antwerp, Belgium), with financial support from NESI.
Amsterdam • Boston • London • New York • Oxford • Paris • Philadelphia • San Diego • St. Louis
Vaccine is an international journal published 52 times a year by Elsevier Ltd.
Author enquiries: For enquiries relating to the submission of articles (including
electronic submission) please visit this journal’s homepage at http://www.elsevier.com/locate/vaccine. Contact details for questions arising after acceptance
of an article, especially those relating to proofs, will be provided by the publisher. You can track accepted articles at http://www.elsevier.com/trackarticle.
You can also check our Author FAQs at http://www.elsevier.com/authorFAQ
and/or contact Customer Support via http://support.elsevier.com.
Address for submissions: See Notes for Authors.
Funding body agreements and policies: Elsevier has established agreements
and developed policies to allow authors whose articles appear in journals published
by Elsevier, to comply with potential manuscript archiving requirements as
specified as conditions of their grant awards. To learn more about existing
agreements and policies please visit http://www.elsevier.com/fundingbodies
Publication information: Vaccine (ISSN 0264-410X). For 2012, volume
30 (52 issues) is scheduled for publication. Subscription prices are available
upon request from the Publisher or from the Elsevier Customer Service
Department nearest you or from this journal’s website (http://www.elsevier.com/
locate/vaccine). Further information is available on this journal and other
Elsevier products through Elsevier’s website: (http://www.elsevier.com).
Subscriptions are accepted on a prepaid basis only and are entered on a
calendar year basis. Issues are sent by standard mail (surface within Europe,
air delivery outside Europe). Priority rates are available upon request. Claims
for missing issues should be made within six months of the date of dispatch.
USA mailing notice: Vaccine (ISSN 0264-410X) is published 52 times a year by
Elsevier Ltd. (The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK).
USA POSTMASTER: Send address changes to Vaccine, Elsevier Customer
Service Department, 3251 Riverport Lane, Maryland Heights, MO 63043,
USA.
AIRFREIGHT AND MAILING in the USA by Mercury International Limited,
365 Blair Road, Avenel, NJ 07001.
© 2012 Elsevier Ltd. All rights reserved.
This journal and the individual contributions contained in it are protected under
copyright by Elsevier Ltd, and the following terms and conditions apply to their use:
Photocopying: Single photocopies of single articles may be made for
personal use as allowed by national copyright laws. Permission of the
Publisher and payment of a fee is required for all other photocopying, including
multiple or systematic copying, copying for advertising or promotional
purposes, resale, and all forms of document delivery. Special rates are available
for educational institutions that wish to make photocopies for non-profit
educational classroom use.
For information on how to seek permission visit www.elsevier.com/permissions
or call: (+44) 1865 843830 (UK) / (+1) 215 239 3804 (USA).
Derivative Works: Subscribers may reproduce tables of contents or prepare
lists of articles including abstracts for internal circulation within their institutions.
Permission of the Publisher is required for resale or distribution outside the
institution. Permission of the Publisher is required for all other derivative works,
including compilations and translations (please consult www.elsevier.com/
permissions).
Electronic Storage or Usage: Permission of the Publisher is required to
store or use electronically any material contained in this journal, including any
article or part of an article (please consult www.elsevier.com/permissions).
Except as outlined above, no part of this publication may be reproduced, stored
in a retrieval system or transmitted in any form or by any means, electronic,
mechanical, photocopying, recording or otherwise, without prior written
permission of the Publisher.
Notice: No responsibility is assumed by the Publisher for any injury and/or
damage to persons or property as a matter of products liability, negligence or
otherwise, or from any use or operation of any methods, products, instructions
or ideas contained in the material herein. Because of rapid advances in the
medical sciences, in particular, independent verification of diagnoses and
drug dosages should be made.
Although all advertising material is expected to conform to ethical (medical)
standards, inclusion in this publication does not constitute a guarantee or
endorsement of the quality or value of such product or of the claims made of
it by its manufacturer.
Advertising information: If you are interested in advertising or other
commercial opportunities please e-mail [email protected] and
your enquiry will be passed to the correct person who will respond to you
within 48 hours.
Sponsored supplements and/or commercial reprints: For more
information please contact Elsevier Life Sciences Commercial Sales,
Radarweg 29, 1043 NX Amsterdam, The Netherlands; phone: (+31) (20)
4852939/2059; e-mail: [email protected].
Orders, claims, and product enquiries: please contact the Elsevier Customer
Service Department nearest you:
St. Louis: Elsevier Customer Service Department, 3251 Riverport Lane,
Maryland Heights, MO 63043, USA; phone: (877) 8397126 [toll free within
the USA]; (+1) (314) 4478878 [outside the USA]; fax: (+1) (314) 4478077;
e-mail: [email protected]
Oxford: Elsevier Customer Service Department, The Boulevard, Langford Lane,
Kidlington, Oxford OX5 1GB, UK; phone: (+44) (1865) 843434; fax: (+44)
(1865) 843970; e-mail: [email protected]
Tokyo: Elsevier Customer Service Department, 4F Higashi-Azabu, 1-Chome
Bldg, 1-9-15 Higashi-Azabu, Minato-ku, Tokyo 106-0044, Japan; phone:
(+81) (3) 5561 5037; fax: (+81) (3) 5561 5047; e-mail: JournalsCustomer
[email protected]
Singapore: Elsevier Customer Service Department, 3 Killiney Road, #08-01
Winsland House I, Singapore 239519; phone: (+65) 63490222; fax: (+65)
67331510; e-mail: [email protected]
The paper used in this publication meets the requirements of ANSI/NISO
Z39.48-1992 (Permanence of Paper)
A member of the Reed Elsevier group.
Abstracted/indexed in: Abstracts on Hygiene and Communicable Diseases,
AIDS, AIDS Information, Adonis, Biological Abstracts, Biotechnology
Abstracts, Chemical Abstracts, Current AIDS Literature, Elsevier
BIOBASE/Current Awareness in Biological Science, Current Contents,
Current Opinion inImmunology, Current Opinion in Infectious Diseases,
EMBASE/Excerpta Medica, Focus on: Veterinary Science and Medicine,
Index Medicus, Index Veterinarius, Medline, SIIC Data Bases, Telegen.
Tropical; Diseases Bulletin, Veterinary Bulletin, Virus Information Exchange
Newsletter. Also covered in the abstract and citation database SciVerse
Scopus®. Full text available on SciVerse ScienceDirect ®.
For a full and complete Guide for Authors, please go to: http://www.elsevier.
com/locate/jvac
Page charges
Vaccine has no page charges.
Printed by Henry Ling Ltd, The Dorset Press, Dorchester, UK
Volume 30 Supplement 3 2012
VACCINE 30 (Suppl 3) S3/C1–S3/C86 ISSN 0264-410X www.elsevier.com/locate/vaccine
Contents
Introducing New Vaccines into the South African National Immunisation Programme - A Case Study
C1
Introducing new vaccines into the South African national immunisation programme – A case study
B.D. Schoub, M.J. Mphahlele, N.J. Ngcobo, A.A. Hoosen and A. Meheus
C3
New vaccine introduction in the East and Southern African sub-region of the WHO African region in the
context of GIVS and MDGs
B.E. Chauke-Moagi and M. Mumba
C9
The decision making process on new vaccines introduction in South Africa
N.J. Ngcobo and N.A. Cameron
C14
Rotavirus vaccination within the South African Expanded Programme on Immunisation
L.M. Seheri, N.A. Page, M.P.B. Mawela, M.J. Mphahlele and A.D. Steele
C21
Introduction of pneumococcal conjugate vaccine into the public immunization program in South Africa:
Translating research into policy
S.A. Madhi, C. Cohen and A. von Gottberg
C28
Introducing human papillomavirus vaccines into the health system in South Africa
M.H. Botha and C. Dochez
C35
Introduction of inactivated polio vaccine (IPV) into the routine immunization schedule of South Africa
B.D. Schoub
C38
Combination vaccines in the South African setting
A. Visser and A. Hoosen
C45
An update after 16 years of hepatitis B vaccination in South Africa
R.J. Burnett, A. Kramvis, C. Dochez and A. Meheus
C52
Haemophilus influenzae type b conjugate vaccines – A South African perspective
A. Visser and A. Hoosen
C58
When, and how, should we introduce a combination measles–mumps–rubella (MMR) vaccine into the
national childhood expanded immunization programme in South Africa?
N.A. Cameron
[continued overleaf]
Amsterdam • Boston • London • New York • Oxford • Paris • Philadelphia • San Diego • St. Louis
[contents continued]
C61
Immunising the HIV-infected child: A view from sub-Saharan Africa
M.J. Mphahlele and S. Mda
C66
Meeting the need for advocacy, social mobilisation and communication in the introduction of three new
vaccines in South Africa – Successes and challenges
A.F. Baleta, J. van den Heever and R.J. Burnett
C72
Addressing public questioning and concerns about vaccination in South Africa: A guide for healthcare
workers
R.J. Burnett, H.J. Larson, M.H. Moloi, E.A. Tshatsinde, A. Meheus, P. Paterson and G. François
C79
Financing vaccinations – The South African experience
M.S. Blecher, F. Meheus, A. Kollipara, R. Hecht, N.A. Cameron, Y. Pillay and L. Hanna
Vaccine 30S (2012) C1–C2
Contents lists available at SciVerse ScienceDirect
Vaccine
journal homepage: www.elsevier.com/locate/vaccine
Guest editorial
Introducing new vaccines into the South African national immunisation
programme – A case study
Over three decades ago the mother of all public health declarations, the 1978 WHO and UNICEF sponsored Alma Ata Conference,
set its goal of achieving ‘Health for All’ by the year 2000. Much has
been achieved since then with vaccines playing a major role in controlling infectious diseases throughout the world. However, much
still remains to be achieved. For example, poliomyelitis remains to
be eradicated over a decade past the original target date of 2000 and
measles, once also targeted for eradication, is still responsible for
1% of all child deaths worldwide [1]. Several global health initiatives
have been established to promote immunisation within the context
of the other primary healthcare interventions. The Global Immunisation Vision and Strategy (GIVS) was established in 2005 with
the specific aim of reducing vaccine-preventable diseases mortality and morbidity by 2/3 by 2015 as compared to 2000 [2] and the
Global Alliance for Vaccines and Immunisation (GAVI) was established in 2000 to provide financial support for immunisation to
the poorest countries of the world [3]. Unfortunately, the toll from
infectious diseases, much of which is vaccine-preventable, remains
depressingly high. It has been estimated that in 2008 some 68%
(5.970 million) of the 8.795 million deaths worldwide in children
less than 5 years of age was due to infectious diseases [1], with subSaharan Africa bearing a major portion of this toll [4]. Of concern is
that inadequate access to vaccines is responsible for over 2 million
deaths annually in low and middle income countries [5]. It is clear
that much ground needs to be made up, in particular in the immunisation field, in order to meet Millennium Development Goal 4 to
reduce the under-five mortality rate by 2/3 by 2015 from the 1990
figure.
The Expanded Programme on Immunisation (EPI) was established in 1974 by the WHO on request from the World Health
Assembly (WHA) in order to provide a set of life-saving vaccines
to the children of the world [6]. In 2008, 106 million children were
immunised against the standard six vaccine-preventable infectious diseases – TB, diphtheria, whooping cough, tetanus, polio and
measles [7], and South Africa was no exception. The hepatitis B vaccine was added to the South African EPI schedule in 1995, in line
with the recommendations by the WHA and WHO. By 2008, it was
shown that the great majority of the infectious diseases burden
in the world lay outside of these diseases. Globally, nearly half of
all deaths in children under 5 years of age were due to pneumonia (18%), diarrhoea (15%) and meningitis (2%) much of which is
preventable by three new vaccines – pneumococcal conjugate vaccine (PCV), rotavirus vaccine and the Haemophilus influenzae type
b (Hib) vaccine. However, new vaccines are costly and well beyond
the financial means of countries in the developing world where
0264-410X/$ – see front matter © 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.vaccine.2012.06.094
these diseases are most problematic. South Africa, classified by the
World Bank as an upper middle income country [8] became the
first country in sub-Saharan Africa to introduce all three new vaccines into its routine immunisation schedule, Hib in 1999, and PCV
and rotavirus a decade later in 2009. In addition a new pentavalent
vaccine containing inactivated polio vaccine (IPV) was introduced
into the routine schedule in 2009. This supplement tells the story
behind introduction of these new vaccines in South Africa.
Introducing new vaccines into a country’s immunisation schedule is by no means a simple exercise, particularly outside of the
developed world, and a comprehensive document issued by WHO
details the myriad of policy and programmatic issues which need
to be evaluated before making this weighty decision [9]. Amongst
these are the disease burden in the country, the efficacy of the vaccine, financial sustainability, public perceptions and community
pressures especially equity issues in a heterogeneous population
as well as programmatic impacts including human resources availability and programme sustainability. As a country South Africa is
a paradigm of many of these sometimes conflicting issues which
face countries outside of the industrialised world. On the one hand
South Africa has fallen short of its EPI targets and, in fact, UNICEF
has even suggested that immunisation rates may well have fallen
since 1994 [10]. Yet, on the other hand, the well-resourced private
health sector of the country, comprising about 15% of the population who are on a medical insurance scheme, have received all the
new vaccines which are part and parcel of the immunisation schedules of the developed world underlining the severe equity pressures
in the country. In addition, although the country’s health budget is
the largest on the continent, its National Department of Health has
to contend with massive conflicting health priorities such as the
world’s largest number of people living with HIV with the world’s
largest antiretroviral treatment programme further aggravated by
a huge TB burden, one of the largest in the world.
This supplement is particularly timely given the number of new
vaccines being introduced into the developed world and the complexity of the challenges faced by the developing world who are
the major victims of these vaccine-preventable diseases. Much
can be learned from the South African experience. The supplement covers nearly every aspect of the spectrum of issues which
needed to be evaluated before the Minister of Health could make
the final decision. The decision-making process is dealt with from a
WHO, an African and a national South African perspective [11,12].
The early successes which followed the introduction of PCV [13]
and rotavirus [14] vaccines are of great interest given the relatively low coverage achieved so far for these vaccines and the
C2
Guest editorial / Vaccine 30S (2012) C1–C2
superimposed spectre of HIV. The addition of a pentavalent (DTaPIPV/Hib) vaccine to the routine schedule at the same time brought a
new dimension to considerations of polio control on the continent
which, in 2012, appears to be the main last bastion of the infection
[15]. The pentavalent vaccine made South Africa the first country
on the continent to introduce IPV. Follow-up surveillance of Hib,
introduced in 1999, has now highlighted significant deficiencies
in the control of the infection which needs to be addressed [16]
while the hepatitis B vaccine immunisation programme, initiated
in 1995, has been far more successful [17]. The merits and obstacles for a future introduction of a costly (HPV) vaccine [18] as well
as a cheap (rubella) vaccine [19] are analysed. The very important
consideration of the influence of HIV infection on vaccine policies
is of special concern in a country like South Africa but also in many
developing countries [20]. The programmatic and logistical advantages of combination vaccines are discussed in the South African
setting [21]. The supplement is then followed by the programmatic
issues of social mobilisation, advocacy and education in the context of new vaccines introduction for the general public [22] as
well as for healthcare workers [23]. Lastly, the all-important issue of
making provision for sustainable financing in the face of mammoth
competing health priorities concludes the supplement [24].
References
[1] Black RE, Cousens S, Johnson HL, Lawn JE, Rudan I, Bassani DG, et al. Global,
regional, and national causes of child mortality in 2008: a systematic analysis.
Lancet 2010;375(9730):1969–87.
[2] Bilous J, Eggers R, Gasse F, Jarrett S, Lydon P, Magan A, et al. A new global
immunisation vision and strategy. Lancet 2006;367(9521):1464–6.
[3] Muraskin W. The Global Alliance for Vaccines and Immunization: is it a new
model for effective public–private cooperation in international public health?
Am J Public Health 2004;94(11):1922–5.
[4] The World Bank. In: Jamison DT, Feachem RG, Makgoba MW, Bos ER, Baingana FK, Hofman KJ, et al., editors. Disease and mortality in Sub-Saharan Africa.
World Bank; 2006.
[5] Chokshi DA, Kesselheim AS. Rethinking global access to vaccines. BMJ
2008;336(7647):750–3.
[6] Okwo-Bele JM, Cherian T. The expanded programme on immunization: a lasting
legacy of smallpox eradication. Vaccine 2011;29(Suppl. 4):D74–9.
[7] Senior K. Childhood vaccination and progress towards MDG4. Lancet
2009;9:730.
[8] The World Bank. World development indicators; 2010.
[9] World Health Organization. Vaccine introduction guidelines. Adding a vaccine to a national immunization programme: decision and implementation.
Geneva: World health Organization; 2005.
[10] UNICEF. UNICEF South Africa annual report 2011; 2011.
[11] Chauke-Moagi BE, Mumba M. New vaccine introduction in the east and Southern African sub-region of the WHO African region in the context of GIVS and
MDGs. Vaccine 2012;30(Suppl. 3):C3–8.
[12] Ngcobo NJ, Cameron NA. The decision making process on new vaccines introduction in South Africa. Vaccine 2012;30(Suppl. 3):C9–13.
[13] Madhi SA, Cohen C, von Gottberg A. Introduction of pneumococcal conjugate
vaccine into the public immunization program in South Africa: translating
research into policy. Vaccine 2012;30(Suppl. 3):C21–7.
[14] Seheri LM, Page NA, Mawela MPB, Mphahlele MJ, Steele AD. Rotavirus vaccination within the South African expanded programme on immunisation. Vaccine
2012;30(Suppl. 3):C14–20.
[15] Schoub BD. Introduction of inactivated polio vaccine (IPV) into the routine
immunization schedule of South Africa. Vaccine 2012;30(Suppl. 3):C35–7.
[16] Visser A, Hoosen A. Haemophilus influenzae type b conjugate vaccines – a South
African perspective. Vaccine 2012;30(Suppl. 3):C52–7.
[17] Burnett RJ, Kramvis A, Dochez C, Meheus A. An update after 16 years of hepatitis
B vaccination in South Africa. Vaccine 2012;30(Suppl.3):C45–51.
[18] Botha MH, Dochez C. Introducing human papillomavirus vaccines into the
health system in South Africa. Vaccine 2012;30(Suppl. 3):C28–34.
[19] Cameron NA. When should we introduce a combination measles-mumpsrubella (MMR) vaccine into the national childhood expanded immunization
programme in South Africa? Vaccine 2012;30(Suppl. 3):C58–60.
[20] Mphahlele MJ, Mda S. Immunizing the HIV infected child: a view from subSaharan Africa. Vaccine 2012;30(Suppl. 3):C61–5.
[21] Visser A, Hoosen A. Combination vaccines in the South African setting. Vaccine
2012;30(Suppl. 3):C38–44.
[22] Baleta AF, van den Heever J, Burnett R. Meeting the need for advocacy,
social mobilisation and communication in the introduction of three new vaccines in South Africa – successes and challenges. Vaccine 2012;30(Suppl. 3):
C66–71.
[23] Burnett RJ, Larson HJ, Moloi MH, Tshatsinde EA, Meheus A, Paterson P, et al.
Addressing public questions and concerns about vaccination in South Africa: a
guide for healthcare workers. Vaccine 2012;30(Suppl. 3):C72–8.
[24] Blecher M, Meheus F, Kollipara A, Hecht R, Cameron NA, Pillay Y, et al.
Financing vaccinations – the South African experience. Vaccine 2012;30(Suppl.
3):C79–86.
Barry D. Schoub
National Institute for Communicable
Diseases/National Health Laboratory Service,
University of the Witwatersrand, Private Bag X4,
Sandringham 2131, South Africa
M. Jeffrey Mphahlele
HIV and Hepatitis Research Unit, University of
Limpopo and National Health Laboratory Service
(NHLS), Dr. George Mukhari Tertiary Hospital,
Medunsa Campus, P.O. Box 173, Medunsa 0204,
Pretoria, South Africa
Ntombenhle J. Ngcobo
National EPI Unit, Cluster: Maternal, Child, Women’s
Health and Nutrition, National Department of Health,
Private Bag X828, Pretoria 001, South Africa
Anwar A. Hoosen
Department of Medical Microbiology, University of
Pretoria and Tshwane Academic Division of the
National Health Laboratory Service (NHLS), Private
Bag X323, Riviera 0007, Pretoria, South Africa
André Meheus ∗
Network for Education and Support in Immunisation
(NESI), Department of Epidemiology and Social
Medicine, University of Antwerp, Universiteitsplein 1,
2610 Antwerp, Belgium
∗ Corresponding
author. Tel.: +32 3 265 25 15;
fax: +32 3 265 28 75.
E-mail address: [email protected]
(A. Meheus)
4 June 2012
Vaccine 30S (2012) C3–C8
Contents lists available at SciVerse ScienceDirect
Vaccine
journal homepage: www.elsevier.com/locate/vaccine
Review
New vaccine introduction in the East and Southern African sub-region of the
WHO African region in the context of GIVS and MDGs
Bafedile E. Chauke-Moagi a,∗ , Mutale Mumba b
a
b
World Health Organization, Expanded Programme on Immunisation, Immunisation and Vaccine Development, South Africa
World Health Organisation, Immunisation and Vaccine Development, Regional Office for Africa, Inter-Country Support Team East and Southern Africa, Harare, Zimbabwe
a r t i c l e
i n f o
Article history:
Received 21 November 2011
Received in revised form 29 May 2012
Accepted 31 May 2012
Keywords:
New vaccines
Immunization
GIVS
MDG
EPI
WHO AFRO
a b s t r a c t
Immunization programmes have over the years proven to be effective and useful in infectious disease
control. However, based on current trends that show that many developing countries will not reach the
Millennium Development Goals (MDG) targets, there is an urgent need to accelerate efforts to control
the most common conditions still responsible for the largest morbidity and mortality in children under
5 years of age, like diarrhoea and pneumonia, for which safe and effective vaccines are now available.
Through World Health Organization (WHO) and United Nations Children’s Fund (UNICEF) strategies
and initiatives like the Global Immunization Vision and Strategy (GIVS), Accelerated Disease Control
and Reach Every District (RED), major positive achievements like the increasing number of children
reached with Diphtheria–Tetanus–Pertussis (DTP) vaccines, significant measles mortality reduction, and
the almost complete eradication of polio, have been realised. Many children in developing countries have
access to life saving vaccines through the Global Alliance for Vaccines and Immunization (GAVI) support.
Supplementary immunization activities against measles and polio continue to offer opportunities to
deliver measles and polio vaccines, and other life-saving interventions.
The Global Immunization Vision and Strategy 2006–2015 (GIVS framework) can effectively be used
to guide countries in addressing some of the remaining challenges to reach the unreached and increase
coverage of traditional vaccines, immunize more people against more diseases, support decision making
to introduce new vaccines, as well as recognize the opportunity to invest in community health through
cost-effective immunization programmes. Introduction of new vaccines should be strengthened and used
as vehicles for health systems strengthening as well as for delivery of comprehensive primary health
interventions to impact positively on the spiralling disease burden and reduce overall child mortality. A
number of countries have adopted and operationalized GIVS through comprehensive multi-year plans
for immunization (cMYP).
This paper reviews progress with respect to introduction of some of the new vaccines in the East and
Southern sub-region of WHO African region in the context of GIVS and MDGs as well as the challenges
thereof.
© 2012 Elsevier Ltd. All rights reserved.
1. Introduction
It was at the World Health Assembly (WHA 27.57) in 1974
that a recommendation was adopted to establish the Expanded
Programme on Immunization (EPI). The EPI has since been
reported to have reached 82% of children with three doses of
Diphtheria–Pertussis–Tetanus (DPT) by 2009 [1]. EPI was established and built on the basis of the successful global smallpox
eradication in 1977. Its aim was to ensure that all children
∗ Corresponding author at: 1639 Thornbrook Estate, Waterbok Street, Theresapark, Pretoria 0182, South Africa. Tel.: +27 82 578 9257; fax: +27 86 515 7141.
E-mail addresses: [email protected], [email protected]
(B.E. Chauke-Moagi).
0264-410X/$ – see front matter © 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.vaccine.2012.05.086
worldwide benefit from relatively affordable, life saving vaccines
[1]. Immunization has not only helped eradicate smallpox, but
also reduced the burden of polio by 99% globally, reduced measles
deaths by 89% in the World Health Organization’s (WHO) African
region by 2009, and is reported to avert 2.5 million deaths annually.
EPI has also played a considerable role as a health system strengthening pillar through which other proven life saving interventions
have been delivered to communities [1].
In its original stages, EPI was designed to deliver six traditional
vaccines against diphtheria, pertussis, tetanus, polio, measles and
tuberculosis. This programme was considered as one of the fundamental elements of the WHO strategy to achieve health for all by
2000. To date, most countries, including the majority of low income
countries have introduced hepatitis B (Hep B) and Haemophilus
influenzae type b (Hib) (currently referred to as under-utilised
C4
B.E. Chauke-Moagi, M. Mumba / Vaccine 30S (2012) C3–C8
Table 1
30 out of the 31 highest U5MR globally are in Sub-Saharan Africa [35].
Country
Under 5 mortality
Gambia
Comoros
Ethiopia
Sudan
United Republic of Tanzania
Malawi
Rwanda
Liberia
Mauritania
Benin
Côte d‘Ivoire
Congo
Uganda
Nigeria
Zambia
Guinea
Mozambique
Equatorial Guinea
Cameroon
Niger
Angola
Burkina Faso
Burundi
Central African Republic
Somalia
Mali
Sierra Leone
Guinea-Bissau
Afghanistan
Democratic Republic of the Congo
Chad
103
104
104
108
108
110
111
112
117
118
119
128
128
138
141
142
142
145
154
160
161
166
166
171
180
191
192
193
199
199
209
vaccines) while an increasing number are in the process of adding
the pneumococcal conjugate and the rotavirus vaccines (i.e., new
vaccines) [1]. By the end of 2010, all 19 countries in the East and
Southern Africa (ESA) sub-region of the African region of WHO, had
introduced the Hep B and Hib vaccines to their routine childhood
immunization schedules.
1.1. Immunization in the context of Millennium Development
Goals (MDG’s)
Affiliated countries signed the United Nations Millennium Declaration of the United Nations in September 2000, where goals
were set for countries to support reduction of poverty and improve
human development. Millennium Development Goal number four
(MDG 4) aims to reduce by two thirds, mortality rates amongst
children under five years (U5MR) by 2015 compared to 1990 [2].
This commitment was reaffirmed at the UN General Assembly
Special Session on Children, calling for intensification of tested,
cost-effective interventions against diseases and malnutrition [3].
Most of the efforts to meet the MDG 4 have concentrated in
developing countries which account for 90% of U5MR [2]. Increasing
immunization coverage, especially with new vaccines, came into
the spotlight as one of the driving forces that can significantly assist
the efforts to meet this goal.
According to the United Nations MDG monitor, with less than 5
years to the set target by 2015, many countries have made tremendous gains in health related targets [2]. Most countries in Africa
are however off track to achieve the MDG’s for maternal and child
mortality reduction. It is also unfortunate that most countries not
likely to meet the set targets are currently plagued by HIV/AIDS,
conflict and economic hardships [2,4].
Sub-Saharan Africa accounts for 11% of the total population of
the world, and is accountable for half of all maternal and child
deaths in the world [6] (Table 1; Fig. 1). In addition, all but one of the
thirty-one countries with the highest U5MR, except Afghanistan are
in Sub-Saharan Africa [5]. Sub-Saharan Africa unfortunately also
bears the largest burden of maternal mortality in the world [6].
It is important to note that while significant strides have been
made towards reducing child deaths, there is still a lot that needs to
be done. The United Nations MDG monitor reports that a child born
in a developing country is 13 times more likely to die before reaching the age of five compared to a child born in an industrialized
country [2]. Vaccine preventable diseases are unfortunately still
responsible for 25% of child deaths. This is mainly due to unavailability of vaccines against pneumonia and diarrhoea. Thus, vaccines
have a significant contribution to play in achieving MDG 4, by offering additional prevention against diarrhoea and pneumonia which
account for almost a third of all child deaths [7].
1.2. Immunization in the context of Global Immunization Vision
and Strategy (GIVS) 2006–2015
The 58th WHA (WHA 58.15) in 2005 recognized the role vaccination can play to meet the MDG’s and urged all countries to
adopt the WHO/UNICEF GIVS as a framework to strengthen immunization programmes between 2006 and 2015. This strategy aims
at protecting more people with immunization beyond infancy in
an environment where immunization is highly valued and all people have access to life saving vaccines. The GIVS aims not only to
sustain high immunization coverage with the traditional vaccines
but also emphasizes the need to reach the unreached, extend vaccines beyond infancy, encourages and anticipates introduction of
new vaccines and technologies for all, encourages packaging of
life saving interventions to reduce mortality, as well as financial
sustainability of immunization programmes.
This strategy was developed in order to use this proven public
health intervention to reduce child mortality and disease burden, in an environment where there is increased demand for
immunization, there are numerous new vaccines against more
infectious diseases, there are more threats for pandemics as well as
opportunities for global partnerships to strengthen health systems
[9]. In order to guide implementation of national immunization
programmes, analyse costs and finances, and plan for financing
and financial sustainability of immunization programmes, WHO
and UNICEF have supported countries to develop comprehensive
multiyear plans (cMYP) for immunization in line with GIVS. The
development of cMYP’s presents an opportunity to link immunization with other interventions, strengthen health systems and
therefore reduce child and maternal mortality [10].
2. Status of introduction
The state of the world’s vaccines and immunization report of
2009 attributes the slow progress in introduction of under-utilised
and new vaccines to amongst others the underlying health system weaknesses in developing countries, the difficulty in delivering
new interventions through already overloaded logistical systems
and infrastructures as well as the lack of understanding of the value
of vaccines especially in the poorest population [8].
Global Alliance for Vaccines and Immunization (GAVI) has
greatly supported delivery of vaccines in 13 low income countries
out of the nineteen (19) countries in the East and Southern African
countries of the AFRO region. Botswana, Lesotho, Mauritius and
Namibia, classified as low middle income states, and South Africa
being an upper middle income country, are the five countries in
the sub-region that are ineligible for GAVI support to procure and
deliver vaccines.
In the first phase of support between the years 2000 and 2005,
GAVI concentrated on supporting countries to introduce hepatitis B, Hib and yellow fever vaccines. GAVI has in the second phase
B.E. Chauke-Moagi, M. Mumba / Vaccine 30S (2012) C3–C8
C5
Fig. 1. Map of global distribution of U5MR [34].
which started in 2006 until 2015 [8], expanded its support to the
introduction of pneumococcal and rotavirus vaccines. The Alliance
furthermore introduced a co-financing system where countries are
expected to gradually take over the financing of immunization systems.
2.1. Hepatitis B vaccine
WHO classifies hepatitis B as a major public health problem and
estimates that nearly 30% of the global population have serological
evidence of hepatitis B virus infection and that 350 million of these
people live with chronic HBV infection, with a million of them dying
annually from chronic liver disease, including cirrhosis and liver
cancer. Nonetheless, there is a safe and effective vaccine against
hepatitis B since 1982. WHO has therefore recommended the inclusion of the hepatitis B vaccine in childhood routine immunization
in all countries [11].
2.1.1. WHO AFRO region
It is estimated that 18.5 million people in the WHO AFRO region
are infected with hepatitis B, with 2,915,000 chronic infections and
276, 000 deaths [12]. Hep B is one of the under-utilised vaccines
that experienced very slow progress in introduction to EPI in most
developing countries, partly due to funding constraints. However,
45 of the 46 countries in the region had introduced Hep B vaccine at
the end of 2010 [12,13]. In East and Southern Africa, the last country
introduced Hep B in September 2009 [15]. AFRO proposed a disease
control goal to include, inter alia, a birth dose in all countries as
recommended by the Strategic Advisory Group of Experts (SAGE)
in 2009 [14].
2.2. H. influenzae type b
The introduction of Hib vaccine has improved following initial delays, since the recommendation by WHO and endorsed by
SAGE through the WHO position paper in November 2006, urging countries to introduce Hib vaccines into national immunization
programmes. It is however still disturbing that only 48% of the 2009
global birth cohort lived in countries where these vaccines are available because countries with larger populations like China, India,
Indonesia and Nigeria are still to introduce Hib vaccines into their
national immunization programmes [16].
2.2.1. WHO AFRO region
44 out of the 46 countries in AFRO had introduced Hib vaccine
at the end of 2010 with Nigeria having made an application to GAVI
for introduction of Hib containing pentavalent vaccine [17].
2.2.2. East and Southern (ESA) sub-region
By the end of 2010, all nineteen ESA countries of WHO AFRO, had
successfully introduced vaccines against Hib. The last two countries to introduce Hib vaccine were Seychelles and Botswana in
November 2010 [18].
2.3. Pneumococcal conjugate vaccines
Pneumococcal infections cause many deaths in developing
countries [19,20], the bulk of which lie in HIV infected individuals;
a further problem is the rising resistance to antibiotics. The WHO
made a recommendation in March 2007 to introduce pneumococcal conjugate vaccines (PCV) to national immunization as a strategy
for control of pneumococcal diseases [20,21]. The introduction of
PCV was also emphasized for countries with child mortality rates
above 50/1000 live births as well as countries with high HIV burden.
Initially, in 2007, when the recommendation to introduce PCV
was made, only the 7-valent vaccine (PCV-7) was available to use
as a safe and effective vaccine. Given the considerable public health
impact of successful introduction of PCV, WHO emphasized the
need to prioritize development of safe, effective and affordable vaccines, offering broader protection against pneumococcal diseases
C6
B.E. Chauke-Moagi, M. Mumba / Vaccine 30S (2012) C3–C8
[20]. This has led to subsequent availability of the 10-valent (PCV10) and 13-valent (PCV-13) vaccines.
2.3.1. WHO AFRO region
In WHO AFRO, 7 out of the 46 countries had introduced PCV by
the end of 2010. An additional 17 countries have however successfully applied for GAVI Support to introduce PCV to their routine
schedule. The countries in West Africa that have made applications
are: Ghana, Guinea Bissau, Guinea, Nigeria, Niger, Liberia, Mauritania, Togo and Senegal; while the countries in Central Africa are:
Angola and Sao Tome and Principe; as well as a further 3 countries
in the ESA sub-region [17].
2.3.2. ESA sub-region
By the end of 2010, 2 countries (South Africa and Rwanda) had
introduced PCV-7 among the 19 countries in the sub-region [18].
Rwanda was supported by GAVI, while South Africa self-financed
the introduction of PCV-7. This was followed by availability of
PCV-10 and PCV-13 globally. This has led Kenya to introduce PCV10 vaccine early in 2011 with the support of GAVI, followed by
DRC which introduced PCV-13. By 2011, South Africa switched to
PCV-13, which offers a slightly broader protection against other
serotypes of pneumococcal diseases [18].
Three countries (i.e., Madagascar, Malawi and Ethiopia) in the
sub-region were approved for GAVI support in 2009 and are planning to introduce pneumococcal vaccines between 2011 and 2012
[18]. Following the April 2011 round of applications, six more
countries applied and five were approved (Mozambique, Tanzania, Uganda, Zambia and Zimbabwe) while Lesotho has to address
some issues prior to getting approval.
2.4. Rotavirus vaccines
Rotavirus infections are the most common cause of severe
diarrhoea in children globally [21]. WHO estimates that rotavirus
infections account for about 15% of diarrheal deaths, with the
largest number occurring in developing countries. It is against
this background that the WHO recommended the introduction of
rotavirus vaccines into routine childhood immunization [21].
The recommendation to introduce rotavirus vaccines, although
initially supported by significant disease burden demonstrated
in developed countries, was further endorsed for developing
countries in 2009, following conclusive evidence of effectiveness
demonstrated in trials form African and Asian countries [21].
2.4.1. WHO AFRO region
By 2010, only 1 out of the 46 WHO AFRO countries had introduced rotavirus vaccine into routine immunization. Applications
for introduction of rotavirus vaccines have been submitted by an
additional 17 countries in the region (i.e., Ghana, Mali, Nigeria, Togo
and Sierra Leone in West Africa and Angola, Burundi, Cameroon,
Central African Republic and Congo in Central Africa) [17].
2.4.2. ESA sub-region
Of the 19 countries in the ESA sub-region, rotavirus vaccination has only been introduced in South Africa. The country
introduced rotavirus vaccination simultaneously with PCV, as well
as inactivated polio and acellular pertussis containing pentavalent
(DTaP-IPV/Hib) vaccination in 2009 [18]. To date, none of the 13
GAVI funded countries of the sub-region have introduced rotavirus
vaccines. There is however an expectation for an increasing number
of countries worldwide to introduce rotavirus vaccines in the near
future [9]. Countries that have submitted applications for GAVI to
introduce rotavirus vaccine in the sub-region are Ethiopia, Eritrea,
Kenya, Madagascar, Malawi, Rwanda, Tanzania, Uganda, Zambia
and Zimbabwe [17]. Out of these countries, Ethiopia, Madagascar,
Malawi, Rwanda and Tanzania have been approved for support.
Based on previous experiences of serious adverse events of
intussusception with RotashieldTM rotavirus vaccines, there is a
need to strengthen surveillance of adverse events following immunization. The challenge is that intussusception is not a notifiable
condition in most countries and may go undetected if surveillance
is not strengthened and clinicians are not sensitized accordingly.
2.5. Human papillomavirus vaccine
Following recognition of the importance of cervical cancer and
other HPV-related conditions as global public health problems, the
WHO recommended in 2009, the introduction of HPV vaccines to
national immunization programmes. This was to be considered if
introduction was programmatically feasible and sustainable funding is available [22].
Although uptake of HPV vaccines in routine immunization in
developed countries is increasing, there is currently one country
(Rwanda) among the 19 in the sub-region that has introduced HPV
vaccine nationwide following HPV vaccine donation and support
from a vaccine manufacturing company in April 2011 [22]. However, the focus for GAVI is currently on the accelerated introduction
of pneumococcal and rotavirus vaccines in an effort to reduce mortality in children under 5 years.
2.6. Post-introduction evaluation of new vaccines
WHO recommends that countries that have introduced new
vaccines should conduct post introduction evaluations (PIE) 6–12
months after introduction to assess impact of new vaccines introduction on immunization programmes and learn lessons for future
vaccines introductions [23]. In the recent past, a number of countries in East and Southern Africa have conducted PIE activities [23].
These countries include Ethiopia in 2007, Zambia in 2009, Rwanda,
Swaziland, Zimbabwe and Lesotho in 2010, and South Africa, Tanzania, and Botswana in 2011.
3. Challenges and proposed way forward
It is clear that in order to achieve the targeted MDG’s of reduction
of child mortality, there is an urgent need for countries to upscale
efforts to reach more children with life saving vaccines in line with
GIVS. About 23 million children remain unreached with traditional
vaccines while many developing countries still need support to
introduce new vaccines against pneumonia and diarrhoea [1,8].
3.1. Competing priorities
Many developing countries are faced with large burdens of competing priorities like TB and HIV/AIDS. This means that although
countries may be aware of the need to prioritize immunization
programmes, there is difficulty in ignoring the more pressing priorities, given the current economic climate and limited resources
available for health in countries. It should however be emphasized
though that the majority of HIV/AIDS patients are co-infected by
the same vaccine preventable pathogens responsible for the commonest causes of death like pneumonia and diarrhoeal diseases.
3.2. Decision making for introduction of new vaccines
Immunization and vaccines, although amongst one of the most
cost-effective public health interventions, are not free. With the
development of new and more expensive vaccines, the cost of
immunizing one child was reported to have risen from an average of US $ 6.00 per live birth in 2000 to US $ 18.00 per live birth in
B.E. Chauke-Moagi, M. Mumba / Vaccine 30S (2012) C3–C8
2010. The cost is furthermore projected to rise to about US $ 30.00
per live birth with new vaccines like pneumococcal and rotavirus
beyond 2010 [8]. Reasons for the rising costs are not only from
procurement of initially expensive new vaccines, but also the cost
of expanding cold chain as well as hidden costs of introducing vaccines through staff training, more frequent distribution of vaccines,
and expanding social mobilization and surveillance systems.
There is sufficient data to confirm cost-effectiveness of immunization programmes, as well as the worth of investing in
immunization even with the rising cost [8]. There is therefore a
need for the WHO and UNICEF to support countries to make a
case for introduction of new vaccines through provision of costeffectiveness information and tools that illustrate the value for
money [8]. The decision to introduce new vaccines, although predominantly political, can be assisted to be more rational and
transparent through thoughtful analysis [25].
3.3. Need for surveillance systems to support new vaccine
introduction
Lack of sound surveillance systems and burden of disease data
can negatively impact on the desire to introduce new vaccines.
It is important for countries to build on some of the relatively
well established existing systems like Accelerated Disease Control systems for polio, measles and integrated disease surveillance
and response (IDSR) to consolidate some valuable information
about disease burden. Absence of disease burden information alone
should, however, not be a reason to not introduce vaccines as similar countries in the region can be used as a proxy [26].
3.4. Additional important logistical considerations that will
impact on cost of introducing new vaccines
Although there is anticipation of a drop in current new vaccine prices as the demand increases, the current cost of vaccines
may not be desirable for developing countries [8]. With the current packaging and presentation of new vaccines, UNICEF estimates
that introduction of pneumococcal, rotavirus and human papillomavirus vaccines will need additional storage capacity of 100 cm3
amounting to between US $ 1.00 and US $ 20.00 per child in the
birth cohort, depending on the equipment requirements [27]. This
is escalated by additional costs of training of staff, distribution of
vaccines and logistics, social mobilization activities, updating and
printing of data recording and reporting tools, and other key activities.
3.5. Need to sustain current routine immunization gains through
high routine coverage
More vaccines with potential benefit to populations will be
available in the future. Countries should not only evaluate disease
burdens and prioritize new vaccine introduction, but they have
to equally assess their capacity to introduce them. New vaccines
introduction can rejuvenate the programme and increase coverage
to more diseases, but this should not be done at the expense of
already poor functioning programmes. This is why GAVI required a
minimum coverage of 50% for DTP3 as a criterion for funding new
vaccines, which has since been increased to 70%. This is based on the
recognition that fixing current problems may be more important
than introducing new vaccines [25,27].
3.6. Sustainability and ownership of immunization programmes
through technical and financial support
Indeed with GAVI support many countries have scaled up efforts
to reach more people with vaccines in line with GIVS. The escalating
C7
cost of vaccinating a child and the expectation for countries to take
over some of the immunization budgets will make the need for costeffectiveness studies more urgent [8,27]. The cost of new vaccines
from international markets, for non-GAVI funded countries, is also
increasing. Previously able countries may also face some financial
constraints in sustaining immunization programme budgets and
will need to be assisted in rectifying disparities in cost of vaccines
[7,21].
GIVS emphasises the crucial role of financial commitment and
ownership of immunization funding by countries in order to aid
long-term sustainability of programmes. According to GAVI, there
is clear marked improvement in countries fulfilling their commitment to co-financing of vaccines, as illustrated by 90% of the 46
WHO AFRO countries having honoured their co-financing commitment in 2009 [26]. In the progress report presented at the 64th
World Health Assembly of 2011, preliminary cMYP’s data analysed
demonstrated that a growing number of countries had a budget line
item for immunization. This analysis showed that average figure
per live birth spent for immunization had increased from US $ 6.00
in 2000 to US $ 25.00 in 2008, and was expected to rise further in
order to accommodate new vaccines [8]. This indicated the urgent
need by WHO, UNICEF and partners to explore more favourable
strategies of reducing vaccine prices.
3.7. Weak health systems hamper progress to achieve high
immunization coverage
In support of the urgent need to implement the GIVS goal of
attainment of MDG’s, GAVI has strengthened its support to health
system strengthening, by allocating funding to assist countries to
address weaknesses in health systems [28]. However, as guided
in GIVS, introduction of new vaccines has presented opportunities to strengthen health systems through procurement of cold
chain equipment and expansion of cold storage capacity, building
of infrastructure, staff training, and other ways.
3.8. Data management for monitoring programme performance
and decision making
Use of immunization coverage data to monitor programme
performance in a timeous manner remains a challenge in many
countries [7,24]. The quality of data needs closer attention as well
as strengthening of surveillance systems for adverse events following immunization. For introduction of new vaccines, the global
framework for immunization monitoring and surveillance (GIFMS)
outlines steps in ensuring the use of coverage data and surveillance
of targeted disease burden to monitor programme performance.
Documentation of number of children vaccinated and trends in disease burden through surveillance is crucial [29]. Further availability
of support through implementation of data quality self-assessment
tool should be utilised to improve data quality [30].
3.9. Integrating immunization with other health interventions
In accordance with GIVS, as vaccines do not protect against all
diseases, there is need to integrate immunization with other proven
life saving interventions to maximize the impact on overall disease burden and child mortality. The recognition of immunization
as a valuable intervention and necessary part of overall disease
control as illustrated in the recently launched Global Action for
Prevention and Control of Pneumonia (GAPP) [31]. This ensures
that decision makers do not view immunization as vertical programmes competing against other conditions, but as an integral
enabler for child survival. Other integrated programmes include
the comprehensive WHO/UNICEF Diarrhoea Control Strategy
C8
B.E. Chauke-Moagi, M. Mumba / Vaccine 30S (2012) C3–C8
(November 2009) and the comprehensive Cervical Cancer Control
Strategy [32,33].
4. Conclusion
There is no doubt that immunization remains amongst the most
cost-effective tools and has a valuable role to play in facilitating
the attainment of specifically MDG 4. With available new vaccines
against diarrhoea and pneumonia, there is a better chance to accelerate reduction of child mortality and positively influence quality of
life for all, through implementation of the clear framework outlined
in the WHO and UNICEF GIVS.
Acknowledgements
Due acknowledgement to the WHO country office – South Africa,
colleagues in WHO AFRO/IST – ESA as well as all partners of WHO.
Conflict of interest. None, but it might be important to note that
although compilation of this article started during the time that the
corresponding author was employed by WHO, she subsequently
left WHO and was no longer with WHO by the time it was published.
References
[1] <http://www.who.int/immunization delivery/en/index.html>
[Accessed
02.05.11].
[2] <http://www.mdgmonitor.org/goal4.cfm> [Accessed 10.06.11].
[3] United Nations General Assembly resolutions. Twenty-seventh special session,
agenda items 8 and 9. A world fit for children. A/RES/S-27/2; October 11, 2002.
[4] Toward reaching the health-related millennium development goals: progress
report and the way forward. Report of the Regional Director. World Health
Organization, Regional Office for Africa; 2010.
[5] The millennium development goals report 2011, United Nations, New York,
11-31339; June 2011.
[6] Axelson H, Bergh A, Black R, Cohen B, Chopra M, Coovadia H, et al.
ASAFF, UNICEF, Save the Children, the National Academies, John Hopkins
Bloomberg School of Public Health. MDG science in action, saving the lives of
Africa’s mothers, newborns and children. 2009 <http://www.who.int/pmnch/
topics/continuum/scienceinaction.pdf>.
[7] Duclos P, Okwo-Bele J, Gacic-Dobo M. Global immunization: status,
progress and challenges. BMC Int Health Hum Rights 2009;9(Suppl. 1):S2,
www.biomedcentral.com/1472-698X/9/S1/S2.
[8] UNICEF, WHO, World Bank. State of the world’s vaccines and immunization.
3rd ed. Geneva, Switzerland: WHO Press; 2009. p. 2–12 [Executive Summary].
[9] Global immunization vision and strategy (GIVS) 2006–2012. WHO/IVB/05.05;
October 2005. <www.who.int/immunization/documents> [Accessed 01.06.11].
[10] WHO-UNICEF guidelines for developing a comprehensive multi-year plan
(cMYP), immunization, vaccines and biologicals. WHO/IVB/05.20. Geneva,
Switzerland; March 2006. <www.who.int/vaccine-documents> [Accessed
01.06.11].
[11] Introduction of hepatitis B vaccine into childhood immunization services.
WHO/V&B/01.31. Geneva, Switzerland; November 2001. <www.who.int/
vaccines-documents> [Accessed 28.05.11].
[12] Mihigo R. Prevention and control of hepatitis infections in the African region
presentation. In: 2nd African regional conference of immunization. 2010.
[13] Mumba M. New vaccine introduction in East and Southern Africa. In: GAVI
sub-regional working group meeting. 2009.
[14] Wiersma S.WHO Geneva presentation. Viral hepatitis: global burden and prevention priorities. 2008.
[15] Sixty-fourth World Health Assembly. Global immunization vision and strategy,
progress report and strategic direction for the decade of vaccines, report by
Secretariat; April 14, 2011. A 64/14 [Accessed 09.06.11].
[16] Mihigo R. WHO AFRO presentation. Progress in NUVI in the African region. New
and under-utilized vaccine implementation retreat, Majestic hotel, Montreaux,
Switzerland; June 21, 2011 [Accessed 15.07.11].
[17] Mumba M, Sahlemariam Y.Progress and challenges to new vaccine introduction
and post introduction evaluations in the East and Southern African region. WHO
and UNICEF EPI Managers meeting, March 21–23. 2011.
[18] Sixth meeting of the WHO/SEAR technical consultative group on vaccine preventable diseases, Dhaka, 3–6 May 1999. Weekly Epidemiological Record;
February 5, 1999.
[19] WHO position paper on Pneumococcal conjugate vaccine for childhood
immunization. Weekly Epidemiological Report, No. 12, vol. 82; 2007.
p. 93–104.
[20] Global plan of action for new and under-utilized vaccines implementation:
2010–2011, version July 28; 2010.
[21] WHO position paper on rotavirus vaccines and update. Weekly Epidemiological
Record, No. 51–52, vol. 84; 2009. p. 533–40. <www.who.int/wer> [Accessed
02.05.11].
[22] WHO position paper on human papillomavirus vaccine. Weekly Epidemiological report, No. 15, vol. 84; 2009. p. 118–32. <www.who.int/wer> [Accessed
02.05.11].
[23] WHO new vaccine post introduction and evaluation tool, WHO/IVB/10.03; July
2010. <www.who.int/immunization/documents/en> [Accessed 02.05.11].
[24] Mansoor O, Shin S, Maher C. The immunization focus of the WPRO; assessing new vaccines for national immunization programmes, a framework to
assist decision makers. Manila: World Health Organization regional office of
the Western Pacific (WPRO); 2000. www.wpro.who.int [Accessed 02.05.11].
[25] WHO Immunization, Vaccines and Biologicals, WHO/IVB/05.18. Vaccine introduction guidelines: adding a vaccine to a national programme—decision and
implementation. 2005.
[26] WHO position paper on Haemophillus influenzae b conjugate vaccines.
Weekly Epidemiological Report, No. 47, vol. 81; November 2006. p. 445–52.
<www.who.int/wer>.
[27] Work group 5 on cold chain and logistics systems for preparedness for introduction of PCV, rotavirus and Human papilloma vaccines. In: 3rd global meeting on
introduction of new and under-utilized vaccines, June 16–18. 2009 [Accessed
09.06.11] www.who.int/nuvi/2009/meetin summary-logistics/en/.
[28] Jorn H. GAVI update 2011. In: WHO and UNICEF East and Southern Africa EPI
managers meeting, March 21–23. 2011.
[29] WHO Department of Immunization, Vaccines and Biological. WHO/IVB/07.06.
Global framework for immunization monitoring and surveillance (GIFMS);
November 2007. <www.who.int/immunization/documents/en>.
[30] The immunization data quality self assessment tool. WHO/IVB/05.04; May
2005. <www.who.int/immunization/documents> (Accessed 3.06.11).
[31] Global Action for Prevention and Control of Pneumonia (GAPP). WHO/CAH/
FCH/NCH/09.04; 2009. <www.who.int/child adolescent health/documents/
fch cah nch 09 04/en> [Accessed 31.08.11].
[32] UNICEF/WHO Diarrhoea: why children are still dying and what can be
done. Geneva, Switzerland; November 2009. <http://whqlibdoc.who.int/
publications/2009/> [Accessed 31.08.11].
[33] WHO comprehensive cervical cancer control strategy. Geneva, Switzerland;
2006.
<http://whqlibdoc.who.int/publications/2006/9241547006 eng.pdf>
[Accessed 31.08.11].
[34] http://gamapserver.who.int/mapLibrary/Files/Maps/global underfivemortality
2009.png [Accessed 31.08.11].
[35] <http://www.who.int/gho/child health/en/index.html> [Accessed 31.08.11].
Vaccine 30S (2012) C9–C13
Contents lists available at SciVerse ScienceDirect
Vaccine
journal homepage: www.elsevier.com/locate/vaccine
Review
The decision making process on new vaccines introduction in South Africa
Ntombenhle Judith Ngcobo a,∗ , Neil A. Cameron b
a
b
Expanded Programme on Immunisation, National Department of Health, Pretoria, South Africa
Division of Community Health, Dept. of Interdisciplinary Health Sciences, Faculty of Health Sciences, Stellenbosch University, South Africa
a r t i c l e
i n f o
Article history:
Received 5 November 2011
Received in revised form 16 March 2012
Accepted 4 April 2012
Keywords:
New vaccines
Introduction
Decision making
Cost-effectiveness
Immunisation policy
a b s t r a c t
South Africa has a functional decision making process for the introduction of new vaccines; with an
established National Immunisation Technical Advisory Group (NITAG), referred to as National Advisory
Group on Immunisation (NAGI). South Africa has played a leadership role in the African continent with
introduction of new vaccines, which dates back to 1995 with the introduction of hepatitis B, followed
by the Haemophilus influenzae type b in 1999 and recently the national roll out of the pneumococcal
conjugate and rotavirus vaccines in 2009.
NAGI has the responsibility to deliberate on key policy issues as part of the process for decision making
on the introduction of new vaccines. In developing recommendations NAGI considers: disease burden,
cost effectiveness, and the impact on the Expanded Programme on Immunisation (EPI). Although guidance and recommendations from WHO are considered, the decision to introduce a new vaccine in South
Africa is based on local data. NAGI recommendations are presented to the National Department of Health
(NDOH). The NDOH pursues the matter further through the involvement of provinces. When an agreement has been reached to accept the NAGI recommendations, the NDOH seeks funding from the Ministry
of Finance (MOF). Once funds are available, the new vaccines are implemented by the immunisation
programme.
Although there is an established functional system for decision making in South Africa, some areas
need to be addressed. A system should be developed to allow the NDOH, NAGI and the MOF to engage
in the deliberations on financial and economic impact of new vaccines. It is further recommended that
a committee be established that will assess the programmatic issues to weigh the potential benefits of
a new vaccine. Furthermore, political commitment should support the immunisation programme and
strengthen it so that it can make an impact in the achievement of the Millennium Development Goal no.
4 of reducing child mortality.
© 2012 Elsevier Ltd. All rights reserved.
1. Introduction
In April 2009 the Expanded Programme on Immunisation (EPI)
in South Africa (SA) rolled out the national implementation of two
new vaccines: pneumococcal conjugate vaccine (PCV) and rotavirus
vaccine (RV). SA was the first country in the African continent to
introduce the two new vaccines. PCV has now been introduced in
other countries in Africa like Kenya and Rwanda that are supported
by the Global Alliance for Vaccines and Immunisation (GAVI). However, as of October 2011 SA remains the only country in the WHO
Africa region that self finances these vaccines [1].
∗ Corresponding author at: EPI Senior Technical Advisor – National EPI Unit,
Maternal, Child, Women’s Health and Nutrition, National Department of Health,
Private Bag X828, Pretoria 0001, South Africa. Tel.: +27 12 395 9025;
fax: +27 12 395 8905.
E-mail addresses: [email protected], [email protected]
(N.J. Ngcobo).
0264-410X/$ – see front matter © 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.vaccine.2012.04.027
The introduction of PCV and RV is a significant public health
milestone for the country and the continent. Furthermore, it points
to the leadership role that South Africa has taken in the continent
with the introduction of new and underutilised vaccines, dating
back to 1995 with the introduction of Hepatitis B (Hep B) and in
1999 with Haemophilus influenzae type b (Hib) vaccines [2].
The decision to introduce a new vaccine is complex and influenced by a number of factors including social, political concerns
and programmatic issues. WHO recommends a decision making
framework for new vaccine introduction, which considers policy
and programme issues [3]. Policy issues consider the disease burden, vaccine safety, effectiveness, the burden and benefits ratio as
well as cost-effectiveness. There are a number of decision making
tools developed, some specifically for policy decision on the use of
PCV; these include Pan American Health Organisation’s (PAHO’s)
Trivac model, the Pneumo ADIP model and the Glaxo Smith Kline
(GSK) SUPREMES model [4].
Considering the complexity of the introduction of new vaccines and that such decision relate to an important public health
C10
N.J. Ngcobo, N.A. Cameron / Vaccine 30S (2012) C9–C13
programme; it is crucial that these decisions which establish immunisation policies are well informed, unbiased, evidence based and
are locally relevant. This has been the basis of the formation of
National Immunisation Technical Advisory Groups (NITAGs) in
many countries; particularly in developed countries where these
groups are well established [5]. South Africa has a functional NITAG,
referred to as the National Advisory Group on Immunisation (NAGI).
NAGI is effective as a source of information and an advisory body
to the National Department of Health (NDOH) in South Africa. This
is evidenced by its major role in the recent introduction of PCV and
RV into the South African Expanded Programme on Immunisation
(EPI-SA) [6].
This paper examines the decision making process on new vaccines introduction in South Africa. It outlines the process focussing
on NAGI’s role, the NDOH decision making structures and other
important factors that facilitate decision making. It points at some
weaknesses in the decision making system and provides recommendations.
2. NAGI and a brief overview of decision making on new
vaccines
In South Africa the introduction of new vaccines comes from
the recommendations of NAGI, a group of experts that advises the
Department of Health on vaccination issues. NAGI’s recommendations are presented to the technical head of the NDOH, the Director
General.
NAGI was established in 1993 to advise the NDOH on technical
matters and policy issues relating to vaccination. It is composed
of experts from different fields that bear on vaccination including: microbiology, virology, public health, epidemiology, infectious
disease control, immunology and paediatrics [6].
NAGI’s primary responsibility is to make recommendations on
the introduction of new vaccines, immunisation policy, vaccine formulations and to advise on control of other infectious diseases.
NAGI has been functional and effective in its mandate; as it has been
instrumental in the introduction of: Hep B vaccine, Hib vaccine, and
PCV and RV. In 2009, NAGI also recommended the introduction
of injectable polio vaccine, which is in combination with acellular
pertussis, diphtheria, tetanus and Hib [6] (Table 1).
NAGI has clear terms of reference (TOR) which include the collation of necessary literature to aid decision making and to identify
key research areas that relate to immunisation. NAGI’s function is
mainly advisory; their recommendations are not legally enforceable [6].
While NAGI decisions on new vaccine introduction are influenced by WHO recommendations, NAGI has ensured that WHO
recommendations and strategies are adapted within the local context in accordance with the TOR. An example is the decision NAGI
took to recommend that PCV be given at 6 weeks, 14 weeks and at
9 months (Table 1). This decision was based on the high prevalence
of HIV within the South African population and provides a booster
dose later in the first year of life. The two plus one schedule was
not part of the WHO recommended schedule but was implemented
into the national EPI schedule.
3. Key policy considerations
The key areas for taking a rational informed technical decision
on the policy of introducing a new vaccine requires information on
the following areas: disease burden, vaccine safety and effectiveness, vaccine cost and the expected net impact on the immunisation
programme and the health sector. The following areas are briefly
discussed in relation to NAGI’s deliberations and collation of relevant information necessary for developing recommendations.
Table 1
Recommended immunisation schedule for infants and children within the South
African Expanded Programme on Immunisation (EPI-SA) since April 2009.
Age
Vaccines
How and where
Birth
BCG (1)
OPV (0)
OPV (1)
RV (1)
DTaP-IPV//Hib (1)
Hep B (1)
PCV (1)
DTaP-IPV//Hib (2)
Hep B (2)
RV (2)*
DTaP-IPV//Hib (3)
Hep B (3)
PCV (2)
Measles (1)
PCV (3)
DTaP-IPV//Hib (4)
Measles (2)
Td (1)
Td (2)
Intradermal, right arm
Drops, oral
Drops, oral
Liquid, oral
IM, left thigh
IM, right thigh
IM, right thigh
IM, left thigh
IM right thigh
Liquid, oral
IM, left thigh
IM, right thigh
IM, right thigh
IM, left thigh
IM, right thigh
IM, left arm
IM, right arm
IM, left arm
IM, left arm
6 weeks
10 weeks
14 weeks
9 months
18 months
6 years (Both boys and girls)
12 years (Both boys and girls)
BCG: Bacille Calmette Guerin (TB); Hep B: hepatitis B vaccine; OPV: oral polio vaccine; PCV: pneumococcal conjugated vaccine; RV: rotavirus vaccine; Td: tetanus
and reduced strength diphtheria; DTaP-IPV//Hib: diphtheria, tetanus, acellular pertussis, inactivated polio vaccine and Haemophilus influenzae type b combined; IM:
intramuscular injection.
*
Rotavirus vaccine should not be given after 24 weeks.
The Disease Burden and Public Health Priority of the condition targeted with a new vaccine is a primary consideration. The
issues to be addressed relate to the incidence, the morbidity and
mortality from the condition, and the public health significance of
the condition. It is not just the numbers affected but is also about
the severity of the condition.
NAGI contributes a major role in the collation of relevant country specific literature and deliberates on disease burden with a
focus on: incidence rate, mortality, disability adjusted life years,
hospitalisation and epidemic potential [6].
South Africa had a number of studies conducted on the disease
burden of pneumococcus. Furthermore, the study on the impact of 9
valent pneumococcal conjugate vaccine was conducted in Soweto,
South Africa with results published as early as 1999 [7]. Similarly
there were a number of disease burden studies on rotavirus and the
WHO multi-centre trial on rotavirus vaccine included South Africa,
with a research site at the University of Limpopo Medunsa campus.
Efficacy and Safety are of primary importance and relate to
licensure. This area is the responsibility of the National Regulatory
Authorities. Most products would have gone through a WHO prequalification process and would have been licensed in the country
of origin. South Africa has the Medicines Control Council (MCC), the
National Regulatory Authority which requires vaccines and other
pharmaceuticals to be registered before they can be used in the
country. In the case of PCV and RV, both vaccines had been recently
registered with the MCC when they were incorporated into EPI in
2009. Furthermore, MCC requires that all batches of vaccines should
be pre-tested by the National Control Laboratory before release [8].
The Cost and Fiscal Impact is an important area for discussion. Immunisation programmes have traditionally represented the
best buys in the health sector as significant health outcomes were
achieved per less than 1 US$ per dose. Although still cost effective,
new vaccines are much more expensive [9].
SA is not GAVI supported and the full cost of vaccination is
financed through taxpayers’ contributions. It is estimated that with
the introduction of RV & PCV vaccines, the cost of a fully immunised
child in SA has increased 10-fold [10]. This emphasises the need
to carefully analyse the costs and benefits of adding new vaccines
N.J. Ngcobo, N.A. Cameron / Vaccine 30S (2012) C9–C13
and their long term potential impact on national budgets to ensure
financial sustainability of the revised schedule [11].
The contributions to NAGI on economic aspects like costeffectiveness studies or estimates are provided by NAGI members
with specific interest in the field. For example, the SUPREMES
model was used in conjunction with WHO guidelines to make a
decision regarding the cost effectiveness of PCV. NAGI also considered the cost utility, and the impact of herd immunity for the whole
population. However, the effects of serotype replacement could not
be incorporated. This may be a limitation of the decision model [4].
The Impact: The difference that a new vaccine will make is
dependent on a number of factors including: disease burden, vaccine effectiveness, safety of the new vaccines and the level of
immunisation coverage. NAGI recommendations aim to support
the Department of Health to strengthen EPI and other child survival strategies. The focus was on how to maximise the benefits of
PCV and RV, considering SA’s heavy burden of HIV/AIDS and that the
HIV infected carry a high proportion of the invasive pneumococcal
disease burden [12].
4. Programme considerations
Programme factors may dictate that the introduction of a new
vaccine be postponed till problems are solved, even when policy
issues are in favour of new vaccine introduction and funds are
available. It should be noted that programmatic issues are not part
of NAGI’s decision making process. The Department of Health has
to deliberate on the feasibility and programme implications. Four
areas are briefly discussed.
Programme strength: The main question addressed here is
whether the immunisation programme is strong enough to effectively absorb the introduction of new vaccine. Programme strength
refers to immunisation coverage, cold chain capacity and functioning, staffing, supervision, surveillance systems for the diseases
covered by the programme and surveillance for adverse events. If an
immunisation programme has serious weaknesses like: staff shortages, poor supervision, lack of planning and budgeting at one or
more levels of service delivery (e.g. district or provincial level) it
may be best to first address these challenges before introducing a
new vaccine.
Immunisation coverage is a good indicator of the functioning of
an immunisation programme. When the new vaccines were introduced in 2009, coverage figures at national level were: DPT-Hib 3rd
dose was 100%, fully immunised coverage was 89% and measles 1
coverage was 91% [13]. Furthermore, all provinces had EPI managers posts filled and practically all technical EPI posts at national
office were filled. EPI’s strength at that time was considered to be
strong enough to absorb the new vaccines.
The vaccine presentation and the schedule of a new vaccine
may complicate storage and administration. For example, the following parameters are considered: is the vaccine a single antigen
or a combination with other vaccines, a mono-dose or multi-dose
vial, does it need reconstitution or it comes as pre-filled syringe,
or is it given orally or by injection? If the proposed administration
schedule fits into the current schedule, there will be no additional
visits by clients.
Both PCV and RV are mono-doses and single antigens. This
had serious implications in that there were significant extra cold
chain requirements and there were extra steps of work per child
immunised. Furthermore, the initial rotavirus vaccine packaging
and presentation had challenges; it was bigger and required reconstitution with a number of steps in that process.
Programme schedule: Both RV and PCV fitted well with the 6,
10, 14 weeks schedule used in South Africa. However, for practical reasons and as described earlier, there was an adjustment to
C11
the generally recommended schedule. Subsequently in the revised
schedule, RV (Rotarix) is given at 6 weeks and 14 weeks and PCV is
given at 6 weeks, 14 weeks and the third dose at 9 months together
with first dose of measles (see Table 1).
Vaccine supply. Current and future supply issues and the projected demand for a new product are important considerations. A
number of market forces particularly early in the production of a
new product may determine the availability of the product. This
needs to be carefully discussed with the: manufacturer/s, other
potential suppliers, local experts and international organisations
like UNICEF and WHO.
The NDOH addressed this area for PCV and RV and meetings
were held with the suppliers through the national distributor, The
Biovac Institute. The Biovac Institute is a vaccine company, which
has a Public Private Partnership (PPP) agreement with the NDOH to
procure vaccines for the South African population [14]. Biovac has
the responsibility to ensure that suppliers have enough stock for an
uninterrupted supply of vaccines. For the new vaccine supply, Biovac liased with the suppliers and there were no vaccine shortages.
However, due to stock availability and the change to the newer RV
presentation, the introduction of RV had to be delayed to August
2009, three months later than the planned joint introduction with
PCV, which was introduced in April 2009.
Once a policy decision has been taken to introduce a new
vaccine, the NDOH deals with programmatic issues. With no external independent support, this is often an area that is neglected
and poorly assessed. With PCV and Rotavirus vaccines some programme constraints and challenges were experienced including
cold chain capacity constraints at district depots and upgrading
of data collection tools and indicators which affect data quality.
A technical committee that assesses programme issues, made up
of advisers and EPI staff would be ideal to address this limitation. Such a committee would also take up the responsibility of
working on strategies to exploit opportunities presented by new
vaccines to strengthen EPI, a point brought up by Duclos et al.
[15].
5. The decision making process for NDOH, Provinces and
Ministry of Finance
In the decision process for new vaccine introduction, the first
stage is for NAGI to make recommendations to the NDOH to include
the new vaccine. The second stage is for the Minister, Director General and other senior officials in the NDOH to deliberate on the issue
and weigh the potential benefits.
The third stage is that of presenting the recommendations to
the National Treasury of the Ministry of Finance (MOF), particularly when a significant financial commitment is to be made. The
Minister of Health normally engages the Minister of Finance, to
ensure availability of funds through the National Treasury. The
National Treasury has the services of a health economist who also
considers the cost utility and the fiscal impact and national budgetary priorities of introducing new vaccines. However there is
no forum for Treasury to discuss with NAGI any concerns or vice
versa.
In the fourth stage the recommendations on a new vaccine are
taken to the National Health Council (NHC). The NHC is comprised
of the Minister, the Provincial Ministers of Health, the Director
General of NDOH and the Provincial Heads of Health. This stage is
critical, as the Provincial Departments of Health have the responsibility to implement national policies and if in agreement, it is
during this phase that the NHC will discuss an implementation
plan. Once the NHC approves the recommendation, this means that
provinces have committed themselves to implementation of the
new vaccines.
C12
N.J. Ngcobo, N.A. Cameron / Vaccine 30S (2012) C9–C13
Following approval by the NHC, the EPI unit together with
provincial counterparts have the responsibility to implement
the decision. Challenges are faced as they arise with support
of local experts, the World Health Organisation and UNICEF.
The actual implementation is a huge undertaking. Many areas
need additional resources and revision of tools like: cold chain
equipment; data records, immunisation registers, patient held
records; training; social mobilisation, advocacy; surveillance
for the targeted conditions and for adverse events following
immunisation.
where there is transparency and budgetary information is shared
with NAGI would be desirable. NAGI could then adjust recommendations to include budget limitations. This was not the case. All
three parties acted independently and the EPI unit had to work
with financial constraints.
Other lessons learnt relate to issues already raised, on the need
to have a specific committee on programmatic issues and on recognised channels of communication.
6. Other factors that influence decision making in South
Africa
South Africa has an established functional system for decision
making on the introduction of new vaccines. Nevertheless, there
are weaknesses which need to be addressed. A system should be
developed to allow the NDOH, NAGI and the MOF to deliberate on
financial and economic impact of new vaccines. This will ensure
that NAGI decisions consider financial constraints faced. It is further
recommended that NAGI has a health economist or a subcommittee, specifically for health economics issues and consult with
National Treasury.
Programmatic problems need a vigorous appraisal system conducted by a committee made up of independent advisors and EPI
staff. The committee should also be tasked with ensuring that the
introduction of new vaccines is used to strengthen the immunisation programme and other child survival interventions. Political
commitment to ensuring an effective immunisation programme
should be maintained and be proactive in its support for EPI to make
an impact in the achievement of the Millennium Development Goal
no. 4 of reducing child mortality.
Over above the process described with introduction of a new
vaccine, there are other factors that have an influence and affect
the process. These factors may either facilitate, hinder or bear pressure on the Department to introduce a particular antigen into the
EPI.
The position and the responsibilities of NAGI should be understood and respected by the NDOH, specifically the offices of the
Director General and the Minister. This allows for creation of clear
communication channels for NAGI and for presentation of NAGI
recommendations to the Department. If this is not the case, the
role of NAGI in influencing decision making is diminished, which
has occurred in the past. However, during the introduction of
PCV and rotavirus vaccines there was a clear link between the
higher offices of NDOH and NAGI as the minister’s advisor served
in NAGI as an ex officio member. This significantly facilitated the
process.
Political commitment plays a significant role in the introduction
of new vaccines in SA and it did for the introduction of PCV and
rotavirus vaccines. The Minister of Health showed clear commitment; which was demonstrated by an announcement during the
61st WHA in May 2008 that SA will introduce PCV and rotavirus
vaccines.
GAVI’s position and plans relating to new vaccines have a significant influence. If GAVI has started to support eligible countries,
there is increased pressure for SA to keep abreast. When South
Africa announced its plans to introduce the two new vaccines in
2008, GAVI had expressed the intention to support the introduction
of PCV for some countries in Africa.
The SA media has to some extent played a role in influencing
decision making. When a vaccine has been launched in the private
sector; the media directly engages the Department on why the vaccine is not available at public facilities. The media did this with PCV
and the NDOH had to respond.
Professional groups and some professional activists have a
potential to influence decision making. Although they did not play
much role for PCV and rotavirus vaccines; the introduction of Hib
vaccine in 1999 is believed to have been influenced by pressure
from paediatricians. This probably did not happen for PCV and RV
vaccines because political commitment came much earlier than
expected.
7. Lessons learnt
One of the main lessons learnt in the introduction of new vaccines in South Africa is regarding the availability of funds to procure
the vaccines and the sustainability of the revised schedule. The
main weakness in South Africa’s decision making process is that
the advisory body, NAGI, is not fully informed on the budget and
the funds available for the new vaccines. So with latest introduction, the recommendations were accepted by the Department yet
initially insufficient funds were allocated by the MOF. A system
8. Conclusion and recommendations
Declaration of potential conflict of interest
The authors hereby solemnly declare that they have no commercial or any other interest that may in any way be relevant to
the work published. The authors have received neither grant nor
any form of financial support from any pharmaceutical company
or any organisation that may have interest or a stake in the matters
raised in this document. Authors have no conflict of interest in the
matters raised.
References
[1] Eastern and Southern Africa EPI Managers Meeting, Harare, 21–24 March 2011.
[2] Von Gottberg A, De Gouveia L, Madhi S, et al. Impact of conjugate Haemophilus influenzae type b (Hib) vaccine introduction in South
Africa. Bulletin of the World Health Organization 2006;84(October (10)):
811–8.
[3] World Health Organization. Immunisation, Vaccines and Biologicals. Vaccine
Introduction Guidelines. Adding a vaccine to a national immunisation programme: decision and implementation. Ordering Code; WHO/IVB/05.18.
[4] Chaiyakunapruk N, Somkrua R, Henao AM, et al. Cost effectiveness
of pediatric pneumococcal conjugate vaccines: a comparative assessment of decision making tools. BioMed Central 2011;9(May (1)):53.
http://www.biomedcentral.com/1741-7015/9/53.
[5] Bryson M, Duclos P, Jolly A, Cakmak N. A global look at national Immunization
Technical Advisory Groups. Vaccine 2010;28S:A13–7.
[6] Schoub BD, Ngcobo N, Shabir M. The National Advisory Group on Immunization
(NAGI) of the Republic of South Africa. Vaccine 2010;28S:A31–4.
[7] Klugman KP, Madhi SA, Huebner RE, et al. A trial of 9-valent pneumococcal
conjugate vaccine in children with and those without HIV infection. The New
England Journal of Medicine 2003;349(October (14)):1341–8.
[8] Medicines and Related Substances Control Act, 1965. Act 101 of 1965 as
Amended. Pretoria: Government Printers.
[9] World Health Organization, UNICEF, World Bank. State of the World Vaccines
and Immunization. 3rd ed. Geneva: World Health Organization; 2009. p. 79.
[10] Ngcobo N, Cameron N. Introducing new vaccines into the childhood immunisation programme in South Africa. South African Journal of Epidemiology and
Infection 2010;25(4):3–4.
[11] Gessener BD, Duclos P, DeRoeck D, Anthony E, Nelson S. Informing decision
makers: experience and process of 15 National Immunisation Technical Advisory Groups. Vaccine 2010;28S:A1–5.
N.J. Ngcobo, N.A. Cameron / Vaccine 30S (2012) C9–C13
[12] Madhi S. Introduction of the pneumococcal conjugate vaccine into the South
African public immunisation programme: a dawn of a new era? South African
Journal of Epidemiology and Infection 2008;23(4):5–9.
[13] National Department of Health South Africa, Expanded Programme on Immunisation. District Health Information System (DHIS). Unpublished. Immunisation
Coverage figures available on request.
C13
[14] The BIOVAC Institute. http://www.biovac.co.za/company-overview.html
(accessed 30 May 2011).
[15] Duclos P, Okwo-Bele JM, Gacic-Dobo M, Cherian T. Global Immunisation: status,
progress, challenges and future. BioMed Central 2009;14(October (9), Suppl. 1
(S2)).
Vaccine 30S (2012) C14–C20
Contents lists available at SciVerse ScienceDirect
Vaccine
journal homepage: www.elsevier.com/locate/vaccine
Review
Rotavirus vaccination within the South African Expanded Programme on
Immunisation
L. Mapaseka Seheri a,∗ , Nicola A. Page a,b , Mothahadini P.B. Mawela c , M. Jeffrey Mphahlele a ,
A. Duncan Steele a,d
a
MRC/UL Diarrhoeal Pathogens Research Unit, Department of Virology, Medunsa Campus, University of Limpopo/National Health Laboratory Service, Pretoria, South Africa
Viral Gastroenteritis Unit, National Institute for Communicable Diseases, National Health Laboratory Service, Johannesburg, South Africa
c
Department of Paediatrics and Child Health, University of Limpopo, Medunsa Campus, Pretoria, South Africa
d
Rotavirus Vaccine Programme, PATH, Seattle, WA, USA
b
a r t i c l e
i n f o
Article history:
Received 9 January 2012
Received in revised form 3 April 2012
Accepted 4 April 2012
Keywords:
Rotavirus
Rotavirus vaccine
Epidemiology
South Africa
Vaccine efficacy, Burden of disease
a b s t r a c t
Diarrhoeal diseases are ranked the third major cause of childhood mortality in South African children less
than 5 years, where the majority of deaths are among black children. Acute severe dehydrating rotavirus
diarrhoea remains an important contributor towards childhood mortality and morbidity and has been
well documented in South Africa. As the preventive strategy to control rotavirus diarrhoea, South Africa
became the first country in the WHO African Region to adopt the rotavirus vaccine in the national childhood immunisation programme in August 2009. The rotavirus vaccine in use, Rotarix® , GSK Biologicals,
is given at 6 and 14 weeks of age, along with other vaccines as part of Expanded Programme on Immunisation (EPI). Studies which facilitated the introduction of rotavirus vaccine in South Africa included the
burden of rotavirus disease and strain surveillance, economic burden of rotavirus infection and clinical
trials to assess the safety and efficacy of vaccine candidates. This paper reviews the epidemiology of
rotavirus in South Africa, outlines some of the steps followed to introduce rotavirus vaccine in the EPI,
and highlights the early positive impact of vaccination in reducing the rotavirus burden of disease based
on the post-marketing surveillance studies at Dr George Mukhari hospital, a sentinel site at University
of Limpopo teaching hospital in Pretoria, South Africa, which has conducted rotavirus surveillance for
>20 years.
© 2012 Elsevier Ltd. All rights reserved.
1. Introduction
Acute severe dehydrating rotavirus diarrhoea remains a major
contributor towards childhood mortality and morbidity worldwide
[1]. Globally, rotavirus infection is estimated to cause 111 million
episodes of gastroenteritis requiring home care, 25 million clinic
visits, 2 million hospitalisations and approximately 453 000 deaths
in children under 5 years of age on annual basis [2,3]. Approximately 50% of 453 000 deaths occur in Africa with an estimated
232 000 deaths [3]. The burden of rotavirus disease is significant in
both developed and developing countries where almost all children
will have experienced rotavirus gastroenteritis by the age of 5 years,
and 1 in 5 will visit the clinic, 1 in 65 will be hospitalised and approximately 1 in 293 will die [4]. In South Africa, diarrhoeal diseases are
∗ Corresponding author at: MRC/UL Diarrheal Pathogens Research Unit, Department of Virology, P.O Box 173, University of Limpopo, Medunsa, 0204, South Africa.
Tel.: +27 12 521 4569/5959; fax: +27 12 521 5794.
E-mail addresses: [email protected], [email protected],
[email protected] (L.M. Seheri).
0264-410X/$ – see front matter © 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.vaccine.2012.04.018
ranked the third major cause of childhood mortality in children less
than 5 years where the majority of deaths are among black African
children [5]. Rotavirus has been documented as causing a third of
all diarrhoea admissions to the hospital [6].
In 2009, the Global Surveillance Rotavirus Network showed
that rotavirus was detected in a median of 41% (range; 16–57%) of
hospitalised children less than 5 years in 9 African countries including Cameroon, Ethiopia, Ghana, Kenya, Tanzania, Togo, Uganda,
Zambia and Zimbabwe [7,8]. The median rotavirus detection rate is
however slightly lower at 35% (range, 23–48%) in a similar cohort of
South African children [6,9,10]. According to the recent estimates
the incidence of diarrhoeal disease in South Africa is 111.8 per
1000 children less than 5 years of age [11]. If we multiply the
median rotavirus detection rate of 35% with diarrhoeal incidence,
it is estimated that 39/1000 children less 5 years will be infected
by rotavirus infection in South Africa. The data from South Africa
based on studies conducted at Dr George Mukhari hospital, a University of Limpopo (Medunsa campus) teaching hospital located
some 30 km north-west of Pretoria city, the estimated annual
incidence of hospitalisation associated with rotavirus diarrhoea is
between 802 and 1165 per 100 000 children less than 2 years [9].
L.M. Seheri et al. / Vaccine 30S (2012) C14–C20
2. Rotavirus epidemiology
2.1. Rotavirus transmission
Rotaviruses are highly infectious and relatively resistant to
chemical disinfectants and antiseptics. It is difficult to control
rotavirus infection because the virus is stable on environmental surfaces and are shed in high concentrations in the faeces of
infected patients [12]. The primary mode of transmission is by the
faecal-oral route, although the respiratory route has been suggested
as an alternative mode of transmission [1]. Rotavirus spreads easily in circumstances of overcrowding and poor hygiene. The virus
can be spread through contaminated food or water, direct contact
with contaminated surfaces and person-to-person contact [12,13].
Transmission of rotavirus can be easily facilitated in children’s’ day
care centres or family day care homes through frequent exposure
of susceptible hosts. Studies have shown that nosocomial rotavirus
infections in paediatric wards and hospital nurseries are quite frequent [14,15].
2.2. Clinical features
The symptoms of rotavirus infection vary from asymptomatic,
mild to severe with occasional fatal dehydrating illness. The incubation period in young children is 24–48 h post-infection [15]. The
classic acute gastroenteritis associated with rotaviruses is characterised by either the onset of vomiting, which lasts for 1–2 days
accompanied by or preceding a fever (≥37 ◦ C), followed by the onset
of watery diarrhoea, which persists for approximately 3–8 days.
The clinical symptoms of rotavirus diarrhoea vary from child to
child. However, rotavirus infections cause severe diarrhoea and are
more likely to be associated with dehydration with up to 10–20
bowel movements per day. This is often accompanied by abdominal cramps. In some cases, children may experience a cough and
runny nose [16]. Rotavirus infections can be fatal if left untreated.
The most frequent cause of death is severe dehydration and electrolyte imbalance. In a study done in Kenya and Ghana, non-bloody
diarrhoea, vomiting and life threatening complications were more
frequently detected in children infected with rotavirus than with
bacterial pathogens [17,18].
Rotavirus infections may also be asymptomatic although the
lack of symptoms may be more common in neonates and infants
or older children with previous history of rotavirus infections [15].
2.3. Seasonality of rotavirus infection
Climatic conditions have a major influence on the incidence of
rotavirus infections, especially in regions where there are seasonal
changes. In temperate climates, rotavirus disease occurs during
epidemic peaks in the cooler, drier months. In the northern hemisphere, rotavirus tends to be predominant between December and
March while in the southern hemisphere rotavirus occurs between
May and September [19–22]. Many studies have shown significant
winter seasonality of rotavirus infection, although endemic and
sporadic cases may occur during warmer months. In the United
States, Europe, India, Asia, Republic of Korea and Japan, hospitalisation rates of rotaviruses peak during winter months [19–22].
In tropical regions, seasonal rotavirus gastroenteritis patterns
are less pronounced and rotavirus infection occurs throughout the
year with minor increases during the drier season [23]. In sub
Saharan Africa, increased cases of rotavirus infection are usually
experienced during the drier months of the year and a low rate of
rotavirus infection during the wet season [7,17,24,25]. The recent
seasonal rotavirus infection data in the tropical regions of Africa
showed a marked increase of rotavirus diarrhoea during the dry
season [7].
C15
Rotavirus infections in Southern Africa display a distinct seasonal pattern with epidemic peaks occurring predominantly in
the cooler and drier winter months of the year [24,25]. The seasonal trend of rotavirus infection in South Africa displays consistent
annual rotavirus gastroenteritis in winter peaks. The proposed
mechanism underlying seasonal variation probably involves the
interplay of many factors including survival of virus in the environment, low indoor relative humidity, higher airborne transmission,
physiological effects on the host and the degree of crowding during
the winter season [26].
2.4. Age distribution of rotavirus
Worldwide, epidemiological studies indicated that all children
are infected with rotavirus before their third birthday. In South
Africa, the burden of disease study showed that a large proportion
(90%) of children less than 24 months of age admitted or visiting the outpatient department were infected with rotavirus and
rotavirus infection occurs as early as 2 months of age [9]. The highest prevalence of rotavirus infection occurred among children aged
3–17 months old [9,24], compared to the European countries where
the highest incidence of rotavirus infection is found in children aged
6–23 months [27]. In addition, the peak incidence rate of symptomatic rotavirus infection in many industrialised countries is from
6 to 18 months whereas in developing countries children tend to
become infected earlier, i.e. below 6 months of age [28].
3. Laboratory diagnosis
The laboratory diagnosis and detection for group A rotavirus
include; electron microscopy (EM), cell culture, variety of enzyme
immunoassays (EIA), polyacrylamide gel electrophoresis (PAGE),
reverse transcriptase polymerase chain reaction (RT-PCR) genotyping, real-time PCR and sequencing. African green monkey kidney
cells (MA104 cell line) are commonly used for rotavirus isolation
[1].
The EM is a reliable method used to detect rotaviruses, mainly
due to their distinctive morphology, although most laboratories do
not have this technology. The viral antigens can be detected using a
variety of commercially available EIA and latex agglutination assays
(rapid diagnostic test). However, the ELISA is the recommended test
system due to its sensitivity and ease of use in virtually all hospital laboratories [7]. PAGE has been used to determine the genomic
diversity of rotaviruses by studying distinct migration patterns of
the 11 segments of dsRNA. The RT-PCR genotyping assays for the
VP4 and VP7 genes are widely utilised for typing the circulating
rotavirus strains [1].
4. Rotavirus virology
Rotaviruses are classified within a Reoviridae family, the segmented double stranded (ds) RNA viruses. The genome codes for
six structural viral proteins (VP1-VP4, VP6 and VP7) and six nonstructural proteins (NSP1-NSP6). The viral particle is surrounded
by triple layered capsid; an inner core layer composed of shell viral
protein VP2 and enzymes VP1 and VP3, an intermediate layer of
VP6 and outer layers made up of VP7 (major outer capsid) and
VP4 (outer spikes) [1]. The inner capsid VP6 antigenic specificity
classifies rotaviruses into seven serogroups (A–G). Rotaviruses are
further classified into different P and G types based on the two outer
capsid proteins: VP4 (protease-sensitive) and VP7 (glycoprotein),
respectively. These proteins independently elicit protective neutralising antibodies [1]. However, the rotavirus particle consists of
more than just the inner and outer capsid proteins and, therefore, a
new rotavirus classification and nomenclature system identifying
C16
L.M. Seheri et al. / Vaccine 30S (2012) C14–C20
genotypes for each of the 11 gene segments was proposed [29]. Currently, among group A rotaviruses, the following genotypes have
been identified VP7: 27 G, VP4: 35 P, VP6: I16, VP1: R9, VP2: C9, VP3:
M8, NSP1: A16, NSP2: N9, NSP3: T12, NSP4: E14 and NSP5/NSP6:
H11 genotypes [30].
5. Rotavirus genetic diversity
The molecular epidemiology of rotavirus strains is complex; the
strains likely to circulate each year cannot be entirely predicted.
Hence, the circulating rotavirus strains vary from year to year, season to season and region to region [31]. The observed phenomenon
could be explained by the role of the selective pressure of serotype
specific antibodies [32] and the segmented nature of the rotavirus
genome that could easily facilitate reassortment between different
strains during mixed infections. Mixed genotype infections might
result in inter- and intra-genotypic diversity or inter-genogroup
strains. Novel rotavirus strains or unusual strains previously isolated from animals have also been detected in humans [33,34].
Surveillance of rotavirus strains have shown five group A
rotavirus strains which are frequently detected globally; i.e. G1P[8],
G2P[4], G3P[8], G4P[8] and G9P[8] [35]. These strains are often
referred to as common or predominant strains and are responsible for 88.5% of infections in North America, Europe and Australia,
while the same strains represent 68% and 50% of infections in
South America and Africa, respectively [35]. A large majority of
rotavirus infections in developing countries display worldwide
unusual strains, mixed genotype infections and untypeable strains
[36].
Since 1998, rotavirus surveillance studies were conducted
in 25 African countries to monitor circulating rotavirus strains
[7,9,37–42]. Between 1983 and 1989, the G1-G4 associated with
P[8] and P[4] were the most common strains detected in South
Africa, Gambia, Nigeria, Kenya and Central Africa. Untypeable
rotavirus strains represented 26% and mixed infections 1.8% [25].
The results from the three African Rotavirus Surveillance Network
Workshops (AFR-RSN) from 1996 to 1999, representing countries
in the North, West, East and Southern Africa supported the idea that
G1 was the most predominant strain, followed by G2, G3, G9, G4
and G8 rotavirus strains [43]. Further studies from the 2006–2008
African Rotavirus Surveillance Network Workshops also identified G1P[8] and G2P[4] genotypes as the most common strains
in 11 countries [7]. In Africa, a large proportion of the circulating rotavirus strains carry the unusual G8 and/or P[6] epitopes and
are considered epidemiologically important strains in the region
Fig. 1. Rotavirus genotypes circulating in South Africa between 2003 and 2010.
[7,40,43–45]. Compared to industrialised countries such as Europe
and North America, there is a relatively high incidence of P[6]
strains identified in Africa [7,40].
The G12 rotavirus strain was first detected in humans in 1987
in Philippines, a decade later, the strain was shown to be the most
important emerging genotype worldwide [46–49]. In Africa, G12
rotavirus strains were first detected in South Africa at Dr George
Mukhari Hospital in 2004 and since then, have been detected at an
increasing rate in the Southern Africa (Zambia and Zimbabwe), East
Africa (Kenya, Ethiopia and Uganda), Central Africa (Cameroon and
DRC) and West Africa (Togo and Burkina Faso) [7,49].
During the past 30 years in South Africa, the G1-G4 associated
with P[8] and P[4] have been the most common strains detected, as
evidenced by recent data from rotavirus burden of diseases study
conducted at Dr George Mukhari Hospital (Fig. 1). These strains
were responsible for 49% of all rotavirus infections, while 51% was
associated with mixed genotype infections, worldwide uncommon
strains and untypeable strains. Interestingly, there was no correlation observed between the circulating genotypes, clinical outcomes
of rotavirus infection and hospitalisation rates. The relative prevalence of the worldwide common rotavirus strain G1P[8] showed
year to year variation, and the strains were further replaced by outbreaks of the G2P[4], G3P[8], G9P[8] and G4P[8] rotaviruses. While
the distribution of G1P[8] rotavirus strains persisted overtime,
the G2P[4] rotavirus strains showed a cyclic peak every 3–4 years
(Fig. 2).
Fig. 2. Rotavirus genotypes circulating in South Africa between 1983 and 1996.
L.M. Seheri et al. / Vaccine 30S (2012) C14–C20
6. Prevention and control
6.1. Treatment
Currently, there is no specific treatment for rotavirus gastroenteritis except supportive care which involves management
of symptoms. The patient is offered oral rehydration solutions
(ORS) or intravenous fluid replacement to restore lost body fluids
and electrolytes (sodium, potassium, bicarbonate). Oral fluids and
supplementary nutrition can be provided to prevent dehydration.
Dehydration can be life threatening if these electrolytes are not
replenished swiftly. In addition, treatment of rotavirus diarrhoea
with anti-rotavirus immunoglobulin of bovine colostrum origin is
effective in controlling symptoms of rotavirus infection mainly in
chronic or immunosuppressed individuals [50], although this is not
routine practice in many developing countries affected by rotavirus
morbidity and mortality.
6.2. Hygiene and sanitation
There is no significant difference between the rotavirus infections rate in industrialised as opposed to poor countries. Practising
good hygiene such as hand washing, access to clean water and
sanitation has shown to be partly effective to control rotavirus diarrhoea. Currently, rotavirus vaccines are considered as the effective
intervention to either reduce or control the incidence of rotavirus
disease [1].
6.3. Immunisation
Rotavirus vaccine development has consisted of different strategies, and of these, three vaccines have been licensed for global
use to date. The first rotavirus vaccine to be licensed for routine
use in 1998, rhesus-human rotavirus reassortment-tetravalent vaccine (Rotashield), was later withdrawn after about 9 months use in
the USA because of its association with increased risk of intestinal intussusception [51]. The vaccine demonstrated high efficacy
in developed countries and lower efficacy in developing countries
[52,53]. Since the withdrawal of Rotashield, two additional vaccines; Rotarix® and RotaTeqTM have been licensed in more than
100 countries and these two vaccines have successfully been incorporated in national immunisation programmes of a number of
countries [54]. Furthermore, the Lanzhou lamb rotavirus (LLR) vaccine, G10P[12] strain, has been licenced for use in China since 2001
[55].
Rotarix® , developed by GlaxoSmithKline Biologicals (Rixensart, Belgium), is a live human attenuated monovalent G1P1A[8]
rotavirus vaccine and its efficacy is based on heterotypic immunity. RotaTeqTM , developed by Merck (Blue Bell, PA, USA), is a
live attenuated bovine-human vaccine containing five reassortant
strains with G1P[7], G2P[7], G3P[7], G4P[7] and G6P[8] specificity
and its efficacy is based on homotypic immunity. Both these vaccines have shown a comparable protective efficacy (85–98%) in
preventing severe rotavirus diarrhoea among children in developed countries, Latin America and Finland. However, lower efficacy
rates were observed in developing countries of Africa (61.2–64.2%)
and Asia (48.3%). Moreover, the vaccines were not associated with
an increased risk of intussusception [56–61]. In 2009, the WHO
SAGE recommended the inclusion of these rotavirus vaccines in all
childhood immunisation programmes of the world [62].
7. Rotavirus vaccine within South African expanded
programme on immunisation
Some of the pivotal studies which provided the policy makers
including National Advisory Group on Immunization (NAGI) and
C17
National Department of Health with required information to make
informed decision and facilitated the introduction of rotavirus vaccine into the South African Expanded Programme on Immunisation
(EPI-SA) included the burden of disease (BOD) and strain surveillance, economic burden of rotavirus infection and clinical trials to
assess the safety and efficacy of vaccine candidates.
7.1. Rotavirus burden of disease study
Although South African researchers have documented the
epidemiology of rotavirus since the early 1980s [6,40,63], the
BOD study provided comprehensive estimates and incidence of
rotavirus disease requiring hospitalisation, contributed to baseline
information against which to measure the impact of rotavirus vaccine after introduction, identified recent common rotavirus strains
circulating in children less than 5 years (Fig. 1), and generated
awareness on rotavirus for policy makers and health care workers [6,9]. The study began in 2003 and involved collection of stool
samples from inpatient and outpatient children less than 5 years
presenting with diarrhoea (Fig. 3). The study adopted a consistent systematic sampling approach and patient recruitment. Each
year, the median and range of rotavirus detection rates were calculated among hospitalised and outpatient children. Overall, the
results showed that rotavirus infections accounted for a quarter
of all diarrhoeal hospitalisation each year with peak prevalence
ranging from 56 to 78% during the cooler dry months of the year.
The seasonal trends of rotavirus infection between 2003 and 2011
demonstrated the rotavirus epidemic season starting from May
through July every year (Fig. 3). It was estimated that 23–25% of
children less than 5 years of age hospitalised with diarrhoea were
infected with rotavirus [6,9].
Between 2003 and 2005, the hospital-based burden of rotavirus
gastroenteritis study estimated that one in every 43–62 children
aged between birth and 2 years will likely be hospitalised for
rotavirus diarrhoea. It was also estimated that 5.5% of all hospitalised children less than 5 years of age were infected by rotavirus
[9]. Comparable results were obtained between 2007 and 2010
(Fig. 3). Similarly, data observed in the US estimated that rotavirus
diarrhoea was associated with 4–5% of all diarrhoeal hospitalisation
and one in 67–85 children less than 5 years would be hospitalised
[8,64].
7.2. Economic burden of rotavirus infection
The BOD study at Dr George Mukhari Hospital was complemented by another study determining the direct and indirect
medical cost of rotavirus diarrhoea at a tertiary hospital [65]. The
direct medical costs of inpatients included hospital stay facility
cost, hospital professional cost, laboratory diagnosis, personnel,
overheads and medication, whereas the direct medical costs for
outpatients were laboratory test and medications. The indirect
medical cost included travel, other out of pocket cost incurred by
the household as a result of diarrhoea and time lost from productive
work by a guardian/parent. The estimated medical cost incurred for
rotavirus gastroenteritis at the tertiary hospital was substantial.
The mean direct and indirect costs of diarrhoeal cases included the
rotavirus diarrhoea and rotavirus negative patients’ hospitalisation
were estimated to be $784.61 and $535.53 respectively ($1 = R7.60).
The large proportion of the cost was due to the tertiary nature of
hospital services [65].
7.3. Rotavirus vaccines safety and efficacy trials in South Africa
The vaccine clinical trials that were conducted in Madibeng
and Ga-Rankuwa district and Soweto, South Africa from 2002 to
2009 comprised phase II imunogenicity trials (2 versus 3 doses)
C18
L.M. Seheri et al. / Vaccine 30S (2012) C14–C20
Fig. 3. Monthly distribution of number of diarrhoeal cases (blue shaded), number of rotavirus positive samples from January 2003 to July 2011 at the Dr George Mukhari
hospital sentinel site, University of Limpopo Medunsa Campus, north-west of Pretoria. The dark black dashed line indicates the national introduction of rotavirus vaccine
into EPI-SA (August 2009). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of the article.)
where Rotarix® was co-administered with routine EPI vaccines
and either oral poliovirus vaccine (OPV) or injectable poliovirus
vaccine (IPV) at 6 and 10 weeks or at 6, 10 and 14 weeks of age
(2001–2004), a phase III efficacy study (2005–2009); and a safety
and immunogenicity study in HIV infected infants (2005–2008).
The results demonstrated that Rotarix® is well tolerated, safe and
immunogenic when co-administered with OPV and other routine
EPI vaccines [66,67]. The results further showed no interference
of Rotarix® with OPV [66,67]. The Rotarix® efficacy studies have
shown an overall protective efficacy of 61.2% in preventing severe
rotavirus diarrhoea in South Africa with an efficacy of 76.9% [59].
The efficacy results further indicated that the vaccine could prevent five cases of severe rotavirus disease per 100 infant-years [59].
Finally, Rotarix® has shown to be well-tolerated and immunogenic,
with no serious reactogenicity profile in HIV-infected infants; all
solicited and unsolicited symptoms were similar in the vaccine and
placebo groups [68].
7.4. Scheduling of rotavirus vaccine within EPI-SA
Based on this data and the WHO global recommendation, South
Africa introduced Rotarix® into routine childhood national immunisation programme in August 2009 (Fig. 3). The recommended
vaccination is a two-dose schedule, administered orally at 6 and
14 weeks of age along with other EPI antigens. To date, more than 3
million doses of Rotarix® had been distributed nationally, although
the uptake varies from province to province. Rotavirus vaccination
coverage has increased rapidly since its introduction in 2009. By
2010, 67% of less than one year-olds had received a complete 2-dose
series of Rotarix® , with 80% of the same cohort having received at
least one dose. The coverage rate appears to be on track to exceed
this figure in 2011.
7.5. Preliminary analysis of the vaccine impact on the burden of
rotavirus infection
Large post-marketing surveillance studies at 5 sentinel sites
in three provinces are underway to measure the rotavirus vaccine impact as part of the national surveillance efforts coordinated
by the National Institute for Communicable Diseases, a division of the National Health Laboratory Services in Johannesburg.
These include Mpumalanga (Mapulaneng and Matikwana Hospitals), Gauteng (Dr George Mukhari and Chris Hani Baragwanath
Hospitals) and KwaZulu Natal (Edendale Hospital). Of the 5 sentinel sites, Dr George Mukhari Hospital, located at University of
Limpopo Medunsa Campus, has extensive epidemiological data
going back to 1982, but systematic sampling for rotavirus BOD
surveillance was only initiated in 2003 [9]. Thus, this sentinel
site provides an opportunity to measure the preliminary impact
of rotavirus vaccination since its introduction into EPI-SA (Fig. 3).
Four trends are evident in the first two rotavirus seasons after the
introduction of the vaccine compared to the rotavirus epidemiological trends observed since 2003. First, comparing pre-vaccination
(2003–2009) and post vaccination (2010–2011) period, the onset of
rotavirus season appears to be delayed by 8 weeks. During the prevaccination period, the onset of rotavirus season observed was in
April, week 13 and the season lasted for nearly 17 weeks (weeks 13
and 30), whereas in post-vaccination period the onset of rotavirus
season was delayed and shifted to week 21 in May, and the average
duration of the rotavirus season was between week 21 and 37 (May
and September). Second, the rotavirus peaks in the winter season
were not as pronounced as the pre-vaccination era. The highest seasonal peak of rotavirus infection during the pre-vaccination seasons
was 104/133 cases in 2006, while the highest peak in number of
cases was 26/41 in 2010, just over a year after vaccine introduction.
Third, the impact of rotavirus vaccination was assessed by comparing the data from 2008 to 2009 (pre-vaccination) and 2010 to 2011
(post vaccination) period, introduction of rotavirus vaccination was
associated with substantial reduction in severe gastroenteritis (i.e.
51% reduction) requiring hospitalisation among children less than
5 years of age, translating into reduction in both direct and indirect
medical costs. Last, there was substantial decline in gastroenteritis
associated with rotavirus infection (i.e. 67%) among children aged
5 years. The post-marketing surveillance studies are still ongoing
and the full report from all five sentinel sites will be published in the
near future. The post marketing surveillance studies for rotavirus
vaccination in the US and Europe also showed a delay in the seasonal peak of rotavirus and significant reduction in the incidence
L.M. Seheri et al. / Vaccine 30S (2012) C14–C20
of rotavirus gastroenteritis in children younger than 2 years of age
[69,70].
8. Conclusion
The introduction of rotavirus vaccine in South Africa is one of
the greatest public health achievements. Childhood immunisation
programmes against different infectious diseases have generally
resulted in a decline in disease morbidity and mortality. It is hoped
that there will be a significant decrease in rotavirus burden of
disease in the coming years in South Africa. Introduction of the
rotavirus vaccine into EPI-SA will contribute to a reduction in all
diarrhoeal deaths, mortality related to rotavirus diarrhoea, diarrhoeal related hospitalisations and high direct and indirect medical
costs of rotavirus disease. This experience will most probably be
shared by other African countries as rotavirus vaccine introduction
in national immunisation programmes deepens in the region.
Acknowledgements
We thank Mrs I Peenze, Ms AL Nermarude, Ms FRR Mapuroma,
Mrs GP Maphalala, Mr K Jere, Ms A Geyer and Mr P Bos of the MRC
Diarrhoeal Pathogens Research Unit and staff from the Department
of Paediatrics and Child Health, University of Limpopo Medunsa
Campus for technical assistance.
We would like to acknowledge the South African Rotavirus Sentinel Surveillance Programme and GlaxoSmithKline for funding the
programme.
We also wish to acknowledge Dr J Tate for technical input in the
preparation of the manuscript.
This review included South African studies which received
financial support from the Medical Research Council of South Africa,
Poliomyelitis Research Fund, World Health Organisation and the
Norwegian Programme for Development, Research and Higher
Education.
Conflict of interest statement: None.
References
[1] Estes MK, Kapikian AZ. Rotaviruses. In: Fields BN, Knipe DM, Howley PM, editors. Fields virology. 5th ed. Philadelphia, PA: Lippincott Williams 7 Wilkins;
2007. p. 1917–74.
[2] Parashar UD, Gibson CJ, Bresee JS, Glass RI. Rotavirus and severe childhood
diarrhoea. Emerging Infectious Diseases 2006;12:304–6.
[3] Tate JE, Burton AH, Boschi-Pinto C, Steele AD, Duque J, Parashar UD, et al. 2008
estimate of worldwide rotavirus-associated mortality in children younger than
5 years before the introduction of universal rotavirus vaccination programmes:
a systematic review and meta-analysis. Lancet Infectious Diseases 2011;S14733099(11):70253–5.
[4] Parashar UD, Hummelman EG, Bresee JS, Miller MA, Glass RI. Global illness and
deaths caused by rotavirus disease in children. Emerging Infectious Diseases
2003;9:565–71.
[5] Bradshaw D, Groenewald P, Laubscher R, Nannan N, Nojilana B, Norman R, et al.
Initial burden of disease estimates for South Africa, 2000. South African Medical
Research Council; 2003. p. 1–84 http://www.mrc.ac.za/bod/bod.htm.
[6] Steele AD, Peenze I, de Beer M, Pager CT, Yeats J, Potgieter N, et al. Anticipating
rotavirus vaccines: epidemiology and surveillance of rotavirus in South Africa.
Vaccine 2003;21:354–60.
[7] Mwenda JM, Ntoto NKM, Abebe A, Laryea CE, Amina I, Diop OM, et al. Burden and
epidemiology of rotavirus diarrhoea in selected African countries – preliminary
results from the African Rotavirus Surveillance Network (AFR RSN). Journal of
Infectious Diseases 2010;202:S5–11.
[8] Centers for Disease Control and Prevention (CDC). Rotavirus surveillance –
worldwide 2009. Morbidity and Mortality Weekly Report 2011;60:514–6.
[9] Seheri LM, Dewar JB, van der Merwe L, Geyer A, Tumbo J, Zweygarth M, et al.
Prospective hospital-based surveillance to estimate rotavirus disease burden
in the Gauteng and North West Province of South Africa during 2003–2005.
Journal of Infectious Diseases 2010:S131–8.
[10] Communicable Diseases Surveillance Bulletin, NICD, NHLS 2010;8(1):11–4.
[11] District health information system database. Nation Department of
Health; 2011 [accessed October 2011] http://www.indicators.hst.org.za/
healthstats/316/data.
C19
[12] Ward RL, Bernstein DI, Knowlton DR, Sherwood JR, Young EC, Cusack TM, et al.
Prevention of surface-to-human transmission of rotaviruses by treatment with
disinfectant spray. Journal of Clinical Microbiology 1991;29:1991–6.
[13] Denney PH. Transmission of rotavirus and other enteric pathogens in the home.
Pediatric Infectious Disease Journal 2000;19:103–5.
[14] Steele AD, Alexander JJ. Molecular epidemiology of rotavirus in black infants in
South Africa. Journal of Clinical Microbiology 1987;25:2384–7.
[15] Bishop RF. Natural history of human rotavirus infection. In: Kapikian AZ, editor.
Viral infections of gastrointestinal tract. 2nd ed. New York/Basel/Hong Kong:
Marcel Dekker, Inc; 1994. p. 131–67.
[16] Christensen ML. Human viral gastroenteritis. Clinical Microbiology
1989;2:51–89.
[17] Binka FN, Anto FK, Oduro AR, Awini EA, Nazzar AK, Armah GE, et al. Incidence
and risk factors of paediatric rotavirus diarrhoea in northern Ghana. Tropical
Medicine and International Health 2003;8:840–6.
[18] Nokes JD, Abawao J, Pamba A, Peenze I, Dewar J, Maghenda JK, et al. Incidence
and clinical characteristics of group A rotavirus infections among children
admitted to hospital in Kilifi, Kenya. PLoS Medicine 2008;5:1154–62.
[19] Koopmans M, Brown D. Seasonality and diversity of group A rotaviruses in
Europe. Acta Paediatrica Supplement 1999;426:14–9.
[20] Kim JS, Kang JO, Cho SC, Jang YT, Min SA, Park TH, et al. Epidemiology profile of rotavirus infection in the Republic of Korea: results from prospective
surveillance in the Jeongeub district, 1 July 202 through 30 June 2004. Journal
of Infectious Diseases 2005;192:S49–56.
[21] Nakagomi T, Nakagomi O, Takahashi Y, Suzuki T, Kilgore PE. Incidence and
burden of rotavirus gastroenteritis in Japan, as estimated from a prospective
sentinel hospital study. Journal of Infectious Diseases 2005;192:S106–10.
[22] Gleizes O, Desselberger U, Tatochenko V, Rodrigo C, Salman N, Mezner Z, et al.
Nosocomial rotavirus infection in European countries; A review of the epidemiology, severity and economic burden of hospital acquired rotavirus disease.
Pediatric Infectious Disease Journal 2006;25:S12–21.
[23] Cook SM, Glass RI, Le Baron CW, Ho MS. Global seasonality of rotavirus infections. Bulletin of the World Health Organization 1990;68:171–7.
[24] Steele AD, Alexander JJ, Hay IT. Rotavirus associated gastroenteritis in black
infants in South Africa. Journal of Clinical Microbiology 1986;23:992–4.
[25] Cunliffe NA, Kilgore PE, Bresee JS, Steele AD, Luo N, Hart CA, et al. Epidemiology of rotavirus diarrhoea in Africa: a review to assess the need for rotavirus
immunization. Bulletin of the World Health Organization 1998;76:525–37.
[26] Bishop RF. Natural History of Human Rotavirus Infection. Archives of Virology
Supplement 1996;96:119–27.
[27] Giaquinto C, Van Damme P, REVEAL Study Group. Age distribution of paediatric rotavirus gastroenteritis case in Europe: the REVEAL study. Scandinavian
Journal of Infectious Diseases 2010;42:142–7.
[28] Glass RI, Kilgore PE, Holman RC, Jin S, Smith JC, Woods PA, et al. The epidemiology or rotavirus diarrhoea in the United States; surveillance and estimates of
disease burden. Journal of Infectious Diseases 1996;174:S5–11.
[29] Matthijnssens J, Ciarlet M, Rahman M, Attoui H, Banyai K, Estes M, et al. Recommendation for the classification of group A rotaviruses using all 11 genomic
RNA segments. Archives of Virology 2008;153:1621–9.
[30] Matthijnssens J, Ciarlet M, McDonald SM, Attoui H, Banyai K, Brister JR, et al.
Uniformity of rotavirus strain nomenclature proposed by the Rotavirus Classification Working Group (RCWG). Archives of Virology 2011;156:1397–413.
[31] Steele AD, van Niekerk MC, Mphahlele MJ. Geographic distribution of human
rotavirus VP4 genotypes and VP7 serotypes in five South African regions. Journal of Clinical Microbiology 1995;33:1516–9.
[32] Franco MA, Angel J, Greenberg HB. Review: immunity and correlates of protection of rotavirus vaccines. Vaccine 2006;24:2718–31.
[33] Gouvea V, de Castro L, Timenetsky C, Greeberg H, Santos N. Rotavirus serotypes
G5 associated with diarrhoea in Brazilian children. Journal of Clinical Microbiology 1994;32:1408–9.
[34] Esona MD, Armah GE, Geyer A, Steele AD. Detection of an unusual human
rotavirus strain with G5P[8] specificity in a Cameroonian child with diarrhoea.
Journal of Clinical Microbiology 2004;42:441–4.
[35] Santos N, Hoshino Y. Global distribution of rotavirus serotypes/genotypes
ant its implication for the development and implementation of an effective
rotavirus vaccine. Reviews in Medical Virology 2005;15:29–56.
[36] Sanchez- Padilla E, Grais RF, Guerin PJ, Steele AD, Burny ME, Luguero
FJ. Burden of disease and circulating serotypes of rotavirus infection in
sub-Saharan Africa: systematic review and meta-analysis. Lancet Infectious
Diseases 2009;9:567–76.
[37] Trabelsi A, Peenze I, Pager C, Jeddi M, Steele AD. Distribution of rotavirus VP7
serotypes and VP4 genotypes circulating in Sousse, Tunisia from 1995–1999:
emergence of natural human reassortants. Journal of Clinical Microbiology
2000;38:3415–9.
[38] Pennap G, Peenze I, de Beer M, Pager CT, Kwaga JKP, Ogalla WN, et al. VP6
subgroup and VP7 serotypes of human rotavirus in Zaria, Northern Nigeria.
Journal of Tropical Pediatrics 2000;46:344–7.
[39] Armah G, Pager CT, Asmah RH, Anto FR, Oduro AR, Binka F, et al. Prevalence
of unusual human rotavirus strains in Ghananian children. Journal of Medical
Virology 2001;63:67–71.
[40] Steele AD, Ivanoff B. Rotavirus strains circulating in Africa during 1996–1999:
emergence of G9 strains and P[6] strains. Vaccine 2003;21:361–7.
[41] Fischer TK, Page NA, Griffin DD, Eugen-Olsen J, Pedersen AG, Valetiner-Branth
P, et al. Characterization of incompletely typed rotavirus strains from GuineaBissau: identification of G8 and G9 types and a high frequency of mixed
infections. Virology 2003;311:125–33.
C20
L.M. Seheri et al. / Vaccine 30S (2012) C14–C20
[42] Bonkoungou IJO, Damanka S, Sanou I, Triendrebeogo F, Coulibaly SO, Bon F,
et al. Genotype diversity of group A rotavirus strains in children with acute
diarrhoea in urban Burkina Faso, 2008–2010. Journal of Medical Virology
2011;83:1485–90.
[43] Steele AD, Parker SP, Peenze I, Pager CT, Taylor MB, Cubitt WD. Comparative
studies of rotavirus serotype G8 strains recovered in South Africa and the United
Kingdom. Journal of General Virology 1999;80:3029–34.
[44] Adah MI, Ronwedder A, Olaleyle OD, Werchau H. Further characterization
of field strains of rotavirus from Nigeria VP4 genotype P6 frequently identified among symptomatically infected children. Journal of Tropical Pediatrics
1997;43:267–74.
[45] Cunliffe NA, Gondwe JS, Broadhead RL, Molyneux ME, Woods PA, Bresee JS, et al.
Rotavirus G and P types in children with acute diarrhoea in Blantyre, Malawi,
from 1997 to 1998: predominance of novel P[6] G8 strains. Journal of Medical
Virology 1999;57:308–12.
[46] Taniguchi K, Urasawa T, Kobayashi M, Gorziglia M, Urasawa S. Nucleotide
sequence of VP4 and VP7 genes of human rotaviruses with subgroup I specificity and long RNA pattern: implication for the new G serotype specificity.
Journal of Virology 1990;64:5640–4.
[47] Shinozaki K, Okda M, Nagashima S, Kaiho I, Taniguchi K. Characterization of
human rotavirus strains with G12 and P[9] detected in Japan. Journal of Medical
Virology 2004;73:612–6.
[48] Rahman M, Matthijnssens J, Yang X, Delbeke T, Arijs I, Taniguchi K, et al. Evolutionary history and global spread of the emerging G12 human rotaviruses.
Journal of Virology 2007;81:2382–90.
[49] Page NA, de Beer MC, Seheri LM, Dewar JB, Steele AD. The detection and molecular characterization of human G12 genotypes in South Africa. Journal of Medical
Virology 2009;81:106–13.
[50] Sarker SA, Casswall TH, Mahalanabis D, Alam NH, Albert MJ, Brussow H, et al.
Successful treatment of rotavirus diarrhea in children with immunoglobulin
from immunized bovine colostrums. Journal of Pediatric Infectious Disease
1998;12:1149–54.
[51] Centers for Disease Control and Prevention. Intussusception among recipients of rotavirus vaccine in United States 1998–1999. Morbidity and Mortality
Weekly Report 1999;48:577–81.
[52] Joensuu J, Koskenniemi E, Xiao-Li P, Vesikari T. Randomized placebo-controlled
trial of rhesus-human reassortant rotavirus vaccine for prevention of severe
rotavirus gastroenteritis. Lancet 1997;350:1205–9.
[53] Perez-Schael I, Guntinas MJ, Perez M, Pagone V, Rojas AM, Gonzalez R, et al.
Efficacy of the rhesus rotavirus-based quadrivalent vaccine in infants and
young children in Venezuela. New England Journal of Medicine 1997;337:
1181–7.
[54] Kirkwood CD, Boniface K, Barnes GL, Bishop FR. Distribution of rotavirus genotypes after introduction of rotavirus vaccines, Rotarix and Rotateq, into the
national immunization program of Australia. Pediatric Infectious Disease Journal 2011;30:S48–53.
[55] WHO. Report of the meeting on future directions for rotavirus vaccine research
in developing countries. Geneva: World Health Organization, WHO/V&B/00;
2000. p. 1–56 www.who.int/vaccines-document/DocsPDF00/www531.pdf.
[56] Ruiz-Palacios GM, Perez-Schael I, Velazquez FR, Abeate H, Breuer T, Clemens
SC, et al. Safety and efficacy of an attenuated vaccine against severe rotavirus
gastroenteritis. New England Journal of Medicine 2006;354:11–22.
[57] Vesikari T, Matson DO, Dennehy SE, Van Damme P, Santosham M, Rodrieguez
Z, et al. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant
rotavirus vaccines. New England Journal of Medicine 2006;354:23–33.
[58] Vesikari T, Karvonen A, Prymula R, Schuster V, Tejedor JC, Cohen R, et al. Efficacy
of human rotavirus against rotavirus gastroenteritis during the first 2 years of
life in European infants: randomised, double-blind controlled study. Lancet
2007;24:1757–63.
[59] Madhi SA, Cunliffe NA, Steele AD, Witte D, Kirsten M, Louw C, et al. Effect of
human rotavirus vaccine on severe diarrhoea in Africa infants. New England
Journal of Medicine 2010;362:289–98.
[60] Armah GE, Sow SO, Breiman RF, Dallas MJ, Tapia MD, Feikin DR, et al. Efficacy of
pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants
in developing countries in sub-Saharan Africa: a randomised, double-blinded,
placebo-controlled trial. Lancet 2011;9741:606–14.
[61] Zaman K, Dang DA, Victor JC, Shin S, Yunus M, Dallas MJ, et al. Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in
developing countries in Asia: a randomised, double-blind, placebo-controlled
trial. Lancet 2010;376:615–23.
[62] World Health Organization. Meeting of the strategic advisory group of experts,
April 2009 – conclusion and recommendations. Weekly Epidemiological Record
2009;84:220–36.
[63] Steele AD, Alexander JJ, Hay IT. Rotavirus-associated gastroenteritis at GaRankuwa. A pilot study. South African Medical Journal 1986;69:21–2.
[64] Malek MA, Curns AT, Holman RC, Fischer TK, Bresee JS, Glass RI, et al. Diarrheaand rotavirus-associated hospitalization among children less than 5 years of
age: United States, 1997 and 2000. Pediatrics 2006;117:1887–92.
[65] MacIntyre UE, De Villiers FPR. The economic burden of diarrhoeal diseases in
a tertiary level hospital, Gauteng, South Africa. Journal of Infectious Diseases
2010;202:S116–25.
[66] Steele AD, De Vos B, Tumbo J, Reynders J, Scholtz F, Bos P, et al. Coadministration study in South African infants of a live-attenuated oral human
rotavirus vaccine (RIX4414) and poliovirus vaccines. Vaccines 2010;28:6542–8.
[67] Steele AD, De Vos B, Tumbo J, Reynders J, Scholtz F, Bos P, et al. Comparison
of 2 different regimens for reactogenicity, safety and immunogenicity of live
attenuated oral vaccine RIX4414 co-administered with oral polio vaccine in
South African Infants. Journal of Infectious Diseases 2010;202:S93–9.
[68] Steele AD, Madhi SA, Louw CE, Bos P, Tumbo JM, Werner CM, et al. Safety, reactogenicity, and immunogenicity of human rotavirus vaccine RIX4414 in human
immunodeficiency virus-positive infants in South Africa. Pediatric Infectious
Disease Journal 2011;30:125–30.
[69] Tate JE, Panozzo CA, Payne DC, Patel MM. Decline and change in seasonality
of US rotavirus activity after the introduction of rotavirus vaccine. Pediatrics
2009;124:465–71.
[70] Zeller M, Rahman M, Heylen E, De Coster S, De Vos S, Arijs I, et al. Rotavirus
incidence and genotype distribution before and after national rotavirus vaccine
introduction in Belgium. Vaccine 2010;28:7507–13.
Vaccine 30S (2012) C21–C27
Contents lists available at SciVerse ScienceDirect
Vaccine
journal homepage: www.elsevier.com/locate/vaccine
Review
Introduction of pneumococcal conjugate vaccine into the public immunization
program in South Africa: Translating research into policy
Shabir A. Madhi a,b,c , Cheryl Cohen a,d , Anne von Gottberg a,c,∗
a
National Institute for Communicable Diseases, a Division of the National Health Laboratory Service, Johannesburg, South Africa
Department of Science and Technology/National Research Foundation: Vaccine Preventable Diseases; University of the Witwatersrand, Johannesburg, South Africa
Medical Research Council: Respiratory and Meningeal Pathogens Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
d
School of Public Health, University of the Witwatersrand, Johannesburg, South Africa
b
c
a r t i c l e
i n f o
Article history:
Received 9 December 2011
Received in revised form 23 April 2012
Accepted 22 May 2012
Keywords:
Streptococcus pneumoniae
Pneumococcus
South Africa
Vaccination
HIV
Expanded Programme on Immunization
(EPI)
a b s t r a c t
In April 2009, South Africa was the first African country to introduce pneumococcal
polysaccharide–protein conjugate vaccine (PCV) into its public immunization program. This review
summarizes studies on pneumococcal epidemiology and PCV undertaken in South Africa, which
contributed to the process of advocating for the inclusion of PCV into the public immunization program.
Surveillance prior to the introduction of 7-valent PCV (PCV-7) indicated that 70% (418/593) of invasive
pneumococcal disease (IPD) in infants, the age-group at highest risk of IPD, was attributable to PCV-7
serotypes. Furthermore, 65% of all IPD in children under-5 years was associated with underlying HIV
infection.
Initial immunogenicity studies reported that PCV vaccination of antiretroviral-naïve HIV-infected
children was associated with lower geometric mean antibody concentrations and proportion with a
serotype-specific antibody concentration above the putative threshold (≥0.35 ␮g/ml) of protection for
IPD for some of the serotypes. The functionality of antibody induced by PCV in HIV-infected infants was
inferior to that of HIV-uninfected infants.
Vaccine efficacy of 9-valent PCV in a trial from South Africa reported an 83% reduction of vaccineserotype IPD in HIV-uninfected children in the first two years of life, with protection persisting thereafter.
However, vaccine efficacy against vaccine-serotype IPD declined from 65% at 2.3 years of age to 39% by
six years of age in antiretroviral-naïve HIV-infected children.
Based on the observation that a two-dose primary series of PCV during infancy resulted in similar immunogenicity compared to a three-dose schedule, as well as similar impact on nasopharyngeal
colonization and effectiveness against IPD in HIV-uninfected children, the South African immunization
program adopted a two-dose primary series with a booster dose at 9 months of age. This schedule was
largely premised on containing the cost of vaccine introduction, whilst including a booster dose of PCV
to assist in prolonging the duration of protection in HIV-infected children.
© 2012 Elsevier Ltd. All rights reserved.
1. Background
In April 2009, South Africa was the first African country to
introduce pneumococcal polysaccharide–protein conjugate vaccine (PCV) into its public immunization program. South Africa, a
upper-middle income country, does not qualify for donor support
from the Global Alliance for Vaccines and Immunisation (GAVI).
Nevertheless, the South African government decided to introduce
PCV into the public immunization program allowing access to this
∗ Corresponding author at: Medical Research Council: Respiratory and Meningeal
Pathogens Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. Tel.: +27 115550316; fax: +27 115550437.
E-mail address: [email protected] (A. von Gottberg).
0264-410X/$ – see front matter © 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.vaccine.2012.05.055
potentially life-saving vaccine to an estimated annual birth cohort
of 1.2 million children. The introduction of PCV at US$ 25 per
dose into the immunization program led to an approximate
quadrupling in the direct cost of vaccines procured by the State for
use in the public immunization program. Prior to this, the routine
immunization programme had included a pentavalent vaccine
containing diphtheria and tetanus toxoids, acellular pertussis,
Hib-tetanus toxoid and inactivated polio (DTaP–Hib–IPV) and
hepatitis B vaccine at 6 (last dose of oral trivalent polio also given),
10 and 14 weeks of age, followed by measles vaccine at 9 and
15–18 months of age.
The introduction of PCV into the South African immunization
program followed a recommendation to the Ministry of Health,
by the ministerial-appointed National Advisory Group for Immunization (NAGI) in South Africa [1]. The recommendation by NAGI
C22
S.A. Madhi et al. / Vaccine 30S (2012) C21–C27
was for South Africa to introduce PCV at 6 weeks, 14 weeks and 9
months dosing schedule. The rational for introducing the vaccine
and adopting this schedule instead of a three-dose primary series
as then recommended by WHO [2], was based on a series of studies
on pneumococcal disease epidemiology and on the immunogenicity and efficacy of PCV in South Africa during the preceding 10–15
years.
The aim of this manuscript is to review studies on pneumococcal
epidemiology and PCV undertaken in South Africa over the past
two decades which contributed to the process of advocating for
the inclusion of PCV into the public immunization program.
2. Pneumococcal disease and HIV infection
Consistent among studies undertaken in South Africa over the
past two decades has been the impact of the HIV epidemic on the
increased incidence of invasive pneumococcal disease, including
pneumococcal bacteremia and meningitis [3–6]. Although less than
five percent of the South African birth cohort during the 2000s were
HIV-infected, the incidence (per 100,000) of IPD in HIV-infected
children less than two years (3036) was observed to be 42-fold
greater compared to HIV-uninfected children [4]. Consequently,
almost two-thirds of all childhood IPD episodes in South Africa
occurred in HIV-infected children in the 1990s up until mid-2000s
[3,4]. Additional effects of the HIV epidemic on the epidemiology
of IPD included that HIV-infected children were more likely to
develop IPD episodes which were associated with reduced antibiotic susceptibility, including a higher prevalence of multiple-drug
resistance (24% vs. 6% in HIV-uninfected children) [4]. Furthermore,
whereas the majority of IPD in otherwise healthy HIV-uninfected
children occurred within the first two years of life, the risk for
IPD persisted beyond this period in HIV-infected children [4,5]. In
addition, case-fatality ratios were higher in HIV-infected compared
with -uninfected children for pneumococcal meningitis (36–38% vs.
12–21%) [4,7], and similar trends were observed in some studies for
bacteremic pneumococcal pneumonia (18.2% vs. 10.5%) [4].
HIV-infected children not receiving antiretroviral treatment
(ART) were also identified to be at 9-fold increased risk of hospitalization for all-cause pneumonia [5]. In the absence of PCV
immunization, Streptococcus pneumoniae was the dominant bacterial isolate from blood in HIV-infected (50% of isolates) and
-uninfected children (41% of isolates) hospitalized for pneumonia
[5].
3. Surveillance of invasive pneumococcal disease in South
African children
In addition to hospital-based studies contributing to our
understanding of pneumococcal disease in South Africa, an
active, nation-wide, laboratory-based surveillance system called
GERMS-SA (Group for Enteric, Meningeal and Respiratory disease
Surveillance in South Africa) was able to provide additional data to
guide prevention strategies. Surveillance was initiated in 1999 [8]
and collects data on all cases of laboratory-confirmed IPD diagnosed
throughout the country. Although clearly underestimating disease
burden, in 2007 in South Africa, pneumococcal meningitis was the
dominant cause of reported acute bacterial meningitis in children
<1 year old (30.5/100,000 population) followed by meningitis due
to Neisseria meningitidis (6.7/100,000) and Haemophilus influenzae
(3.9/100,000) [9]. Case-fatality ratios amongst children aged <5
years were high for pneumococcal meningitis (28%, 44/156), the
majority caused by 7-valent PCV (PCV-7) serotypes (78%, 281/360).
Using this laboratory-based surveillance system, a reduction in
the incidence of IPD was observed from 2003–2004 to 2007–2008
in HIV-infected but not in -uninfected children [10]. This
reduction (51%; 95% CI 42–59) among HIV-infected children less
than 14 years of age was temporally related to an increase in access
to antiretroviral treatment (ART) by HIV-infected children [10].
Notably, this decline occurred independent of introduction of PCV
into the public immunization program since 2009. Nevertheless,
even in the presence of increased ART access for HIV-infected children, the incidence of IPD in these children remained 21-fold (95%
CI 16–28) greater compared with HIV-uninfected children. The relative contribution of HIV to the burden of pneumococcal disease
is likely to have diminished further in South Africa since 2009 due
to improved ART regimens used in the prevention of mother-tochild transmission programs. Vertical transmission rates of HIV
had decreased from 12% in 2008 when mainly intra-partum nevirapine was used, to less than 3% with the current ART regimen
recommended for pregnant HIV-infected women and including
post-partum nevirapine prophylaxis during the neonatal period
(personal correspondence Avy Violari).
Important in the prevention of pneumococcal disease by vaccination is the distribution of serotypes in different settings. Overall,
IPD episodes in HIV-infected children were more likely to be due
to serogroups commonly associated with pneumococcal colonization; i.e. serogroups 6, 9, 14, 19, 23 (74% vs. 57% in HIV-uninfected
children) [4]. Using the national laboratory-based surveillance data,
rates of reported disease were highest in children <1 year [11], confirming the age group most at risk of IPD and who should be targeted
for national prevention strategies. Serotype 14 (a vaccine serotype)
was the commonest serotype in this group. PCV-7 was estimated
to potentially prevent 70% (418/593) of IPD in infants if the 6B antigen was considered to cross protect against serotype 6A [11]. In
addition, 90% of penicillin non-susceptible disease in children <1
year was due to PCV-7 serotypes including serotype 6A. PCV-10
and PCV-13 increased coverage for all IPD in infants to ∼75% and
∼85%, respectively. The percentage of isolates that were multipledrug resistant increased from 16% in 2003 to 20% in 2008 (P < 0.001)
[12]. The majority of these strains were vaccine serotypes. The risk
factors associated with multidrug resistance included age <1 year
(adjusted odds ratio [AOR], 2.1; 95% CI 1.8–2.4) and HIV co-infection
(AOR, 1.4; 95% CI 1.2–1.7).
4. Immunogenicity of PCV in South African children
Since 1996, a series of studies were conducted in South Africa
involving an investigational 9-valent PCV (PCV-9) which included
all the serotypes included in PCV-7 (Prevenar® ), i.e. serotypes 4,
6B, 9V, 14, 18C, 19F and 23F; as well as serotypes 1 and 5. Immunogenicity was evaluated in infants immunized at 6, 10 and 14 weeks
of age; including following each dose of vaccine [13,14], and following a booster dose [15]. Although the initial immunogenicity
study did not screen for HIV infection status in the children, it was
imputed that less than 4.5% of the 500 enrolled children may have
been HIV infected based on 18% HIV sero-positivity prevalence in
pregnant women at the time and vertical transmission rates of HIV
being 26% in the absence of ART [16].
The immune responses one-month after the third of the primary
series of PCV-9 in the initial study, confirmed the immunogenicity of PCV-9 for all serotypes. In addition, the serotype-specific
geometric mean antibody concentrations (GMC) (range 2.73 ␮g/ml
for serotype 23F to 6.18 ␮g/ml for serotype 5) observed in African
children were greater than that observed in studies on PCV-7 in
European and North American children [13,14,17,18]. The initial
study on PCV immunogenicity in South Africa also reported that
>92% of the children had antibody concentrations of >0.5 ␮g/ml
measured by an ELISA assay not incorporating the 22F adsorption step [14]. This threshold would, however, have provided
a conservative estimate as to the proportion of children with
S.A. Madhi et al. / Vaccine 30S (2012) C21–C27
serotype-specific antibody concentration of ≥0.35 ␮g/ml (using the
22F adsorbed ELISA assay), which was subsequently proposed as a
putative measure of protection against IPD at a community level
[19].
The immune response following each of the three doses of PCV
indicated significant serotype-specific antibody production being
induced following the first dose of PCV and increase in GMCs after
each subsequent dose of PCV. The difference in fold increase in
GMCs following the third PCV dose was, however, less marked
than after the second PCV dose. In addition, greater-fold increase
was observed following the second PCV dose compared with after
the first PCV dose [14]. Similarly, there were fewer differences in
the proportion of children with serotype-specific antibody concentration of >0.5 ␮g/ml following the third compared to after the
second dose of PCV, with >75% of all children having antibody concentrations to each of the 9 serotypes after two doses of PCV-9
[14]. Whereas there was a one-month interval between the primary series of PCV in this study [14], a subsequent study from the
United Kingdom reported that immune response during a primary
series of two doses of PCV during infancy was enhanced if there
was greater interval between the two doses; i.e. eight weeks rather
than four weeks apart [20]. These data were used in part in deciding to include PCV as a two-dose primary series given at 6 and 14
weeks of age in the South African immunization program.
The initial South African immunogenicity study also evaluated
the persistence of anti–polysaccharide antibody in the second year
of life and immune responses to either a booster dose of PCV or 23valent pneumococcal polysaccharide vaccine (PPV) at 18 months
of age [15]. Higher antibody concentrations persisted in previous
PCV-9 recipients at 9 and 18 months of age compared with placebo
recipients.
The immune response to PCV-9 was also evaluated in ART-naïve
HIV-infected children. In general, GMCs following the primary
series of three doses of PCV-9 were lower in HIV-infected compared with HIV-uninfected children, although only significantly
so for serotypes 1 and 18C [21]. Among HIV-infected children,
those with CDC clinical stage C HIV/AIDS illness had lower GMCs
compared with children who were asymptomatic or only mildly
symptomatic for HIV disease (Category N or A). In addition, a lower
proportion of HIV-infected children had serotype-specific antibody
≥0.35 ␮g/ml for four (serotypes 1, 5, 18C and 23F) of the nine
serotypes compared with HIV-uninfected children. The proportion
of children with serotype-specific antibody ≥0.35 ␮g/ml ranged
from 80% (serotype 6B) to >95% for the other serotypes in HIVuninfected children, compared with 62% (serotype 6B) to 82–95%
for other serotypes in HIV-infected children.
An additional measure of PCV immunogenicity, that is suggested
to be more predictive of protection against IPD, is the presence
of antibody-killing activity measured by opsonophagocytic assay
activity (OPA). HIV-infected children were observed to be less likely
than HIV-uninfected children to have detectable killing activity
(titer of ≥8) on OPA for all three serotypes evaluated, i.e. serotypes
6B (78% vs. 96%), 19F (46% vs. 91%) and 23F (57% vs. 93%) [21].
In addition, the concentration of antibody required for 50% killing
activity on the OPA was significantly higher for all serotypes in
HIV-infected compared with -uninfected children. This suggests
that antibody concentration required to protect against IPD may
be higher in HIV-infected children, and that OPA assays may be a
more useful measure as a putative measure of protection in these
immune-compromized children [21].
A subsequent study in South Africa indicated that persistence
of serotype-specific antibody was significantly lower for six of the
serotypes evaluated 5.3 years after vaccination [22]. In addition,
a lower proportion of HIV-infected children had serotype-specific
antibody concentration of ≥0.35 ␮g/ml for all seven evaluated
serotypes (excluded 1 and 5) which ranged from 60% for serotype
C23
9V to 79% for serotype 6B, compared with >98% for all serotypes
in HIV-uninfected children. The GMCs following a booster dose of
PCV at 5.3 years after the primary series of three doses of PCV
in HIV-infected children were similar in magnitude compared to
the response to a single dose of PCV among HIV-infected children
who had previously received placebo. This indicated either failure
to induce memory B-lymphocytes following the primary series of
PCV, or the subsequent loss of anamnestic response among ARTnaïve HIV-infected children whose immune systems deteriorated
progressively [22].
In addition, a single dose of PCV-7 in previously unvaccinated children during the 5th–6th year of life was associated with
markedly lower GMCs in HIV-infected compared with -uninfected
children for all seven serotypes. Furthermore, the proportion of
HIV-infected children with antibody concentrations ≥0.35 ␮g/ml
ranged between 38% (serotype 23F) and 60% for other serotypes
(except 79% for 19F), compared with >94% for all serotypes (except
78% for 6B) in HIV-uninfected children following the single dose of
PCV. These data indicated that HIV-infected children may require
booster doses of PCV to sustain their protection against IPD, as well
as that multiple doses of PCV may be required when vaccinating
HIV-infected children for the first time beyond the infancy period.
5. Efficacy of PCV against nasopharyngeal colonization in
South African infants
Nasopharyngeal colonization by pneumococcus, although
possibly innocuous in the majority of colonized children, is nevertheless a pre-requisite for the development of mucosal and invasive
pneumococcal disease. The risk of developing pneumococcal disease is greatest within two months of becoming colonized by a
new serotype [23]. An initial study in The Gambia using an investigational pentavalent pneumococcal conjugate vaccine was the
first to report a reduced risk of nasopharyngeal acquisition of the
vaccine serotypes following immunization [24]. In South Africa,
this was further corroborated in a study by Mbelle et al. [13] in
which 50% reduction in colonization by the vaccine serotypes was
reported at 9 months of age. There was, however, a 30% increase
in nasopharyngeal colonization by the non-vaccine serotypes and
consequently PCV vaccination did not change the overall prevalence of pneumococcal colonization. In addition, notably, PCV
vaccination was associated with a reduction in colonization by
pneumococcal strains associated with penicillin-resistance (21% vs.
41%) and cotrimoxazole-resistance (23% vs. 35%). The effect of PCV
on reducing the risk of vaccine-serotype nasopharyngeal acquisition has since been corroborated by a number of studies including
one in The Netherlands which reported a similar effect using a twoversus a three-dose primary series of PCV followed by a booster
dose in the 2nd year of life [25].
Childhood PCV immunization has been associated with a temporal reduction in vaccine-serotype IPD and all-cause pneumonia in
age-groups not targeted for vaccination, including the elderly and
HIV-infected adults [26–30]. This indirect effect, due to decreased
pneumococcal acquisition in vaccinated children resulting in
decreased transmission overall, may also contribute to the observation that the effectiveness of PCV against all-cause pneumonia in
USA among the age-group targeted for vaccination (22–45%), postintroduction of vaccine into immunization programs [27,29,31],
has exceeded the expectations based on the efficacy trial in Northern California (5%) [18].
6. Efficacy of PCV against IPD in South African children
A phase 3 study, which enrolled 39,836 children from March
1998 to October 2000, with follow-up being extended until October
C24
S.A. Madhi et al. / Vaccine 30S (2012) C21–C27
2005, was undertaken in South Africa [32]. Although children were
screened for HIV upon admission to the hospital, the overall prevalence of HIV in the cohort was imputed to be 6.47% (approximately
2580). This study involved a primary series of three doses of PCV-9
or placebo given at a mean of 6.6, 11.2 and 14.9 weeks of age and
did not include a booster dose of vaccine.
Following a mean 2.3 years of follow-up, vaccine efficacy against
vaccine-serotype IPD was 83% (95% CI 39–97) in HIV-uninfected
children compared with 65% (95% CI 24–86) in HIV-infected children [32]. Despite the lower vaccine efficacy in HIV-infected
children, the absolute burden of vaccine-serotype IPD prevented
in HIV-infected children (570 per 100,000 child years) was 18-fold
greater compared with HIV-uninfected children (32 per 100,000
child years). Whereas vaccine efficacy against vaccine-serotype IPD
remained relatively unchanged in HIV-uninfected children (78%;
95% CI 34–93) following a mean follow-up of 6.2 years, there was a
decline in efficacy in HIV-infected children (39%; 95% CI <0–65) [22].
This indicated loss of protection in the absence of a booster dose of
PCV and was corroborated by the poor long-term immunogenicity
data in ART-naïve HIV-infected children [22].
A meta-analysis [33] of vaccine efficacy against IPD due to the
seven serotypes included in PCV-7, although reporting homogeneity in efficacy between studies, nevertheless indicated lower point
efficacy estimates against vaccine-serotype IPD in both African
studies [32,34] (77%) compared with that observed in North American children (94%) [18] (Fig. 1). PCV-9 efficacy was also evaluated
against IPD due to any serotype. Inclusive of the extended follow-up
period, vaccine efficacy in South African HIV-infected children was
surprisingly greater in HIV-infected (46.1%) compared with HIVuninfected children (35.0%; P < 0.0001). This was primarily driven
by protection against serotype 6A disease, due to cross-protection
by the inclusion of serotype 6B in the vaccine. Serotype 6A singularly contributed to 27% of all IPD cases in the HIV-infected
placebo group; and serotype-specific protection was observed in
HIV-infected children even 5 years after vaccination. In addition,
despite the waning immunity against vaccine-serotype IPD in HIVinfected children, the overall burden of IPD prevented by PCV-9
was 59.2 (95% CI 43.0–81.6) fold greater in HIV-infected compared
with HIV-uninfected children (2250 vs. 38 IPD cases prevented per
100,000 children vaccinated, respectively).
Notably, in HIV-uninfected children, the absolute overall reduction in IPD was almost halved (38 per 100,000) relative to the
reduction for vaccine type IPD (75 per 100,000), primarily due to
a non-significant increase (75%; 95% CI −17.8 to 94.7; P = 0.11) in
IPD due to non-vaccine serotypes (mainly serotype 19A). The study
was however not powered to determine whether this increase in
non-vaccine serotype IPD was significant. An increase (27%) in nonvaccine serotype IPD was also observed in HIV-infected children,
although this increase in incidence was only 10% of the decline
in vaccine-serotype IPD among these children. Contrary to the
meta-analysis on vaccine-serotype IPD, significant heterogeneity
was observed between studies in efficacy against overall IPD. This
ranged in vaccine efficacy estimates in HIV-uninfected children of
35–45% in the two studies from Africa compared with 89% in USA.
The lower efficacy against overall IPD in African studies [32,34]
compared with studies from USA [18] may have been due to the
greater diversity of serotypes associated with IPD in African compared with North American children, as well as possibly greater,
albeit not statistically significant, increase in non-vaccine serotype
IPD.
7. Efficacy of PCV against pneumonia in South African
children
Although IPD provides a useful specific outcome for measuring PCV efficacy, it undermines the public health potential of PCV.
In particular, IPD accounts for less than 10% of the annual 14
million episodes of severe disease and 847,000 deaths attributed
to pneumococci globally [35]. The major clinical manifestation of
severe and fatal pneumococcal disease is pneumonia. However, a
major challenge in evaluating the effect of PCV against pneumococcal pneumonia relates to the lack of sensitive assays to make
an etiologic specific diagnosis causing pneumonia, and particularly
relevant to bacterial pneumonia. Although lung aspirates allow
for increasing the yield of making an etiologic specific diagnosis,
these are rarely undertaken and are also biased by largely being
limited to pneumonia episodes associated with alveolar consolidation in the periphery of the right lung. Hence, the spectrum of
pathogens identified through lung aspirates may not be fully representative of all cases of pneumonia. To overcome this challenge in
part, as well as to provide a standardized outcome measure against
which efficacy trials could be compared, a working-group under
the auspices of the WHO recommended a radiologic outcome to be
used when measuring the efficacy of PCV against pneumonia [36].
This outcome, commonly referred to as “radiological-confirmed
pneumonia (RCP)” was subsequently reported on in studies which
evaluated the efficacy of PCV against pneumonia [32,34,37,38]. In
addition, many studies also reported on the broader clinical syndrome of clinically diagnosed pneumonia.
In South Africa, the efficacy of PCV-9 against RCP following
an average of 2.3 years of follow-up was 20% (95% CI 3–35) in
HIV-uninfected and 13% (95% CI −7 to 28) in HIV-infected children [32]. Despite the lower point-efficacy estimate in HIV-infected
children, the vaccine-preventable burden (per 100,000 vaccinated
children) of hospitalized RCP was nine-fold greater in HIV-infected
(909) compared with -uninfected children (100). Furthermore,
the burden (per 100,000 children) of vaccine-serotype bacteremic
pneumococcal pneumonia prevented was 38-fold greater in HIVinfected children (344) compared with -uninfected children (9).
The evaluation of PCV in the South African setting was also used as a
tool with which to probe the clinical presentation and pathogenesis
of pneumonia in HIV-infected and -uninfected children. Included
in this was the recognition, that whilst only 3% of all pneumococcal
pneumonia that was prevented in HIV-uninfected children were
associated with bacteremia, this proportion was much greater in
HIV-infected children (18%) [16].
Post hoc analysis of the South African efficacy trial also probed
the role of pneumococcus in the broader spectrum of pneumonia.
This was especially pertinent as radiologic-confirmed pneumonia
in placebo-recipients only accounted for 19.2% of all hospitalized
pneumonia episodes in South Africa [16], as well as only 16.7% of
episodes in The Gambian study on PCV-9 [34]. Although vaccine
efficacy was notably lower for the less specific outcome measure being evaluated in South African children, the public health
relevance of examining vaccine efficacy against the broader syndrome of clinical pneumonia was noted. In particular, less specific
endpoints with lower point-efficacy estimates detected a larger
burden of pneumococcal pneumonia which was prevented by PCV
compared with those endpoints with outcomes which were more
specific for pneumococcal pneumonia (Fig. 2) [16].
8. Recommendation of NAGI on PCV dosing schedule in
South Africa
The high cost of introducing PCV into South Africa, which is
non-eligible for GAVI support, required interrogation of the epidemiology and existing evidence on PCV to inform decision-making
as to what schedule PCV should be used in the immunization
program. Limited funds to support the program precluded using
a three-dose primary series with booster dose (i.e. 3 + 1 schedule). However, the lack of sustained protection against IPD in
S.A. Madhi et al. / Vaccine 30S (2012) C21–C27
C25
Fig. 1. Meta-analysis: efficacy in randomized-controlled trials of pneumococcal conjugate vaccine (PCV) against invasive pneumococcal disease due to serotypes included
in 7-valent PCV among HIV-uninfected children [33].
Adapted from reference number [33].
HIV-infected children who contributed to more than two-thirds
of IPD in South Africa, indicated a need for a booster dose of vaccine.
Based on the observation that a two-dose primary series of
PCV during infancy resulted in similar immunogenicity compared
to a three-dose schedule [14,20] as well as similar impact on
nasopharyngeal colonization and effectiveness against IPD in HIVuninfected children [25,39], NAGI recommended that the South
African immunization program adopt a two-dose primary series
with a booster dose at 9 months of age. Providing the booster dose
of PCV at 9 months of age optimizes the number of children who
are likely to receive the booster dose. In particular, there is an attrition of children who are brought for their routine immunizations
at 9 months (95%) compared with 18 months (83%), according to
official country estimates for 2010 [40].
9. Main questions needing to be addressed with
introduction of PCV in South Africa/Africa
Despite the broad repertoire of research undertaken on pneumococcal disease and PCV over the past two decades in South Africa,
a number of questions remain. These include the immunogenicity of the novel 2 + 1 dose, in both HIV-infected and -uninfected
children. In addition, with increased access to ART in management of HIV-infected children, the persistence of antibody,
anamnestic responses and sustainability of protection against
IPD in HIV-infected children on anti-retroviral treatment needs
evaluation.
The effectiveness of the novel 2 + 1 schedule used, and in particular in protecting against IPD in HIV-infected children, is currently
being evaluated in South Africa. Furthermore, there are concerns
that a two-dose primary series may be less effective than a threedose primary series against pneumonia [41]. Considering that >90%
of severe pneumococcal disease morbidity and mortality relates
to pneumonia [35], the effectiveness of the 2 + 1 schedule, in both
HIV-infected and -uninfected African children requires confirmation and is also currently being studied in South Africa. This will
be supported by an ecological time-series analysis on the impact
of PCV introduction on all-cause pneumonia hospitalization at a
sentinel hospital site in South Africa.
Whereas the above studies were initiated at the time when 7valent PCV was used, the transition from PCV-7 to 13-valent PCV as
of May 2011 will likely need to be extended to include evaluating
the effectiveness of the immunization program against the dominant IPD-causing serotypes, i.e. 1 and 19A, which contributed to a
greater proportion of IPD post PCV-7 introduction.
Other studies also currently underway include the national
laboratory-based surveillance system monitoring trends in incidence of IPD, including stratification by HIV, across various
age-groups to delineate the direct and indirect impact of childhood
PCV immunization on vaccine-serotype IPD. The IPD surveillance
study examining the effect of infant PCV immunization, in the
absence of a childhood catch-up campaign as was the case in
South Africa, on indirect protection is also being supplemented
by an ecological study on the effect of infant PCV immunization on the epidemiology of vaccine and non-vaccine serotype
nasopharyngeal colonization in both rural and urban areas, across
70
267
60
PCV efficacy (%)
VAR
61
250
50
200
40
164
150
30
20
20
17
100
100
11
50
10
14
0
Clinical pneumonia
WHO-defined severe
pneumonia
CXR-confirmed
pneumonia
VAR (cases per 100,000 child years)
300
PCV efficacy
0
Vaccine serotypeconfirmed pneumonia
PCV=pneumococcal conjugate vaccine; WHO=World Health Organization; CXR=chest X-ray
Fig. 2. Inverse relationship between vaccine efficacy and vaccine attributable reduction (VAR) (per 100,000 children) in HIV-uninfected children [16].
PCV: pneumococcal conjugate vaccine; WHO: World Health Organization; CXR: chest X-ray.
C26
S.A. Madhi et al. / Vaccine 30S (2012) C21–C27
various age-groups as well as stratification by HIV-infection status.
The IPD surveillance system would also provide vital information as to the temporal trends in non-vaccine serotype IPD
post-introduction of PCV-7 to help understand the public-health
relevance of serotype-replacement disease in South Africa. Archiving of the pneumococcal isolates will also provide an opportunity
of evaluating the molecular basis of any excessive replacement disease which may be observed in South Africa.
Conflict of interest statement
SAM has participated in speakers’ bureau (GlaxoSmitKline and
Pfizer), received grant funds (GlaxoSmitKline, Pfizer and sanofiaventis) and honoraria (GSK, Pfizer, sanofi-aventis, MERCK). AvG
has received grant funding from GlaxoSmithKline, Pfizer and
sanofi-aventis.
Acknowledgements
The roles of Professors Keith P Klugman and Hendrik Koornhof, who have been instrumental in the research and surveillance
agenda on pneumococcal disease and who continue to collaborate
and serve as mentors in the field in South Africa is greatly recognized. In addition, we acknowledge other colleagues, hospital staff,
children and their parents who made all these studies possible.
We thank all laboratory and clinical staff throughout South
Africa for contributing to national surveillance as part of GERMS-SA
(Group for Enteric, Meningeal and Respiratory disease Surveillance
in South Africa).
References
[1] Schoub BD, Ngcobo NJ, Madhi S. The National Advisory Group on Immunization (NAGI) of the Republic of South Africa. Vaccine 2010;28 Suppl 1(A31-4):
A31–4.
[2] Pneumococcal conjugate vaccine for childhood immunization. WHO position
paper. Wkly Epidemiol Rec 2007;82:93–104.
[3] Karstaedt AS, Khoosal M, Crewe-Brown HH. Pneumococcal bacteremia during a
decade in children in Soweto, South Africa. Pediatr Infect Dis J 2000;19:454–7.
[4] Madhi SA, Petersen K, Madhi A, Wasas A, Klugman KP. Impact of human immunodeficiency virus type 1 on the disease spectrum of Streptococcus pneumoniae
in South African children. Pediatr Infect Dis J 2000;19:1141–7.
[5] Madhi SA, Petersen K, Madhi A, Khoosal M, Klugman KP. Increased disease burden and antibiotic resistance of bacteria causing severe community-acquired
lower respiratory tract infections in human immunodeficiency virus type 1infected children. Clin Infect Dis 2000;31:170–6.
[6] Jones N, Huebner R, Khoosal M, Crewe-Brown H, Klugman K. The impact of HIV
on Streptococcus pneumoniae bacteraemia in a South African population. AIDS
1998;12:2177–84.
[7] Nyasulu P, Cohen C, de Gouveia L, Feldman C, Klugman KP, von Gottberg A.
Increased risk of death in human immunodeficiency virus-infected children
with pneumococcal meningitis in South Africa, 2003–2005. Pediatr Infect Dis J
2011;30:1075–80.
[8] Huebner RE, Klugman KP, Matai U, Eggers R, Hussey G. Laboratory surveillance
for Haemophilus influenzae type b, meningococcal, and pneumococcal disease.
Haemophilus surveillance working group. S Afr Med J 1999;89:924–5.
[9] Meiring S, Cohen C, Govender N, Keddy K, Msimang V, Quan V, et al. Bacterial
and fungal meningitis amongst children <5 years old, South Africa, 2007. S Afr
J Epidemiol Infect 2009;24:30.
[10] Nunes MC, von Gottberg A, de Gouveia L, Cohen C, Moore DP, Klugman KP, et al.
The impact of antiretroviral treatment on the burden of invasive pneumococcal disease in South African children: a time series analysis. AIDS 2011;25:
453–62.
[11] von Gottberg A, de Gouveia L, Quan V, Meiring S, Cohen C, Whitelaw A, et al.
Vaccine-preventable invasive pneumococcal disease, South Africa, 2006. S Afr
J Epidemiol Infect 2007;22:95–6.
[12] Crowther-Gibson P, Cohen C, Klugman KP, de Gouveia L, von Gottberg A, For
GERMS-SA. Risk factors for multidrug-resistant invasive pneumococcal disease
in South Africa, 2003–2008. In: Poster 12.018. The International Meeting on
Emerging Diseases and Surveillance (IMED). 2011.
[13] Mbelle N, Huebner RE, Wasas AD, Kimura A, Chang I, Klugman KP.
Immunogenicity and impact on nasopharyngeal carriage of a nona-valent
pneumococcal conjugate vaccine. J Infect Dis 1999;180:1171–6.
[14] Huebner RE, Mbelle N, Forrest B, Madore DV, Klugman KP. Immunogenicity after one, two or three doses and impact on the antibody response to
co-administered antigens of a nona-valent pneumococcal conjugate vaccine
in infants of Soweto, South Africa. Pediatr Infect Dis J 2002;21:1004–7.
[15] Huebner RE, Mbelle N, Forrest B, Madore DV, Klugman KP. Long-term antibody
levels and booster responses in South African children immunized with nonavalent pneumococcal conjugate vaccine. Vaccine 2004;22:2696–700.
[16] Madhi SA, Kuwanda L, Cutland C, Klugman KP. The impact of a 9-valent
pneumococcal conjugate vaccine on the public health burden of pneumonia in HIV-infected and -uninfected children. Clin Infect Dis 2005;40:
1511–8.
[17] Nurkka A, Ahman H, Korkeila M, Jantti V, Kayhty H, Eskola J. Serum and salivary
anti-capsular antibodies in infants and children immunized with the heptavalent pneumococcal conjugate vaccine. Pediatr Infect Dis J 2001;20:25–33.
[18] Black S, Shinefield H, Fireman B, Lewis E, Ray P, Hansen JR, et al. Efficacy,
safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in
children, Northern California Kaiser Permanente Vaccine Study Center Group.
Pediatr Infect Dis J 2000;19:187–95.
[19] Jodar L, Butler J, Carlone G, Dagan R, Goldblatt D, Kayhty H, et al. Serological
criteria for evaluation and licensure of new pneumococcal conjugate vaccine
formulations for use in infants. Vaccine 2003;21:3265–72.
[20] Goldblatt D, Southern J, Ashton L, Richmond P, Burbidge P, Tasevska J, et al.
Immunogenicity and boosting after a reduced number of doses of a pneumococcal conjugate vaccine in infants and toddlers. Pediatr Infect Dis J
2006;25:312–9.
[21] Madhi SA, Kuwanda L, Cutland C, Holm A, Kayhty H, Klugman KP. Quantitative and qualitative antibody response to pneumococcal conjugate vaccine
among African human immunodeficiency virus-infected and -uninfected children. Pediatr Infect Dis J 2005;24:410–6.
[22] Madhi SA, Adrian P, Kuwanda L, Jassat W, Jones S, Little T, et al. Long-term
immunogenicity and efficacy of a 9-valent conjugate pneumococcal vaccine
in human immunodeficient virus infected and non-infected children in the
absence of a booster dose of vaccine. Vaccine 2007;25:2451–7.
[23] Gray BM, Converse III GM, Dillon Jr HC. Epidemiologic studies of Streptococcus
pneumoniae in infants: acquisition, carriage, and infection during the first 24
months of life. J Infect Dis 1980;142:923–33.
[24] Obaro SK, Adegbola RA, Banya WA, Greenwood BM. Carriage of pneumococci
after pneumococcal vaccination. Lancet 1996;348:271–2.
[25] van Gils EJ, Veenhoven RH, Hak E, Rodenburg GD, Bogaert D, Ijzerman EP,
et al. Effect of reduced-dose schedules with 7-valent pneumococcal conjugate
vaccine on nasopharyngeal pneumococcal carriage in children: a randomized
controlled trial. JAMA 2009;302:159–67.
[26] Whitney CG, Farley MM, Hadler J, Harrison LH, Bennett NM, Lynfield R, et al.
Decline in invasive pneumococcal disease after the introduction of proteinpolysaccharide conjugate vaccine. N Engl J Med 2003;348:1737–46.
[27] Grijalva CG, Nuorti JP, Arbogast PG, Martin SW, Edwards KM, Griffin MR.
Decline in pneumonia admissions after routine childhood immunisation with
pneumococcal conjugate vaccine in the USA: a time-series analysis. Lancet
2007;369:1179–86.
[28] Flannery B, Heffernan RT, Harrison LH, Ray SM, Reingold AL, Hadler J, et al.
Changes in invasive pneumococcal disease among HIV-infected adults living in the era of childhood pneumococcal immunization. Ann Intern Med
2006;144:1–9.
[29] Simonsen L, Taylor RJ, Young-Xu Y, Haber M, May L, Klugman KP. Impact of
pneumococcal conjugate vaccination of infants on pneumonia and influenza
hospitalization and mortality in all age groups in the United States. MBio
2011;2:e00309–10.
[30] De Wals P, Robin E, Fortin E, Thibeault R, Ouakki M, Douville-Fradet M. Pneumonia after implementation of the pneumococcal conjugate vaccine program
in the province of Quebec. Canada Pediatr Infect Dis J 2008;27:963–8.
[31] Zhou F, Kyaw MH, Shefer A, Winston CA, Nuorti JP. Health care utilization for
pneumonia in young children after routine pneumococcal conjugate vaccine
use in the United States. Arch Pediatr Adolesc Med 2007;161:1162–8.
[32] Klugman KP, Madhi SA, Huebner RE, Kohberger R, Mbelle N, Pierce N. A trial of
a 9-valent pneumococcal conjugate vaccine in children with and those without
HIV infection. N Engl J Med 2003;349:1341–8.
[33] Klugman KP, Cutts F, Adegbola RA, Black S, Madhi SA, O’Brien KL, et al. Efficacy
and safety: Meta-analysis of the efficacy of conjugate vaccines against invasive
pneumococcal disease. In: Siber GR, Klugman KP, Makela PH, editors. Pneumococcal vaccines: the impact of conjugate vaccine. Washington, D.C., USA: ASM
Press; 2008. p. 317–37.
[34] Cutts FT, Zaman SM, Enwere G, Jaffar S, Levine OS, Okoko JB, et al. Efficacy of
nine-valent pneumococcal conjugate vaccine against pneumonia and invasive
pneumococcal disease in The Gambia: randomised, double-blind, placebocontrolled trial. Lancet 2005;365:1139–46.
[35] O’Brien KL, Wolfson LJ, Watt JP, Henkle E, Deloria-Knoll M, McCall N, et al.
Burden of disease caused by Streptococcus pneumoniae in children younger than
5 years: global estimates. Lancet 2009;374:893–902.
[36] Cherian T, Mulholland EK, Carlin JB, Ostensen H, Amin R, de CM, et al.
Standardized interpretation of paediatric chest radiographs for the diagnosis of pneumonia in epidemiological studies. Bull World Health Organ
2005;83:353–9.
[37] Black SB, Shinefield HR, Ling S, Hansen J, Fireman B, Spring D, et al. Effectiveness of heptavalent pneumococcal conjugate vaccine in children younger than
five years of age for prevention of pneumonia. Pediatr Infect Dis J 2002;21:
810–5.
S.A. Madhi et al. / Vaccine 30S (2012) C21–C27
[38] Lucero MG, Nohynek H, Williams G, Tallo V, Simoes EA, Lupisan S, et al.
Efficacy of an 11-valent pneumococcal conjugate vaccine against radiologically confirmed pneumonia among children less than 2 years of age in
the Philippines: a randomized, double-blind, placebo-controlled trial. Pediatr
Infect Dis J 2009;28:455–62.
[39] Whitney CG, Pilishvili T, Farley MM, Schaffner W, Craig AS, Lynfield
R, et al. Effectiveness of seven-valent pneumococcal conjugate vaccine
against invasive pneumococcal disease: a matched case-control study. Lancet
2006;368:1495–502.
C27
[40] World Health Organization. Programmes and Projects: Immunization
Surveillance, Assessment and Monitoring; WHO Vaccine-Preventable Diseases: Monitoring System; 2011 [accessed 08.12.11] http://apps.who.int/
immunization monitoring/en/globalsummary/countryprofileresult.cfm.
[41] Pelton SI, Weycker D, Klein JO, Strutton D, Ciuryla V, Oster G. 7-Valent
pneumococcal conjugate vaccine and lower respiratory tract infections:
effectiveness of a 2-dose versus 3-dose primary series. Vaccine 2010;28:
1575–82.
Vaccine 30S (2012) C28–C34
Contents lists available at SciVerse ScienceDirect
Vaccine
journal homepage: www.elsevier.com/locate/vaccine
Review
Introducing human papillomavirus vaccines into the health system in South
Africa
Matthys H. Botha a,∗ , Carine Dochez b
a
Unit for Gynaecological Oncology, Stellenbosch University and Tygerberg Hospital, P.O. Box 19063, Tygerberg 7505, South Africa
Network for Education and Support in Immunisation, Department of Epidemiology and Social Medicine, University of Antwerp, Campus Drie Eiken, Universiteitsplein 1, 2610
Antwerpen, Belgium
b
a r t i c l e
i n f o
Article history:
Received 24 September 2011
Received in revised form 20 February 2012
Accepted 15 March 2012
Keywords:
Cervical cancer
HPV vaccines
South Africa
a b s t r a c t
South Africa has a high incidence of cervical cancer, with an age-standardised rate of approximately 27
per 100,000. In 2000, South Africa launched a national screening programme for cervical cancer prevention, offering three Papanicolaou smears per lifetime starting after the age of 30 with 10-year intervals.
However, in the public sector, this national screening programme has not been implemented widely.
Vaccination would offer the best primary prevention. Currently there are two HPV vaccines registered in
South Africa: the bivalent vaccine CervarixTM , containing VLP antigens for oncogenic HPV types 16 and
18; and the quadrivalent vaccine GardasilTM , containing VLP antigens for HPV types 16 and 18, as well as
non-oncogenic HPV types 6 and 11, which are the most common types causing genital warts. The vaccines are recommended for prophylactic use, and should ideally be given before exposure to HPV, which
is before sexual debut, to girls aged 11–12 years. Possible routes for delivering the HPV vaccine could be
either the routine EPI programme at the age of 12 years when dT is being administered, or through the
school system, e.g. to girls attending grade 5 or 6.
© 2012 Elsevier Ltd. All rights reserved.
1. Introduction
South Africa is classified as an upper middle-income country by
the World Bank [1]. The Gross Domestic Product is around $5800
per capita but the distribution is unequal. The rate of poverty (the
percentage of the population living below the national poverty
line as defined by the World Bank) declined significantly over the
last few years but still stands at 23%. South Africa spends 3% of
its GDP and just over 15% of government expenditure on healthcare. When compared to low- and middle-income countries the
level of total health expenditure is relatively high. This high spending does unfortunately not translate into a healthy population [2].
Human development challenges are enormous and there is a low
life-expectancy of only 51 years.
Accurate data on causes of death are not always available and
cancer statistics are often lacking and inaccurate [3]. Cancer prevention as a health priority has to compete with communicable
diseases like HIV and tuberculosis. Partly related to the poor quality
of cancer preventative services there is a high incidence of cervical
cancer in South Africa.
∗ Corresponding author.
E-mail address: [email protected] (M.H. Botha).
0264-410X/$ – see front matter © 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.vaccine.2012.03.032
South Africa has a two tier medical system with considerable
overlap. Approximately 20–25% of the population is covered by
private medical insurance and makes use of modern, generally
well-resourced, private sector facilities. Approximately 75–80% of
the population depends on the state sponsored health-care of
which the quality is quite variable according to geographical areas.
A small but significant part of the population will access primary
care in the private sector but will use the public sector for hospitalisation and specialised services.
2. The burden of HPV associated disease
Persistent HPV infection with an oncogenic strain of HPV is a
necessary risk factor for the development of invasive cervical cancer [4]. The most important oncogenic viruses seem to be similar in
many different geographical areas and HPV16, 18 and 33 were identified in the majority of cervical cancer biopsies from South Africa
[5]. Oncogenic strains of HPV have the ability to integrate viral DNA
into the human genome. The onco-proteins E6 and E7 deactivate
important processes associated with tumour suppressor genes like
p53 and pRb gene functions. HPV is highly infectious and “most sexually active people will get HPV at some time in their lives” [6]. This
ubiquitous infection does not cause disease in all the infected individuals and certain processes make individuals more susceptible to
the development of pre-malignant and malignant disease. Because
M.H. Botha, C. Dochez / Vaccine 30S (2012) C28–C34
HPV is almost exclusively an epithelial disease, the virus is poorly
presented to the adaptive immune system which is important for
induction of long term immunity. Most natural infections of HPV do
not cause significant immunoglobulin responses and therefore the
immune response after natural infections is not very pronounced
[7].
After initial exposure to HPV there is an incubation period of
between 1 and 8 months after which the first HPV-related lesions
might appear. There is active growth of the virus for a period
of between 3 and 6 months but usually there are host-immune
responses that will, in most cases, clear the infection by about 9
months. A large percentage of the population will have sustained
clinical remission but a small proportion will develop chronic infection and become HPV-DNA positive on repeated testing. These are
the individuals that will be at highest risk for the development of
pre-malignant conditions and later invasive cancer [7]. We now
know that changes in cells due to HPV infection of the cervix is the
first step in a series of slow changes that can lead to cancer years
later.
The age-standardised incidence rate of cervical cancer in Southern Africa is approximately 27 per 100,000 [8]. There is a significant
difference in reported rates between black (42.1) and white women
(14.5) which may be partly related to unequal access to healthcare,
differences in socio-economic status and exposure to HPV and HIV
infection [9]. Not only is the incidence of cervical cancer unacceptably high, but also most cases of invasive carcinoma present late
with a high case-fatality.
Other malignant diseases associated with human papillomavirus infection like oesophageal tumours, head and neck
tumours and invasive vulva carcinoma are not uncommon in South
Africa [10]. Cancer of the penis represents less than 0.5% of cancers
in men [11]. There is geographical correlation between the incidence of cancer of the penis and cervix, and concordance of these
two cancers in married couples, which suggests that HPV is the
common aetiology.
Despite the fact that screening services are inadequately developed, many women still undergo cervical excision procedures for
premalignant conditions. In this population premature delivery is
already an important health problem [12]. Additionally, it has been
reported that treatment for cervical intra-epithelial neoplasia (CIN)
significantly increases the risk for preterm delivery and low birthweight infants [13,14]. The risk for premature delivery may be
higher after cold knife conisation when compared to loop excision
and laser procedures [15].
Non-oncogenic HPV (mainly types 6 and 11) is the cause
of serious benign conditions such as recurrent juvenile papillomatosis and condylomata acuminata (genital warts) [16]. External
genital disease including condylomata acuminata (and vulva
intra-epithelial neoplasia) often presents as a clinical dilemma;
particularly in the HIV-infected population. No accurate figures
are available for the incidence of condylomata acuminata in the
South African population. However in clinical practice it is abundantly clear that genital warts is a common clinical problem that
cause serious morbidity and cost to the health system. Massive
condylomata acuminata will not infrequently be diagnosed during
pregnancy or in HIV infected individuals.
3. Screening for cervical cancer
3.1. Cytology
The South African National policy for cervical cancer prevention was launched in 2000. The screening programme offers three
Papanicolaou smears per lifetime starting after the age of 30 at
10-year intervals [17]. This policy is based on a mathematical
C29
model that predicts a reduction in cervical cancer incidence in
excess of 60% if the policy is universally introduced. If a lowgrade abnormality is found the cytology smear is repeated after 12
months. Referral threshold for colposcopy include two consecutive
low-grade lesions, one high-grade lesion or a macroscopic lesion
suspicious of cancer. For women with HIV infection, the clinical
guidelines for the management of HIV and AIDS in adults and adolescents advises one cervical cytology at diagnosis of HIV and then
every 3 years if normal regardless of antiretroviral treatment status
[18].
In certain parts of South Africa (particularly in the private sector)
opportunistic screening with regular Pap smears has resulted in a
significant drop in the rate of cervical cancer [19]. However, in the
state sector, the national cytology screening programme has not
been implemented widely. Some provinces in South Africa have
fairly well-developed cytology screening services but overall there
is poor uptake of secondary prevention services for cancer. In those
women identified with abnormal cytology there is a significant loss
to follow up after the initial screening test [20].
3.2. Human papillomavirus testing
Human papillomavirus testing has been extensively investigated as an alternative to cervical cytology for screening. The high
sensitivity to detect precursor lesions may make HPV testing more
suitable than cytology in an once-in-a-lifetime programme or a
programme with long screening intervals. HPV testing as a primary screening tool has been compared to various other methods
in the South African setting [21]. Certain subgroups of the population are not suited to HPV screening due to a very high prevalence
of HPV. This includes women below the age of 30 years where HPV
detection is mostly transient [21]. In immune compromised women
the incidence of HPV is also high but the high negative predictive
value of HPV DNA testing may be useful as a triage method. Cost
effectiveness calculations from South Africa indicate that HPV testing to screen for cervical cancer may be a cost-effective strategy
although analyses are affected significantly by the specific protocol
and situation [22].
3.3. Visual Inspection
In certain rural areas of South Africa visual inspection with acetic
acid (VIA) is the preferred option for secondary prevention.
4. The role of Human Immune Deficiency Virus (HIV)
co-infection
Southern Africa has the highest incidence of HIV-infected
individuals anywhere. Despite that the biggest anti-retroviral programme in the world has been rolled out over the last few years,
the life expectancy of South Africans has fallen drastically largely
due to an excess mortality associated with AIDS related illnesses.
One of the recognised HIV associated diseases is cervical cancer
and its precursors. Unpublished data collected at the first author’s
institution confirms the fact that HIV infected individuals have significantly more abnormalities on cervical cytology, are far more
likely to be HPV positive and test positive for many HPV types, have
a higher failure after excisional treatment for pre-cancer lesions
and present much younger with invasive carcinoma. These findings
are confirmed by publications from other authors [23–25].
There are an increasing number of reports supporting a possible
relationship between HPV infection and the risk for HIV acquisition
[26,27]. HIV and genital HPV infection share similar risk factors. It
seems that the presence of HPV infection actually increases the risk
for HIV acquisition and transmission and the biological plausibility
of this phenomenon is explored in recent publications [28,29]. An
C30
M.H. Botha, C. Dochez / Vaccine 30S (2012) C28–C34
effective HPV prevention strategy may therefore also reduce the
risk for HIV infection.
5. Treatment facilities available in Southern Africa
Treatment facilities for invasive cervical cancer are limited.
Despite the fact that most cancers are diagnosed quite late, a significant number of women qualify for radical surgery as primary
treatment. There are less than 20 registered gynaecological oncologists in the country. Radiotherapy facilities are in high demand
and waiting lists for treatment are often unacceptably long. Palliative support is lacking in many parts of the country particularly in
rural areas.
6. Primary preventative strategies
HPV vaccines are produced using recombinant technology,
whereby the L1 capsid protein is inserted into a host (e.g. yeast or
baculovirus). These L1 proteins can self-assemble into empty shells
or virus like particles (VLPs) that are similar in size and shape to
the HPV virion. VLPs do not contain viral DNA, and are therefore
non-infectious and non-oncogenic [30,31].
Currently there are two vaccines registered in South Africa: the
bivalent vaccine CervarixTM , containing VLP antigens for HPV types
16 and 18; and the quadrivalent vaccine GardasilTM , containing VLP
antigens for HPV types 16 and 18, as well as non-oncogenic HPV
types 6 and 11, which are the most common types causing genital warts. VLPs are combined with an immune stimulant, called
an adjuvant, which leads to an improved immunoglobulin production. The bivalent vaccine uses a unique type of adjuvant, ASO4,
including 3-O-desacyl-4 monophosphoryl lipid A and aluminium
salt. Amorphous aluminium hydroxyl-phosphate sulphate is used
as adjuvant in the quadrivalent vaccine [30,31].
Both vaccines are given as intramuscular injection in a threedose schedule: 0, 1 and 6 months for the bivalent vaccine; 0, 2 and
6 months for the quadrivalent vaccine [30].
Both vaccines have been studied in large populations and have
been found to be safe and well tolerated. Local reactions like pain,
swelling and redness can occur and are of short duration. Systemic adverse events could include fever, nausea, dizziness, fatigue,
headache and myalgia [32]. The HPV vaccines are also well tolerated in boys [33,34]. It is safe to co-administer the HPV vaccines
with other paediatric and adolescent vaccines [30].
6.1. Efficacy
A study that provides recent comprehensive data pertaining
to the clinical efficacy of CervarixTM is the HPV-008 PATRICIA
study (the PApilloma TRIal against Cancer In young Adults) [35].
The primary objective of this study was to assess vaccine efficacy against CIN2+ associated with HPV16/18 in women who were
sero-negative and DNA negative at baseline and month 6 for the
corresponding type. The study was a randomised 1:1, double blind,
controlled Phase III trial involving 18,644 young women aged
15–25 years. The interim analysis was reported after a mean followup of 14.8 months [32] and the final analysis conducted after a mean
follow-up of 34.9 months [35]. A total of 92% of the participants
received three doses of the study vaccine.
The final analysis included 3 study cohorts, Total Vaccinated
Cohort (TVC), Total Vaccinated Cohort-Naive (TVC-Naive) and
According to Protocol Cohort (ATP-E). The TVC-Naive cohort
approximated the primary target population for organised vaccination programmes, namely adolescent girls before sexual debut.
The efficacy of the vaccine after 34.9 months in the ATP-E cohort
was 92.9% for CIN2+ associated with HPV16/18 in the primary
analysis and 98.1% in an analysis in which probable causality to
HPV type was assigned in lesions infected with multiple oncogenic types. Within the TVC-Naive cohort the protection against
HPV16/18 CIN2+ was 98.4% and against HPV16/18 CIN3+ it was
100% [35]. This study also reported cross-protection against persistent HPV infection and CIN2+ associated with HPV31, HPV33
and HPV45. Vaccination with the bivalent vaccine decreased colposcopy referrals and cervical excision procedures [36].
End of study data obtained after 4 years of the randomised,
double-blind PATRICIA trial, showed that the vaccine efficacy in the
TVC was considerably less than observed in the TVC-naive. Vaccine
efficacy against CIN3+ associated with HPV16/18 was 100% in the
TVC-Naive group and 45.7% in the TVC group. When stratified by
age in the TCV group, the highest vaccine efficacy was observed
in the youngest age group (15–17-year old), and decreased with
increasing age (18–20-year old; 21–25-year old) [37]. Vaccine efficacy against all CIN3+ irrespective of HPV type in the lesion and
including lesions with no HPV DNA was 93.2% in the TVC-naive,
and 45.6% in the TVC.
De Carvalho et al. reported efficacy data of the bivalent vaccine
up to 7.3 years after first vaccination [38]. The study was conducted in Brazil and enrolled 433 young women (age 15–25 years)
who were sero-negative and DNA-negative in a double-blind, randomised trial. Vaccine efficacy at 94.5% against incident infection
remained high up to 7.3 years. Hundred percent vaccine efficacy
was observed against 6-month and 12-month persistent infection
with HPV16/18, as well as CIN1+ and CIN2+.
The quadrivalent vaccine has been evaluated in 2 phase III randomised placebo controlled clinical trials in women aged 16–26
years: protocol 013 (termed FUTURE 1) and protocol 015 (termed
FUTURE II) [39]. In the per-protocol population, the vaccine efficacy was 96% for CIN1, and 99% for condylomata after 4 years of
follow-up.
Steben reported the end of study data for the quadrivalent vaccine after 4 years of follow-up of women aged 16–26 years [40].
The vaccine efficacy for HPV16/18 related CIN2/3 was 98%. For
women aged 24–45 years, per-protocol vaccine efficacy for any
HPV6/11/16/18-related disease was 92%. Efficacy of the quadrivalent vaccine has been shown in adult women aged 24–45 years in a
combined analysis of 4 randomised placebo controlled clinical trials [41]: after an average of 3 years of follow-up, vaccine efficacy
was 99% in the per protocol study population for the prevention of
CIN2/3 and adenocarcinoma in situ. External genital lesions were
also significantly reduced in the vaccinated cohort and there was
a significant reduction in colposcopy, cervical biopsy and in surgical therapy [42]. In a study among 4065 healthy men 16–26
years of age, the quadrivalent HPV vaccine significantly reduced the
incidence of persistent HPV infection and external genital lesions
related to HPV6, 11, 16, and 18 [43].
Information on the use of the quadrivalent vaccine in immunecompromised patients is limited to a small study done in 126
children in the United States who were between the ages of 7 and
12 years. Some of these children were on antiretroviral therapy and
some were not. Around 99.5% developed antibodies to HPV when
vaccinated with the quadrivalent vaccine [44]. A trial on the safety
and immunogenicity of the bivalent vaccine in HIV infected females
is currently on-going in South Africa [45].
6.2. Immunogenicity/duration of protection
Both the bivalent and the quadrivalent vaccine are highly
immunogenic across a wide age-range, but the highest immune
responses were observed in young girls aged 9–15 years
[32,33,46,47]. Both vaccines induce HPV16 antibody titres several
fold higher than after natural infection: these titres remain high for
at least 8.4 years for the bivalent vaccine with 100% seropositivity
M.H. Botha, C. Dochez / Vaccine 30S (2012) C28–C34
maintained and at least 5 years for the quadrivalent vaccine with
98.8% seropositivity maintained [48]. The bivalent vaccine induces
sustained antibody titres for HPV18 several fold higher than after
natural infection, 8.4 years after initial vaccination with 100%
seropositivity maintained. However, for the quadrivalent vaccine,
18 months after first vaccination, the induced antibody titres for
HPV18 return to the level of natural infection, with a reduction
in seropositivity over time [48]. A minimum protective level of
antibodies has not yet been established and despite falling levels
of antibodies, protection against detectable disease was demonstrated for the quadrivalent vaccine for more than 5 years.
A strong anamnestic response was induced after administering
a fourth dose after 5 years for the quadrivalent vaccine [49] and
after 7 years for the bivalent vaccine [50]. These findings would
support a long term efficacy of both vaccines.
Einstein compared the immunogenicity of the bivalent with
the quadrivalent vaccine. Neutralising antibodies against HPV16
and HPV18 were 3.7 and 7.3-fold higher, respectively for the bivalent vaccine compared to the quadrivalent vaccine in women aged
18–26 years [51]. These differences remained similar in older age
groups. This difference in immunogenicity could be due to the
different adjuvants used in the bivalent and quadrivalent vaccine
[38,52]. A higher immune response may indicate a longer duration
of protection against HPV16/18, however, long-term studies are
needed to assess the clinical relevance of the observed differences
in antibody response [51].
6.3. Cross-protection
Both HPV vaccines protect against other HPV types than just
those that are present in the vaccines. HPV31 and HPV45 are
responsible for about 10% of cervical cancer worldwide. HPV31 is
phylogenetically related to HPV16 and HPV45 is related to HPV18.
The bivalent vaccine showed cross-protection against HPV31
and HPV45 [38,53]. Vaccine efficacy against 6-month persistent
infection was 79% for HPV31, and 76% for HPV45 [53]. No crossprotection was observed against HPV52 or HPV58. In addition
to cross-protection against HPV31 and HPV45, Paavonen et al.
reported also vaccine efficacy of 51.9% against CIN2+ for HPV33
[35]. HPV33 is phylogenetically related to HPV16 and an important
HPV type in South Africa. End of study data obtained after 4 years
of the randomised, double-blind PATRICIA trial, showed vaccine
efficacy against persistent infection and CIN2+ (with or without
HPV16/18 co-infection) for HPV31, HPV33, HPV45 and HPV51
[54]. Vaccine efficacy against CIN2+ with or without HPV16/18 coinfection for HPV31 was 87.5% in the ATP-E, 89.4% in the TVC-naive
and 47% in the TVC group. For HPV33, a vaccine efficacy against
CIN2+ was observed of 68.3% for the ATP-E, 82.3 for TVC-naive, and
51.5% for the TVC group. For HPV45, a vaccine efficacy against CIN2+
was observed of 81.9% for the ATP-E, 100% for TVC-naive, and 90.5%
for the TVC group. For HPV51, a vaccine efficacy against CIN2+ was
observed of 54.4% for the ATP-E, 70.2 for TVC-naive, and 50.0% for
the TVC group [54].
The quadrivalent vaccine showed cross-protection against
HPV31 and HPV33, in subjects who were sero-negative and DNA
negative at enrolment. Vaccine efficacy against 6-month persistent infection was 46.2% for HPV31, and 28.7% for HPV33 [55,56].
Vaccine efficacy against CIN2+ or adenocarcinoma in situ was 70%
for HPV31 and 24% against HPV33. There was no cross-protection
observed against infection and lesions with HPV45 [56].
7. Public health
The vaccines are recommended for prophylactic use, they do
not clear an existing infection or disease. In order for the vaccine
C31
to be effective in preventing HPV infection, it must be given before
exposure to HPV, which is before sexual debut. Studies on the natural history of HPV infection and disease have shown that the peak
incidence of HPV infection occurs in most populations within 5–10
years of first sexual experience (age 15–25 years). There may be
some differences between countries but in general most authorities
recommend that girls around age 11–12 years, just before leaving
primary school, may be the most suitable for mass vaccination. The
vaccine can however be administered as young as 9 years of age.
Catch-up vaccination is considered cost-effective for females aged
13–18 years [57,58].
High vaccine coverage is needed if significant improvement of
cervical cancer rates is to be achieved. In many industrialised countries the introduction of the vaccines has been rapid and very well
organised. Examples of well-organised vaccination programmes for
girls are the National Health Service in the United Kingdom, the
Australian government programme and the programme in Belgium
[59]. These programmes aim to vaccinate all girls around the age
of 12 but for the first few years also include a catch-up group of
slightly older adolescents/young women. At present HPV vaccination for males is not recommended, but it could be considered to
include them when the vaccines become less expensive [60]. The
uptake of these vaccines has been good in developed countries with
an acceptance rate of over 70% in both Australia and the United
Kingdom [61,62]. In Belgium, vaccination coverage of 83.2% for the
third dose was observed [63]. Even in developing countries demonstration projects have been met with local enthusiasm and support
and it was found in Uganda that “. . .people in diverse contexts are
supportive of action to address cervical cancer, in spite of concerns
and obstacles that will need to be addressed” [64].
Rwanda became the first country in Africa to announce a
national prevention programme for cervical cancer that includes
HPV vaccination. The programme will aim to vaccinate girls aged
12–15 years and HPV testing for women between 35 and 45 years.
This programme has been made possible because of a 3-year donation of 2 million doses of the quadrivalent vaccine and 250,000
HPV screening tests. The vaccine company also agreed to provide
Rwanda with a discounted price after 3 years. The price is unknown
at present but Rwanda will probably require help from donors to
pay for the vaccine [65]. In South Africa GardasilTM and CervarixTM
are both available in the private sector and are currently being
considered for a national vaccination programme. A vaccination
programme in South Africa will almost certainly make a significant
difference in the cervical pre-cancer and cancer incidence in the
future. South Africa has a high rate of infant vaccination and the
principles of vaccination are well known to health care professionals and trusted by the general public. The benefit over the medium
to long term will likely be substantial in terms of cost of treatment
and diagnosis of pre-malignant and malignant cervical disease.
7.1. Ethical and cultural considerations
Children over the age of 12 who are of sufficient maturity and
have the mental capacity to understand the benefits, risks, social
and other implications are able to consent to medical treatment
(Children’s Act of South Africa No. 38 of 2005). No parent, guardian
or care-giver of a child may withhold consent by reason only of
religious or other beliefs, unless that parent or guardian can show
that there is a medically acceptable alternative. Consent for vaccination may lie ultimately with the young woman/girl but adequate
parental information and assent will strengthen a comprehensive cancer prevention programme. Demonstration projects are in
progress in South Africa to study a combined screening and vaccination policy for mothers and daughters.
In the US some religious and cultural groups expressed concern
about the availability of a vaccine against a sexually transmitted
C32
M.H. Botha, C. Dochez / Vaccine 30S (2012) C28–C34
infection as it could undermine abstinence-based prevention messages. Others counter that while committed fidelity is the most
effective way to combat cervical cancer, many people either do not
want to make such changes in their personal behaviour or, even if
they want to, find it impossible to do so in their personal circumstances. Some express concern for potential harm caused by HPV
vaccination, including adverse reactions, a hypothetical reduction
in safer sex practices, reduced preventive cervical screening, and a
misconception that HPV vaccine would protect against other STIs.
All of these factors need to be taken into account before population wide introduction of HPV vaccines in South Africa. Thorough
and culturally specific education programmes for providers and
the general population is of importance to prevent negative perceptions [66]. The situation in India is one example of a failure
in communication that led to the cancellation of a promising programme [67]. The results of a survey done in North Carolina showed
that only few parents believed that HPV vaccine would increase
sexual activity. Reassuringly, most parents did not believe that a
reduction of screening is safe in vaccinated women [68].
8. Introduction of a population based vaccination
programme
Internationally HPV vaccines are not marketed as low cost
items. In a health economics equation the cost of immunisation
must be weighed against the cost of screening and treatment for
cervical cancer with the understanding that the cost saving benefits of immunisation will only become apparent in one to two
decades. The principle of justice dictates that medical care should
be available to all who need it including economically disadvantaged communities.
A recent calculation of cost effectiveness of introducing HPV
vaccination performed in South Africa found that the price of the
vaccine (taken at $120 a dose for the purpose of the calculation) was
the main cost driver. A price reduction of 60% or more would make
vaccine-plus-screening more cost effective than the screening-only
option [69]. The current cost of a single dose of the bivalent vaccine in private retail pharmacies is around $70 and around $110 for
the quadrivalent vaccine. Cooperative buying and bargaining may
reduce vaccine cost and one example is the Pan American Health
Organization (PAHO) Revolving Fund. Members of PAHO can buy
the HPV vaccine at a reduced cost per dose of around $17 [65].
8.1. HIV infected
Studies on HPV immunisation in HIV infected individuals are
not readily available. The efficacy of HPV vaccination in immunecompromised individuals is largely unknown. It has been suggested
that natural immunity against HPV will be lost as immunity deteriorates and this may also be true for immunity acquired by
vaccination. HIV infected women are at more risk of rapid progression to cervical cancer when they acquire oncogenic HPV infections.
The Advisory Committee on Immunization Practices (ACIP) of the
Centers for Disease Control and Prevention states that the quadrivalent and bivalent vaccines “are not live vaccines, and can be
administered to females who are immunosuppressed (from disease
or medications). However, the immune response and vaccine efficacy might be less than that in immunocompetent persons” [70].
HIV testing prior to immunisation should be discouraged because
it may jeopardise uptake.
9. Programmatic issues for South Africa
Vaccination of older children/young adolescents is not common in developing countries. Pilot studies are necessary in advance
of a national immunisation programme. The studies should serve
as evidence for the South African government on how to introduce HPV vaccination into the preventive armaments of health
programmes.
Schools serve as trusted sources for education and could be used
for conveying carefully crafted health messages about HPV and
vaccination. School based immunisation programmes are the most
promising vehicle for a HPV vaccination programme. HPV vaccination could be offered in primary schools to girls attending grade
5 or 6. South Africa has a National School Health policy administered within the Department of Health. Sexuality and reproductive
health are already incorporated into the life orientation curriculum
in schools. The less than ideal service for youth health has been
identified as one of the key deliverables by the Minister of Health
in a recent budget speech.
The Expanded Programme on Immunisation (EPI) is well established in South Africa and could serve as a possible home for HPV
vaccination. At age 12 the HPV vaccine could be administered with
diphtheria/tetanus booster (dT) which is already in the EPI programme.
The cold chain remains a highly vulnerable and critical part of a
vaccination programme. The Department of Health has developed
a cold chain and immunisation operations manual based on the
WHO tool for assessing vaccine handling and management.
10. Conclusions
During the past 20 years tremendous insight into the oncogenic
process leading to invasive cervical carcinoma has been gained.
Major progress has also been made in the understanding of the
oncogenic potential of the HPV virus. At the end of 2002 the
first HPV16 VLP vaccine trial was published where prevention of
infection was proved [71]. In a population where childhood immunisation is already a way of life, even in rural South Africa, HPV
vaccination may be the best solution for a very serious problem.
It would be unethical not to advocate for HPV immunisation. At
the same time screening should continue and programmes for
the diagnosis and treatment of premalignant disease should be
strengthened.
There is generally good trust in the medical system and vaccination is a part of life in most rural and urban communities.
Schools and the education system are also generally regarded as
reputable and could be ideal partners in adolescent vaccination. At
present there are demonstration projects to evaluate the introduction of a school based adolescent vaccination programme. There are
discussions between professional advisory groups and the government about a national cervical cancer prevention strategy that will
include vaccination. Despite competing health priorities, of which
the management of the HIV epidemic and the control of tuberculosis are two of the most pressing, cervical cancer prevention is seen
as a high priority.
South Africa is often regarded as economically similar to the
BRIC countries (Brazil, Russia, India and China). Brazil registered
both HPV vaccines in 2009. In a joint publication by the International AIDS Vaccine Initiative and the Programme for Appropriate
Technology in Health (PATH) it was calculated that HPV vaccination
at a cost of $10 per girl will contribute 0.03% of public spending on
health [72]. There is no government funded programme in Brazil at
time of writing. In India, a large post-licensure observational study
was suspended by the government as a precaution after concerns
about safety was raised [67]. There are no indications of a national
vaccination policy in the near future. In the Russian Federation
both vaccines are registered but there is no national programme
[73]. In China the prophylactic HPV vaccines are not licensed yet
but phase III trials are in progress. A per-dose HPV vaccine cost
M.H. Botha, C. Dochez / Vaccine 30S (2012) C28–C34
of approximately less than $9–14 would be required for strategies
involving vaccination to be cost-effective [74]. If South Africa can
move forward rapidly with policy and financing for prophylactic
HPV vaccination it may become Primus inter pares.
It is clear that for a well-functioning cervical cancer control
programme, a good interaction between different disciplines and
services is required, including sexual and reproductive health,
adolescent health, immunisation and cancer control [75]. HPV
vaccination could be regarded as the nucleus for developing
and strengthening the adolescent immunisation programme and
overall adolescent health services. With a good functioning immunisation programme and school system being present in South
Africa, the major ingredients should be available to develop a comprehensive programme to combat cervical cancer.
Conflict of interest statement
None declared.
References
[1] World Bank. South Africa: Country Brief; 2010. http://go.worldbank.
org/GSBYF92330 [cited 2011 June].
[2] Castro-Leal F, Dayton J, Demery L, Mehra K. Public spending on health care
in Africa: do the poor benefit? Bulletin of the World Health Organization
2000;78(1):66–74.
[3] Bradshaw D, Pillay-Van Wyk V, Laubscher R, Nojilana B, Groenewald P, Nannan
N, et al. Cause of death statistics for South Africa: challenges and possibilities
for improvement. Medical Research Council of South Africa; 2010.
[4] Stanley M. Prevention strategies against the human papillomavirus: the effectiveness of vaccination. Gynecologic Oncology 2007;107(2 Suppl):S19–23.
[5] Kay P, Soeters R, Nevin J, Denny L, Dehaeck CM, Williamson AL. High prevalence of HPV 16 in South African women with cancer of the cervix and cervical
intraepithelial neoplasia. Journal of Medical Virology 2003;71(2):265–73.
[6] Centers for Disease Control and Prevention. What women with a positive HPV test result should know. http://www.cdc.gov/std/hpv/commonclinicians/InsertPos.pdf [cited 2009 March].
[7] Stanley M. Immunobiology of HPV and HPV vaccines. Gynecologic Oncology
2008;109(2 Suppl):S15–21.
[8] International Agency for Research on Cancer (IARC). GLOBOCAN.
Southern Africa: Fast Stats; 2008. http://globocan.iarc.fr/factsheets/
populations/factsheet.asp?uno=913 [cited 2011 June].
[9] Mqoqi N, Kellett P, Sitas F, Jula M. Incidence of histologically diagnosed cancer
in South Africa, 1998–1999. Johannesburg: National Cancer Registry of South
Africa, National Health Laboratory Service; 2004.
[10] Hendricks D, Parker MI. Oesophageal cancer in Africa. IUBMB Life
2002;53(4–5):263–8.
[11] WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Human papillomavirus and related cancers in world; 2010.
www.who.int/hpvcentre [cited 2011 November].
[12] Talip Q, Theron G, Steyn W, Hall D. Total perinatally related losses at Tygerberg
Hospital – a comparison between 1986: 1993 and 2006. South African Medical
Journal 2010;100(4):250–3.
[13] Noehr B, Jensen A, Frederiksen K, Tabor A, Kjaer SK. Loop electrosurgical excision of the cervix and subsequent risk for spontaneous preterm delivery: a
population-based study of singleton deliveries during a 9-year period. American Journal of Obstetrics and Gynecology 2009;201(1):33e1–6.
[14] Jakobsson M, Gissler M, Paavonen J, Tapper AM. Loop electrosurgical excision procedure and the risk for preterm birth. Obstetrics and Gynecology
2009;114(3):504–10.
[15] Kyrgiou M, Koliopoulos G, Martin-Hirsch P, Arbyn M, Prendiville W, Paraskevaidis E. Obstetric outcomes after conservative treatment for intraepithelial
or early invasive cervical lesions: systematic review and meta-analysis. Lancet
2006;367(9509):489–98.
[16] Seedat RY, Thukane M, Jansen AC, Rossouw I, Goedhals D, Burt FJ. HPV types
causing juvenile recurrent laryngeal papillomatosis in South Africa. International Journal of Pediatric Otorhinolaryngology 2010;74(3):255–9.
[17] South African Department of Health. Cervical cancer screening programme; 1999. http://www.doh.gov.za/docs/factsheets/guidelines/cancer.pdf
[cited 2011 November].
[18] South African Department of Health. Clinical guidelines for the
management of HIV & AIDS in adults and adolescents; 2010.
http://www.fidssa.co.za/Guidelines/2010 Adult ART Guidelines.pdf
[cited
2011 June].
[19] Bailie RS, Selvey CE, Bourne D, Bradshaw D. Trends in cervical cancer mortality
in South Africa. International Journal of Epidemiology 1996;25(3):488–93.
[20] Cronje HS. Screening for cervical cancer in the developing world. Best Practice
and Research Clinical Obstetrics and Gynaecology 2005;19(4):517–29.
[21] Denny LA, Wright Jr TC. Human papillomavirus testing and screening. Best
Practice and Research Clinical Obstetrics and Gynaecology 2005;19(4):501–15.
C33
[22] Vijayaraghavan A, Efrusy M, Lindeque G, Dreyer G, Santas C. Cost effectiveness of high-risk HPV DNA testing for cervical cancer screening in South Africa.
Gynecologic Oncology 2009;112(2):377–83.
[23] Clifford GM, Goncalves MA, Franceschi S. Human papillomavirus types among
women infected with HIV: a meta-analysis. AIDS 2006;20(18):2337–44.
[24] Moodley JR, Hoffman M, Carrara H, Allan BR, Cooper DD, Rosenberg L, et al.
HIV and pre-neoplastic and neoplastic lesions of the cervix in South Africa: a
case–control study. BMC Cancer 2006;6:135.
[25] Ellerbrock TV, Chiasson MA, Bush TJ, Sun XW, Sawo D, Brudney K, et al. Incidence of cervical squamous intraepithelial lesions in HIV-infected women.
JAMA 2000;283(8):1031–7.
[26] Averbach SH, Gravitt PE, Nowak RG, Celentano DD, Dunbar MS, Morrison CS,
et al. The association between cervical human papillomavirus infection and
HIV acquisition among women in Zimbabwe. AIDS 2010;24(7):1035–42.
[27] Veldhuijzen NJ, Vyankandondera J, van de Wijgert JH. HIV acquisition is associated with prior high-risk human papillomavirus infection among high-risk
women in Rwanda. AIDS 2010;24(14):2289–92.
[28] van der Loeff MF, Nyitray AG, Giuliano AR. HPV vaccination to prevent HIV
infection: time for randomized controlled trials. Sexually Transmitted Diseases
2011;38(7):640–3.
[29] Auvert B, Lissouba P, Cutler E, Zarca K, Puren A, Taljaard D. Association of oncogenic and nononcogenic human papillomavirus with HIV incidence. Journal of
Acquired Immune Deficiency Syndromes 2010;53(1):111–6.
[30] World Health Organization. Human papillomavirus vaccines. WHO position
paper. Weekly Epidemiological Record 2009;84(15):118–31.
[31] World Health Organization. The immunological basis for immunization series.
Module 19: human papillomavirus infection. WHO, Department of Immunization, Vaccines and Biologicals; 2011.
[32] Paavonen J, Jenkins D, Bosch FX, Naud P, Salmeron J, Wheeler CM, et al. Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against
infection with human papillomavirus types 16 and 18 in young women: an
interim analysis of a phase III double-blind, randomised controlled trial. Lancet
2007;369(9580):2161–70.
[33] Block SL, Nolan T, Sattler C, Barr E, Giacoletti KE, Marchant CD, et al. Comparison of the immunogenicity and reactogenicity of a prophylactic quadrivalent
human papillomavirus (types 6: 11, 16, and 18) L1 virus-like particle vaccine in male and female adolescents and young adult women. Pediatrics
2006;118(5):2135–45.
[34] Petaja T, Keranen H, Karppa T, Kawa A, Lantela S, Siitari-Mattila M, et al.
Immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04adjuvanted vaccine in healthy boys aged 10–18 years. Journal of Adolescent
Health 2009;44(1):33–40.
[35] Paavonen J, Naud P, Salmeron J, Wheeler CM, Chow SN, Apter D, et al. Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against
cervical infection and precancer caused by oncogenic HPV types (PATRICIA):
final analysis of a double-blind, randomised study in young women. Lancet
2009;374(9686):301–14.
[36] Paavonen J, on behalf of the HPV PATRICIA Study Group. Efficacy of HPV16/18
ASO4-adjuvanted vaccine against abnormal cytology, colposcopy referrals and
cervical procedures. Eurogin 2010;abstract SS 4-1:107.
[37] Lehtinen M, Paavonen J, Wheeler CM, Jaisamrarn U, Garland SM, Castellsague X,
et al. Overall efficacy of HPV-16/18 AS04-adjuvanted vaccine against grade 3 or
greater cervical intraepithelial neoplasia: 4-year end-of-study analysis of the
randomised, double-blind PATRICIA trial. Lancet Oncology 2012;13(1):89–99.
[38] De Carvalho N, Teixeira J, Roteli-Martins CM, Naud P, De Borba P, Zahaf T, et al.
Sustained efficacy and immunogenicity of the HPV-16/18 AS04-adjuvanted
vaccine up to 7.3 years in young adult women. Vaccine 2010;28(38):6247–55.
[39] Dillner J, Kjaer SK, Wheeler CM, Sigurdsson K, Iversen OE, Hernandez-Avila
M, et al. Four year efficacy of prophylactic human papillomavirus quadrivalent
vaccine against low grade cervical, vulvar, and vaginal intraepithelial neoplasia
and anogenital warts: randomised controlled trial. BMJ 2010;341:c3493.
[40] Steben M. Update on Gardasil (quadrivalent human papillomavirus 6/11/16/18
vaccine) clinical trial efficacy results. Eurogin 2010;abstract SS 3–5:106.
[41] Ault KA. Effect of prophylactic human papillomavirus L1 virus-like-particle
vaccine on risk of cervical intraepithelial neoplasia grade 2, grade 3, and adenocarcinoma in situ: a combined analysis of four randomised clinical trials. Lancet
2007;369(9576):1861–8.
[42] Castellsague X, Munoz N, Pitisuttithum P, Ferris D, Monsonego J, Ault K, et al.
End-of-study safety: immunogenicity, and efficacy of quadrivalent HPV (types
6, 11, 16, 18) recombinant vaccine in adult women 24–45 years of age. British
Journal of Cancer 2011;105(1):28–37.
[43] Giuliano AR, Palefsky JM, Goldstone S, Moreira Jr ED, Penny ME, Aranda C, et al.
Efficacy of quadrivalent HPV vaccine against HPV Infection and disease in males.
New England Journal of Medicine 2011;364(5):401–11.
[44] Moscicki AB, Weinberg A, Song LY. Safety and immunogenicity of Gardasil in
HIV infected Children. In: Programmes and abstracts of the 25th international
papillomavirus conference and clinical workshop. 2009, abstract O-16.02.
[45] Safety and Immunogenicity of GlaxoSmithKline Biologicals’ HPV
Vaccine 580299 (Cervarix TM) in HIV Infected Females; 2011.
http://clinicaltrials.gov/ct2/show/NCT00586339 [cited 2011 August].
[46] Pedersen C, Petaja T, Strauss G, Rumke HC, Poder A, Richardus JH, et al. Immunization of early adolescent females with human papillomavirus type 16 and 18
L1 virus-like particle vaccine containing AS04 adjuvant. Journal of Adolescent
Health 2007;40(6):564–71.
[47] Schwarz TF, Spaczynski M, Schneider A, Wysocki J, Galaj A, Perona P,
et al. Immunogenicity and tolerability of an HPV-16/18 AS04-adjuvanted
C34
[48]
[49]
[50]
[51]
[52]
[53]
[54]
[55]
[56]
[57]
[58]
[59]
M.H. Botha, C. Dochez / Vaccine 30S (2012) C28–C34
prophylactic cervical cancer vaccine in women aged 15–55 years. Vaccine
2009;27(4):581–7.
Harper DM, Williams KB. Prophylactic HPV vaccines: current knowledge of impact on gynecologic premalignancies. Discovery Medicine
2010;10(50):7–17.
Olsson SE, Villa LL, Costa RL, Petta CA, Andrade RP, Malm C, et al. Induction
of immune memory following administration of a prophylactic quadrivalent
human papillomavirus (HPV) types 6/11/16/18 L1 virus-like particle (VLP) vaccine. Vaccine 2007;25(26):4931–9.
McKeage K, Romanowski B. AS04-adjuvanted human papillomavirus (HPV)
types 16 and 18 vaccine (Cervarix(R)): a review of its use in the prevention
of premalignant cervical lesions and cervical cancer causally related to certain
oncogenic HPV types. Drugs 2011;71(4):465–88.
Einstein MH, Baron M, Levin MJ, Chatterjee A, Edwards RP, Zepp F, et al. Comparison of the immunogenicity and safety of Cervarix and Gardasil human
papillomavirus (HPV) cervical cancer vaccines in healthy women aged 18–45
years. Human Vaccines 2009;5(10):705–19.
Giannini SL, Hanon E, Moris P, Van Mechelen M, Morel S, Dessy F, et al. Enhanced
humoral and memory B cellular immunity using HPV16/18 L1 VLP vaccine
formulated with the MPL/aluminium salt combination (AS04) compared to
aluminium salt only. Vaccine 2006;24(33–34):5937–49.
Kemp TJ, Hildesheim A, Safaeian M, Dauner JG, Pan Y, Porras C, et al. HPV16/18
L1 VLP vaccine induces cross-neutralizing antibodies that may mediate crossprotection. Vaccine 2011;29(11):2011–4.
Wheeler CM, Castellsague X, Garland SM, Szarewski A, Paavonen J, Naud P,
et al. Cross-protective efficacy of HPV-16/18 AS04-adjuvanted vaccine against
cervical infection and precancer caused by non-vaccine oncogenic HPV types:
4-year end-of-study analysis of the randomised, double-blind PATRICIA trial.
Lancet Oncology 2012;13(1):100–10.
Herrero R. Human papillomavirus (HPV) vaccines: limited crossprotection against additional HPV types. Journal of Infectious Diseases
2009;199(7):919–22.
Brown DR, Kjaer SK, Sigurdsson K, Iversen OE, Hernandez-Avila M, Wheeler
CM, et al. The impact of quadrivalent human papillomavirus (HPV; types 6:
11, 16, and 18) L1 virus-like particle vaccine on infection and disease due to
oncogenic nonvaccine HPV types in generally HPV-naive women aged 16–26
years. Journal of Infectious Diseases 2009;199(7):926–35.
Jit M, Choi YH, Edmunds WJ. Economic evaluation of human papillomavirus
vaccination in the United Kingdom. BMJ 2008;337:a769.
Dochez C, van der Veen F, Meheus A. HPV vaccines and prevention of cervical cancer. Belgian Journal of Medical Oncology 2009;3(6):
275–81.
Simoens C, Sabbe M, Van Damme P, Beutels P, Arbyn M. Introduction of human
papillomavirus (HPV) vaccination in Belgium, 2007–2008. Eurosurveillance
2009;14(46).
[60] Bogaards JA, Kretzschmar M, Xiridou M, Meijer CJ, Berkhof J, Wallinga
J. Sex-specific immunization for sexually transmitted infections such as
human papillomavirus: insights from mathematical models. PLoS Medicine
2011;8(12):e1001147.
[61] Australian National HPV Vaccination Program. Information about the National
Human Papillomavirus (HPV) Vaccination Program funded under the Immunise Australia Program; 2011. http://www.health.gov.au/internet/immunise/
publishing.nsf/Content/immunise-hpv#figure1 [cited 2011 July].
[62] Department of Health. Annual HPV vaccine coverage in England
in
2009/2010;
2011.
http://www.dh.gov.uk/prod consum dh/groups/
dh digitalassets/documents/digitalasset/dh 123826.pdf [cited 2011 July].
[63] Vlaams Agentschap Zorg en Gezondheid; 2011. http://www.zorg-engezondheid.be/HPV/ [cited 2011 August].
[64] PATH and Child Health and Development Centre (CHDC). Shaping a strategy to
introduce HPV vaccines in Uganda: formative research results from the HPV
vaccines: evidence for impact project. Seattle: PATH; 2009.
[65] Editorial Financing HPV vaccination in developing countries. Lancet
2011;377(9777):1544.
[66] Harries J, Moodley J, Barone MA, Mall S, Sinanovic E. Preparing for HPV vaccination in South Africa: key challenges and opinions. Vaccine 2009;27(1):38–44.
[67] Feinberg M. HPV vaccine suspension in India. Lancet 2010;376(9753):1644–5.
[68] Schuler CL, Reiter PL, Smith JS, Brewer NT. Human papillomavirus vaccine and
behavioural disinhibition. Sexually Transmitted Infections 2011;87(4):349–53.
[69] Sinanovic E, Moodley J, Barone MA, Mall S, Cleary S, Harries J. The potential
cost-effectiveness of adding a human papillomavirus vaccine to the cervical
cancer screening programme in South Africa. Vaccine 2009;27(44):6196–202.
[70] Centers for Disease Control and Prevention. FDA licensure of bivalent human
papillomavirus vaccine (HPV2, Cervarix) for use in females and updated
HPV vaccination recommendations from the Advisory Committee on Immunization Practices (ACIP). Morbidity and Mortality Weekly Report (MMWR)
2010;59(20):626–9.
[71] Koutsky LA, Ault KA, Wheeler CM, Brown DR, Barr E, Alvarez FB, et al. A controlled trial of a human papillomavirus type 16 vaccine. New England Journal
of Medicine 2002;347(21):1645–51.
[72] International AIDS Vaccine Initiative and PATH. HPV Vaccine Adoption in Developing Countries: Cost and Financing Issues; 2007. http://
www.rho.org/files/IAVI PATH HPV financing.pdf [cited 2011 December].
[73] WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information
Centre). Human Papillomavirus and Related Cancers in Russian Federation.
Summary Report 2010. http://www.who.int/hpvcentre [cited 2011 December].
[74] Canfell K, Shi JF, Lew JB, Walker R, Zhao FH, Simonella L, et al. Prevention of
cervical cancer in rural China: evaluation of HPV vaccination and primary HPV
screening strategies. Vaccine 2011;29(13):2487–94.
[75] World Health Organization. Preparing for the introduction of HPV vaccines:
policy and programme guidance for countries. WHO; 2006.
Vaccine 30S (2012) C35–C37
Contents lists available at SciVerse ScienceDirect
Vaccine
journal homepage: www.elsevier.com/locate/vaccine
Review
Introduction of inactivated polio vaccine (IPV) into the routine immunization
schedule of South Africa
Barry D. Schoub a,b,∗
a
b
National Institute for Communicable Diseases/National Health Laboratory Service, Private Bag X4, Sandringham 2131, South Africa
University of the Witwatersrand, Johannesburg, South Africa
a r t i c l e
i n f o
Article history:
Received 11 October 2011
Received in revised form 7 December 2011
Accepted 21 February 2012
Keywords:
Inactivated polio vaccine
Oral polio vaccine
Mucosal immunity
Herd immunity
Vaccine associated paralytic polio
Pentavalent vaccine
Endgame planning
a b s t r a c t
South Africa is currently the only country on the African continent using inactivated polio vaccine (IPV)
for routine immunization in a sequential schedule in combination with oral polio vaccine (OPV). IPV is a
component of an injectable pentavalent vaccine introduced nationwide in April 2009 and administered
according to EPI schedule at 6, 10 and 14 weeks with a booster dose at 18 months. OPV is administered
at birth and together with the first IPV dose at 6 weeks, which stimulates gut immune system producing
a memory IgA response (OPV), followed by IPV to minimize the risk of vaccine associated paralytic polio
(VAPP). OPV is also given to all children under 5 years of age as part of regular mass immunizations
campaigns. The decision to incorporate IPV into the routine schedule was not based on cost-effectiveness,
which it is not. Other factors were taken into account: Firstly, the sequence benefits from the initial
mucosal contact with live(vaccine) virus which promotes the IgA response from subsequent IPV, as well as
herd immunity from OPV, together with the safety of IPV. Secondly, given the widespread and increasing
use of IPV in the developed world, public acceptance of vaccination in general is enhanced in South Africa
which is classified as an upper middle income developing country. Thirdly, to address equity concerns
because of the growing use of IPV in the private sector. Fourthly, the advent of combination vaccines
facilitated the incorporation of IPV into the EPI schedule.
© 2012 Elsevier Ltd. All rights reserved.
In April 2009, South Africa introduced three new vaccines into
its universal immunization schedule, pneumococcal conjugate vaccine, rotavirus vaccine and a pentavalent vaccine consisting of
diphtheria, acellular pertussis, tetanus, Haemophilus influenzae
type b and inactivated polio vaccine (IPV). The schedule for the pentavalent vaccine follows the WHO EPI recommended intervals of 6,
10 and 14 weeks, with an additional booster dose at 18 months
of age. Presently South Africa is the only country on the African
continent which has introduced IPV into its routine EPI schedule.
The last laboratory documented case of wild-type poliomyelitis in South Africa was detected in 1989 [1] and this followed a
major outbreak of type 1 poliomyelitis in the eastern province of
KwaZulu-Natal the previous year [2]. More recently, however, cases
of polio have occurred in countries bordering South Africa and an
imported case of polio type 1 was diagnosed in Botswana in 1994
[3] and an outbreak of polio type 1 occurred in Namibia in 1996
[4]. Over the past 3 years some 20 countries on the continent have
seen outbreaks of polio imported from Nigeria or India [5] and 4
∗ Correspondence address: National Institute for Communicable Diseases/National Health Laboratory Service, Private Bag X4, Sandringham 2131,
South Africa. Tel.: +27 11 3866401.
E-mail address: [email protected]
0264-410X/$ – see front matter © 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.vaccine.2012.02.056
African countries, Angola, Chad, Democratic Republic of the Congo
and Sudan have re-established polio (i.e. circulation of the virus has
persisted beyond 12 months) [6]. The risk of importation of polio
into South Africa, given the extensive population movement from
countries throughout the continent into South Africa as refugees or
as work seekers is at least moderate if not high. WHO policy recommendations published in its 2010 position paper on polio vaccines,
expressed a firm view discouraging an all-OPV strategy [7]. Similarly a WHO African regional meeting in 2008 recommended not to
introduce IPV in the region [8]. The decision to introduce IPV into
the routine schedule of South Africa was thus taken against this
backdrop and this paper examines the factors taken into consideration when the policy switch was made in 2008.
1. Increasing global use of IPV
Although universal immunization with oral polio vaccine (OPV)
has been responsible for the elimination of polio in a major portion
of the world, an increasing number of polio-free developed countries have now replaced OPV with IPV in their routine immunization
schedules, primarily because of the risk of vaccine-associated paralytic polio (VAPP). Thus in 3 WHO regions, which have been certified
as polio-free, 69 of the 124 (56%) countries use IPV alone for routine immunization [9]. Of the remaining 3 WHO regions, 9 countries
C36
B.D. Schoub / Vaccine 30S (2012) C35–C37
(8 in the Eastern Mediterranean region and South Africa) use a combined IPV/OPV schedule. All the remaining countries of the world
still rely on OPV alone. The major reason for the increasing use of IPV
worldwide is due to IPV being one of the safest of all vaccines including the elimination of the risk of VAPP. It has been very effective in
eliminating polio from many developed countries with excellent
public health facilities able to achieve and sustain high levels of
immunization coverage. In the developing world, however, experience with IPV has been far more limited, chiefly because of cost.
Studies in Senegal, West Africa, have demonstrated an 89% clinical
efficacy in preventing paralytic poliomyelitis after 2 doses [10] and
in Cuba IPV immunization achieved a seroconversion rate of 90%
[11]. However seroconversion was seen to be significantly lower
in Cuba and in studies from Gambia, Oman and in Thailand, when
vaccine was administered at the WHO recommended EPI immunization intervals of 6, 10 and 14 weeks than at 2, 4 and 6 months
which is generally used in the developed world [11,12]. This was
probably due to the influence of passively acquired maternal antibody and perhaps also to the shorter interval between doses in the
EPI schedule.
2. IPV and OPV combinations
The first country to introduce the combination of IPV and OPV
was Denmark in 1968 [13]. The rationale behind the combined
schedules is to benefit from the excellent gut mucosal immunity
and therefore effective herd immunity provided by OPV while, at
the same time, minimizing the risk of VAPP and ensuring good
humoral immunity, and thus personal protection, through the use
of IPV. Different combinations of IPV and OPV have been evaluated
in clinical trials and have been implemented in different countries.
Essentially there have been 3 approaches. Firstly, sequential schedules where IPV is given first to protect against the risk of VAPP
followed by OPV to provide good gut mucosal and herd immunity. The superiority of this schedule for type 1 and 3 responses
has been evaluated in a number of developing countries such as
Gambia, Oman and Thailand [12] and it is now used in most countries which employ a combined schedule. A second combination
schedule reverses this sequence. Here OPV is given first and is then
followed by IPV. This combination schedule has been adapted in
South Africa where two doses of OPV are given at birth followed by
a second dose at 6 weeks together with the first of the IPV doses in
the pentavalent vaccine. Subsequent doses of pentavalent including
IPV are then administered at 10 and 14 weeks with a booster at 18
months. Further OPV supplementation takes place through mass
immunization programmes which are carried out at intervals of
approximately every 3 years and involve all children under 5-year
of age. The scientific rationale for administering OPV as the initial
dose is based on the finding that IPV immunization is significantly
more effective if preceded by contact of the gut mucosal immune
system with a live virus infection (such as OPV) and production of
IgA [14]. The relatively poor ability of IPV alone to effect a significant
gut immune response is greatly enhanced by preceding gut contact
with live polio vaccine resulting in the production of a strong memory IgA response. The risk of VAPP from the administration of OPV
at birth is extremely low due to the protective effect of maternal
antibodies and paralysis due to wild-type polio or vaccine-derived
polio has not been reported in infants less than 3 months of age. In
addition a neonatal dose is less likely to be affected by interference
from endogenous intestinal viral flora. A similar schedule has been
practised in the West Bank and Gaza (Palestinian authority) since
1978 [15]. In 1988 following an outbreak on polio in Hadera, Israel,
in a community which was reliant on IPV alone, the immunization policy was changed to a sequential schedule of IPV followed
by both IPV and OPV [16] and effective intestinal immunity was
demonstrated [17]. Since 1988 this combination schedule has succeeded in eliminating polio in the West Bank, Gaza and Israel.
A third combination is the simultaneous administration of OPV
and IPV, and this has been evaluated in Pakistan where it was
similarly demonstrated that simultaneous administration of IPV,
together with OPV in the EPI schedule produced a significantly better immune response compared to OPV alone in the routine EPI
schedule [12,18].
3. Cost-effectiveness of IPV
One of the major barriers to the introduction of IPV into the
immunization schedule of developing countries has been cost –
IPV being several-fold more expensive per dose than OPV, although
countries which have switched to IPV regimens have not been influenced by vaccine cost implications. Cost effectiveness studies have
only been published from 3 countries, USA, Australia and South
Africa [19]. Replacement of OPV with IPV has been calculated to
carry an additional cost of between US$740,000 and US$7.2 million
per VAPP case averted. The cost-effectiveness calculated as per discounted DALY averted varied between US$61,000 and US$594,000.
In all 3 countries it was clear that a switch from OPV to IPV was not
cost-effective. The risk of VAPP in South Africa is unclear. While one
would expect between 1 and 2 VAPP cases per year (from a birth
cohort of 1.08million [20]) only one proven case of VAPP has been
confirmed in South Africa [19], despite satisfactory AFP surveillance which was instituted in 1995 [21]. This may well be due to
inadequate follow-up or VAPP may genuinely be less common in
developing countries as has been reported from India [22].
4. Post-eradication endgame planning
A world free of polio can only be achieved with the cessation
of the use of OPV because of the risk of VAPP, circulating vaccinederived poliovirus, cVDPV and, immunodeficient vaccine-derived
poliovirus, iVDPV. Because of cost it is probable that most developing countries will simply cease vaccination once the world has
been declared to be polio-free. However, because of the potential
risks of re-introduction of polio, as small as they may be, either from
accidental or deliberate release, many developed countries will not
cease immunization in the post-eradication era.
5. Conclusion
South Africa has been classified by the World Bank as an upper
middle income developing country [23] and is one of the wealthiest
and most developed countries on the continent. Nevertheless South
Africa resisted introducing IPV into its routine immunization schedule for several years because of the risk of importation from other
African countries, especially given the extent of population migrations. The resistance to change from an all-OPV vaccination policy,
supplemented with regular mass immunization campaigns, was
due to the need to ensure reliable and sustained intestinal immunity and herd protection. Nevertheless, for a number of cogent
reasons the country’s Department of Health was advised to introduce IPV in a sequential schedule into the routine vaccination
programme. It was first introduced as a component of a pentavalent vaccine in September 2008 to a limited extent in the Eastern
Cape Province and countrywide in April 2009.
These reasons include the following:
(i) Firstly, a neonatal dose of OPV (when the risk of VAPP is
very low, if not unknown) and a second OPV dose at 6 weeks
would stimulate the gut immune system to generate a solid
intestinal IgA response and immunological memory when IPV
B.D. Schoub / Vaccine 30S (2012) C35–C37
is subsequently given at the EPI intervals. In addition, mass
immunization with OPV provides supplementary immunological contact with OPV.
(ii) Secondly, introduction of IPV contributes significantly to building public confidence in the vaccination programmes given the
widespread use of IPV in the developed world.
(iii) The increasing use of IPV in the private sector created an equity
discord with the public sector which could have further damaged confidence in the vaccination programme.
(iv) The advent of combination vaccines incorporating IPV simplified multi-antigen administration and also facilitates the
introduction of other needed new vaccines, such as acellular
pertussis.
Conflict of interest statement: None declared.
References
[1] Schoub BD, Chezzi C, Blackburn NK. Last virologically confirmed cases
of wild-type poliomyelitis in South Africa. S Afr Med J 1995;85(1):
55.
[2] Van Middelkoop A, van Wyk JE, Küstner HGV, Windsor I, Vinsen C, Schoub
BD, et al. Poliomyelitis outbreak in Natal/KwaZulu, South Africa, 1987–1988. I.
Epidemiology. Trans R Soc Trop Med Hyg 1992;86:83–5.
[3] World Health Organization. Polio reported in Botswana. http://www.who.int/
mediacentre/news/notes/2004/np11/en/ (last access 23/03/2011).
[4] Van Niekerk ABW, Vries JB, Baard J, Schoub BD, Blackburn NK. Outbreak of
paralytic poliomyelitis in Namibia. Lancet 1994;344:661–4.
[5] Centers for Disease Control and Prevention (CDC). Outbreaks following wild
poliovirus importations – Europe, Africa, and Asia, January 2009–September
2010. MMWR Morb Mortal Wkly Rep 2010;59(November (43)):
1393–9.
[6] Centers for Disease Control and Prevention (CDC). Progress toward interrupting wild poliovirus circulation in countries with reestablished transmission
– Africa, 2009–2010. MMWR Morb Mortal Wkly Rep 2011;60(March
(10)):306–11.
[7] World Health Organization. Polio vaccines and polio immunization in the
pre-eradication era: WHO position paper. Wkly Epidemiol Rec 2010;85(June
(23)):213–28.
[8] 2nd Meeting of the Working Group on Pre- and Post-Polio Eradication Issues,
Brazzaville, Congo – 13 and 14 August 2008, WHO African Regional Office,
Brazzaville.
C37
[9] Second Meeting of the SAGE Working Group on IPV. 3 and 4 June
2009. Geneva: WHO. http://www.who.int/immunization/sage/3 IPV WG
NFR 2nd Mtg June 09version Oct8.pdf.
[10] Robertson SE, Traverso HP, Drucker JA, Rovira EZ, Fabre-Teste B, Sow A, et al.
Clinical efficacy of a new, enhanced-potency, inactivated poliovirus vaccine.
Lancet 1988;1(April (8591)):897–9.
[11] Cuba IPV Study Collaborative Group. Randomized, placebo-controlled trial
of inactivated poliovirus vaccine in Cuba. N Engl J Med 2007;356(April
(15)):1536–44.
[12] World Health Organization. Combined immunization of infants with oral and
inactivated poliovirus vaccines: results of a randomized trial in The Gambia,
Oman, and Thailand. WHO Collaborative Study Group on Oral and Inactivated
Poliovirus Vaccines. Bull World Health Organ 1996;74(3):253–68.
[13] von Magnus H, Petersen I. Vaccination with inactivated poliovirus vaccine and
oral poliovirus vaccine in Denmark. Rev Infect Dis 1984;6(May–June (Suppl.
2)):S471–4.
[14] Herremans TM, Reimerink JH, Buisman AM, Kimman TG, Koopmans MP.
Induction of mucosal immunity by inactivated poliovirus vaccine is dependent on previous mucosal contact with live virus. J Immunol 1999;162(April
(8)):5011–8.
[15] Tulchinsky T, Abed Y, Shaheen S, Toubassi N, Sever Y, Schoenbaum M, et al.
A ten-year experience in control of poliomyelitis through a combination
of live and killed vaccines in two developing areas. Am J Public Health
1989;79(December (12)):1648–52.
[16] Goldblum N, Gerichter CB, Tulchinsky TH, Melnick JL. Poliomyelitis control
in Israel, the West Bank and Gaza Strip: changing strategies with the goal of
eradication in an endemic area. Bull World Health Organ 1994;72(5):783–96.
[17] Swartz TA, Green MS, Handscher R, Sofer D, Cohen-Dar M, Shohat T, et al. Intestinal immunity following a combined enhanced inactivated polio vaccine/oral
polio vaccine programme in Israel. Vaccine 2008;26(February (8)):1083–90
[Epub 2008 January 7].
[18] Parent du Châtelet I, Merchant AT, Fisher-Hoch S, Luby SP, Plotkin SA, Moatter T, et al. Serological response and poliovirus excretion following different
combined oral and inactivated poliovirus vaccines immunization schedules.
Vaccine 2003;21(April (15)):1710–8.
[19] Griffiths UK, Botham L, Schoub BD. The cost-effectiveness of alternative polio
immunization policies in South Africa. Vaccine 2006;24(July (29–30)):5670–8.
[20] World Health Organization. WHO vaccine-preventable diseases: monitoring system 2010 global summary. http://apps.who.int/immunization
monitoring/en/globalsummary/countryprofileresults.
[21] World Health Organization. Progress towards eradicating poliomyelitis in
India, January 2009–October 2010. Wkly Epidemiol Rec 2010;85(December
(50)):497–503.
[22] Kohler KA, Banerjee K, Gary Hlady W, Andrus JK, Sutter RW. Vaccine-associated
paralytic poliomyelitis in India during 1999: decreased risk despite massive use
of oral polio vaccine. Bull World Health Organ 2002;80(3):210–6.
[23] The World Bank. http://data.worldbank.org/country/southafrica.
Vaccine 30S (2012) C38–C44
Contents lists available at SciVerse ScienceDirect
Vaccine
journal homepage: www.elsevier.com/locate/vaccine
Review
Combination vaccines in the South African setting
Adele Visser a,∗ , Anwar Hoosen b
a
b
Division of Clinical Pathology, Department of Medical Microbiology, University of Pretoria, National Health Laboratory Service, Tshwane Academic Division, South Africa
Department of Medical Microbiology, University of Pretoria, National Health Laboratory Services, Tshwane Academic Division, South Africa
a r t i c l e
i n f o
Article history:
Received 7 November 2011
Received in revised form 29 April 2012
Accepted 1 May 2012
Keywords:
Combination vaccines
Expanded programme for immunisation
Component vaccines
Vaccine safety
Inter-changeability of vaccines
a b s t r a c t
The number of vaccines available and included as part of the national immunization schedules, has
increased significantly over the past few decades. This impacts on patient/parent compliance and creates a challenge for health care providers for implementation of schedules necessitating training and
infrastructure improvements. Use of combination rather than component vaccines offers advantages for
compliance by single dose administration of various antigens, reducing stock costing as well as reducing cost of additional health care visits. Combination vaccines are often significantly more expensive
than individual constituent vaccines. Concerns regarding an increased incidence of adverse events with
use of combination vaccines have not been confirmed and rates may seem high as the adverse events
seem to mimic the sum total of adverse event rates for each individual antigen used but may in fact
be lower. Manufacturers typically advise against interchanging use of vaccine products. Despite this,
health authorities advocate use of an alternative vaccine where the original vaccine in not available, to
ensure continuity of vaccination. A notable exception is the acellular pertussis vaccine. Partly, because
no serological correlates of immunity exist, but also a general lack of convincing follow up studies has
prompted the recommendation for manufacturer fidelity for at least the first 3 vaccine doses. According
to the South African Medicines Formulary, a variety of vaccines are available in South Africa. Although
a large number are available in the private sector, the only true combination vaccine included in the
current state EPI, modified in 2009, is the DTaP-IPV/Hib vaccine (Diphtheria, Tetanus, acellular Pertussis,
inactivated Poliomyelitis virus and Haemophilus influenzae type b). There are many reasons justifying the
use of combination vaccines rather that the individual constituent formulations. Implementation of use
in the South African setting at this point is still limited, but may offer an exciting avenue of expanding
the antigen repertoire without impacting on side-effects, efficacy or complexity of scheduling.
© 2012 Elsevier Ltd. All rights reserved.
1. Introduction
The number of vaccines available and included as part of the
national immunization schedule, has drastically increased over the
past few decades [1,2]. This not only impacts on patient/parent
compliance, but also on the complexity of schedules, making
implementation progressively more difficult [3]. Since the first
combination vaccines became available in the 1940s in the form of
DTP [4], there has been a drive to increasing the amount of antigens
captured within single administration doses, with preservation of
vaccine efficacy [5]. Initial efforts included reconstitution of various component just prior to administration [6,7], dual-chambered
syringes which is mixed just prior to administration [8] to present
day true combination vaccines with individual components merged
at time of production [9].
∗ Corresponding author.
E-mail addresses: [email protected], [email protected] (A. Visser),
[email protected] (A. Hoosen).
0264-410X/$ – see front matter © 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.vaccine.2012.05.001
Development has been subject to many teething problems.
Chemical incompatibility was the first major obstacle noted with
use of thimerosal as preservative in whole cell and some acellular pertussis vaccines, detrimentally impacting on the immune
response to IPV. Although current Hib vaccines have not been subject to carrier-induced epitope suppression, this was a significant
problem in previous formulations. The issue of carrier-induced epitope suppression is specifically noted in certain bacterial pathogens
with multiple serotypes causing disease. This requires inclusion
of a multitude of conjugates into the vaccine, leading to a diminished immune response, particularly upon booster doses [10].
Furthermore, antigenic competition in formulations containing
more than one related live virus (notably OPV and MMR) required
adjustment of titres to ensure adequate response to all strains
[11].
Use of combination vaccines is advocated by the American Advisory Committee on Immunization Practices (ACIP) rather than component vaccines as they offer the possibility of reducing issues surrounding compliance by single dose administration of various antigens [5]. Furthermore, it has the potential advantage of reducing
A. Visser, A. Hoosen / Vaccine 30S (2012) C38–C44
stock costing (syringes, disposables and disposal), reducing cost
of additional health care visits and facilitates the introduction of
novel vaccines into the vaccination schedule [5]. The indirect costs
of deferral or delay of vaccination and storage cost are often not
even included in cost–benefit analyses but well worth considering. These advantages are balanced against certain theoretical
disadvantages. Most notably, conflicts in dosing schedules may
paradoxically confuse current scheduling [5]. Any alteration of
convention in vaccination timing, may have far-reaching effects
to the detriment of vaccination. However, some authors feel that
it will inevitably lead to marked simplification of schedules and
consequently improved compliance [12]. In addition, chemical
incompatibility and immunological interference is a theoretical risk
which should be studied and overcome prior to implementation of
use [13–15] in the pre-licensing phase.
2. Implementation considerations
2.1. Compliance and vaccination timeliness
There is no doubt that the availability of vaccines has significantly reduced morbidity and mortality within most communities
[1,2]. This has been shown to be a shared sentiment amongst most
parents; however, concern is often raised regarding adverse events
associated with the high vaccine load administered in one injection
[16]. It has been suggested that the process of reducing the amount
of injections, while maintaining the amount of antigens administered will improve patient and parent compliance significantly
[3,17]. Meyerhoff and Jocobs showed that up to 26% of patients
deferred one vaccine dose when 3 or less injections were indicated,
with the deferral rate increasing to 48% when the doses increased
to 5 injections [18].
The most frequently cited reasons for vaccination deferral
include the number of injections, complexity of the dosing schedule
and pain or discomfort experienced [19]. Therefore, use of combination vaccines has shown to improve on timeliness of vaccination
(decreasing deferrals), and therefore coverage rates per age [20,21].
From the health care provider’s perspective, combination vaccines are also well received, citing increased staff efficiency, ease of
record keeping and improved relations with parents and patients,
and therefore compliance as significant advantages to this practice [3]. From a health and safety perspective, handling of fewer
sharps also reduces the risk of occupational exposures by staff and
personnel [22].
2.2. Financial implications
Vaccines are considered the most cost effective tool for prevention of infectious disease [23]. Therefore, the true issue surrounding
vaccination is not whether or not to implement immunization,
but rather acquisition of the most cost-effective formulations.
Combination vaccines are often more expensive than individual
constituent vaccines [20]. In fact, pricing has evoked multiple
studies leading to pricing algorithms to ensure preferential implementation in vaccination schedules [24]. At present, vaccines
other than the 6 original Expanded Programme on Immunization
(EPI) formulations as stipulated by the World Health Organization
(WHO), are distributed at much higher prices as compared to the
EPI vaccines [25]. In light of all these controversies, bulk procurement by Governments, with or without external financial aid by
organizations like Global Alliance for Vaccines and Immunization
(GAVI), may negate the issues surrounding cost of these vaccines
[1]. South Africa is not included amongst the 75 countries receiving support from GAVI [1,26] as the annual per capita gross national
income is more than $1000 [27].
C39
Some US based studies place some emphasis on the impact
of fewer injections translating in lower administrative costs. This
leads to lower charges to the patient but consequently lower
income to the clinician [20]. South Africa shows some similarity
in that a clear delineation exists between public and private health
care, with full vaccination cost being R1 275 [28] and R4 396 (whole
sale) respectively. The financial impact of combination vaccines in
the South African setting has not been studied.
Despite the enormous success that has been attained by global
use of vaccines [29–31], more than 80 million cases of vaccine
preventable disease and 1.5 million deaths are reported annually,
worldwide [31]. This is by and large due to inadequate delivery and
lack of infrastructure and communication within the developing
world [31]. Despite this, marked improvement in vaccine coverage has already been attained – in 1974 less than 5% of children
worldwide had access to the 6 major vaccines targeting poliomyelitis, tuberculosis, pertussis, measles, tetanus and whooping cough
[32]. Since initiation of the World Health Organization’s (WHO)
Expanded Programme on Immunization (EPI) in 1974 [33], DTP3
rates have increased to 81% by 2006 [24], preventing an estimated
3 million deaths annually [2]. Combination vaccines offer an additional avenue to facilitate global distribution of multiple antigens
simultaneously [30], also improving administration safety and relative reduction in biohazardous waste [34].
2.3. Safety and adverse events
Concerns regarding an increased incidence of adverse events
with use of combination vaccines have to date not been confirmed.
These rates may seem higher as the adverse events seem to mimic
the sum total of adverse event rates for each individual antigen
used [35–37] but may even have lower rates [11]. However, the
reduction in amount of vaccine preparations will lead to decrease
in cumulative exposure to stabilizers and preservatives contained
in vaccines [35,38], a benefit well worth considering.
Questions surrounding immune system overload by exposure
to multiple antigens arose both due to the observation of carrierassociated immunosuppression [15] as well as occasional transient
delayed-type hypersensitivity reactions to certain antigens in the
MMR vaccine [39,40]. This requires inclusion of a multitude of conjugates into the vaccine, leading to a diminished immune response,
particularly upon booster doses [10]. Despite these findings, the
effects caused by combination vaccines seem to have a shorter
duration of immune modification as compared to individual vaccines administered separately, and should be considered a major
advantage [41]. It should also be considered that immunization
leads to exposure to a significantly lower number of antigens as
compared to infection with the pathogen itself. Hib vaccine typically contains 2 antigens, as opposed to the more than 50 antigens
associated with invasive disease [11]. The same can be said for
Hepatitis B vaccine containing 1 antigen as opposed to the 4 or
more antigens associated with this viral infection [11,42]. Considering that the immune system has been estimated to be capable of
responding to >10 million antigens [11,43], immune overstimulation is highly unlikely through the practice of vaccination [11].
2.4. Efficacy
Evaluation of the efficacy of combination vaccines is typically
conducted as a non-inferiority-based study format, thereby proving similar efficacy to individual component vaccines [44,45]. These
studies need to be interpreted with clear consideration of what the
final endpoint of evaluation is [46] as it can reflect in vivo models
of antibody geometric mean concentrations [46,47], or epidemiological disease rates [41,48]. Epidemiological proof of effectiveness
is defined by the US Code of Federal Regulations as proof through
C40
A. Visser, A. Hoosen / Vaccine 30S (2012) C38–C44
controlled investigations, of clinically significant prevention of disease in a significant proportion of the target population [49].
Licensing of combination products are required when either
unlicensed components are added to existing vaccines or when
licensed vaccines are combined [50]. Licensing procedures aim at
ensuring that the act of combining antigens does not negatively
impact on purity, potency, safety or efficacy of individual components [51]. Once efficacy has been established to be non-inferior to
individual components through preclinical phase 1, 2 and 3 trials by
manufacturers and licensing has been procured, vaccines use can
be implemented [52]. This is followed by extensive post-licensing
surveillance during which time the epidemiological impact can be
thoroughly investigated [46].
Combination vaccine formulations currently available not only
have extensive research backing from manufacturers and independent researchers, but also through independent evaluation of
combination vaccines compared to individual components [53–56]
as well as effect of administration with additional vaccines at varying time intervals [57,58]. Through this rigorous process, vaccine
efficacy is therefore by and large proven, and thereby immunogenicity established.
2.5. Interchangeability of vaccine products
Manufacturers typically advise against interchanging use of
vaccine products. Despite this, the ACIP still recommends administration of vaccines from various manufacturers if original vaccine
is not available, to ensure continuity of vaccination [5]. A notable
exception is the acellular pertussis vaccine. Partly, because no serological correlates of immunity exist, but also a general lack of
convincing follow up studies [5,59] has prompted the recommendation for manufacturer fidelity for at least the first 3 vaccine doses
[5]. Interchangeability studies are not typically conducted formally,
but rather derived from either known correlates for protection or
post-licensing surveillance data [60,61].
2.6. Antigen redundancy
Inclusion of combination vaccines into a vaccination programme may lead to over-administration of certain antigens, as
these vaccines are less adaptable. Additionally, administration of
extra doses of many live-virus vaccines, Hib and Hepatitis B vaccine
has not been associated with harmful events [5]. However, certain
vaccines, most notably tetanus toxoid [62–68] and pneumococcal polysaccharide vaccine, may cause adverse events if additional
doses are administered [69,70] and this practise is therefore not
advocated.
3. Local availability and use of combination vaccines in the
South African EPI
The South African Medicines Formulary (SAMF) lists a variety of
combination vaccines that are available in South Africa (Table 1).
Although these are all available in the private sector, the only true
combination vaccine included in the current EPI as modified in
2009, is the DTaP-IPV/Hib vaccine (PentaximTM ) by Sanofi Pasteur
(Diphtheria, Tetanus, acellular Pertussis, inactivated Poliomyelitis virus and Haemophilus influenzae type b) [71,72]. Safety and
immunogenicity data has been produced in abundance, including
within South African cohorts [73,74]. These studies seem to suggest a favourable safety profile with acceptable rates of adverse
reactions [73]. As to be expected, booster doses seemed to show
a slightly higher incidence of adverse reactions as compared to
primary vaccinations. Local efficacy data is also promising. Recent
work by Madhi et al. showed significant protection extending
throughout the vaccination period. Following a single vaccine,
protective responses could be demonstrated just prior to booster
dosing at 18–19 months in more than 97% of patients for tetanus,
diphtheria, polio virus and Hepatitis B virus. Although it seemed as
though titres for the Haemophilus influenzae type B component PRP
had waned, a booster increased titres by more than 400% in more
than 95% of cases [74].
South Africa was declared to be free of wild-type poliovirus in
2006 by the Africa Region Certification Commission (ARCC), based
on adequate surveillance showing no local cases since 1989 [75].
South Africa is unique in utilizing both IPV and OPV vaccines within
the EPI [76]. Since the eventual move to IPV, a more expensive vaccine, has been shown to be cost-effective, the cost of complications
of OPV like vaccine-associated paralytic poliomyelitis (VAPP) needs
to be considered [77]. Complications like VAPP are very rare, however, certain risk factors may predispose to its development. These
include specific immunosuppressive states, most notably congenital agammaglobulinaemia, which has been associated with a single
case of VAPP in South Africa in 2011 [78]. Although no other cases
have been confirmed in South Africa, numerous cases have been
described in other African countries (Nigeria and Ethiopia) [79].
For these reasons, the inevitable change to IPV may be prudent to
prevent further cases of VAPP.
A significant reduction in maternal and neonatal tetanus has
also been demonstrated and the WHO declared South Africa to be
free of disease in these populations in 2002 [75].
Although invasive infection by Haemophilus influenzae type b
still occurs, incidence has dramatically declined [80]. Hib vaccine
was introduced as part of the South African EPI in 1999 [81]. In a
subseqent evaluation looking at the rates of invasive disease caused
by Haemophilus influenzae type b from 1999 to 2004, a 65% reduction could be demonstrated [80]. Unfortunately, the impact pre-and
post-vaccination cannot be determined reliably as the national
laboratory-based surveillance system was introduced in conjuction
with Hib vaccination [82]. However, a survey performed in Cape
Town in 1994 cited rates of invasive Hib disease amongst <1 year
olds, to be as high as 169 cases per 100,000 population [83]. This
stand in contrast to 1999–2000 rates of 55 cases per 100,000 population amongst <1 year olds [80]. Efficacy has been shown locally
in both outcome-related- as well as behaviour-related productivity
gains, and use is therefore advocated [84], however contradictory
views do exist [85,86].
Use of MMR vaccines is currently not included in the EPI and only
measles vaccine is utilized at 9 and 18 months of age [87–89]. The
decision to not include rubella vaccine was based on the premise
that if sustained high coverage of vaccine cannot be guaranteed,
a paradoxical increase the number of susceptible young females
could occur. This in turn would lead to an increase in congenital
rubella syndrome (CRS) [90,91]. This issue is currently compounded
by the lack of formal surveillance for both primary rubella infection
and CRS [90]. The MMR vaccine, however, is available in the private
sector [90]. Although not formally studied over the greater South
Africa, a study conducted in Gauteng revealed private sector vaccination to account for as much as 21% of all cases. Ironically, rates of
complete vaccination seem to have been higher amongst attendees
of public sector immunization clinics (83%) as compared to private
clinics (75%) [92]. It is therefore clear that the private sector should
not be neglected in consideration, as it both constitutes a significant portion of the population and current practices are clearly not
optimal.
At present, there are some variations offered by the private sector. In terms of combination vaccines, the major difference lies
in the availability of Infanrix® hexa (GlaxoSmithKline) to private
patients. In addition to the antigens contained in Pentaxim (Sanofi
Pasteur), it also contains Heptitis B virus surface antigen. The
implication is administration of one less injection at both the 6–8
week, 10–12 week and 14–16 week intervals. With regard to other
A. Visser, A. Hoosen / Vaccine 30S (2012) C38–C44
C41
Table 1
Summary of combination vaccines currently available in South Africa.
Pharmaceutical
name
Target pathogens
Formulation
Constituents
Adjuvant(s)
Primary
administration
Special instructions
Infanrix® DTPa
GlaxoSmithKline
Diphtheria,
Tetanus, Pertussis
Prefilled syringe
None
3 doses of 0.5 mL
4 weeks apart
Starting age 6
weeks
Booster at 18
months
Diftavax®
Aventis Pasteur
Diphtheria
(reduced dosage),
Tetanus
Prefilled syringe
Diphtheria
toxoid ≥ 30 IU
Tetanus toxoid ≥ 40 IU
Pertussis toxoid
(acellular) 25 mcg
FHA 25 mcg
Outer membrane
protein 8 mcg
Diphtheria
toxoid ≥ 2 IU
Tetanus toxoid ≥ 20 IU
Aluminium
hydroxide
3 doses of 0.5 mL
4 weeks apart
After 12 years of
age
Can be utilized as
booster from age 6
Repeated boosting
every 5–10 years
Only available in
public sector
TdPolio
Sanofi Pasteur
Diphtheria,
Tetanus, Polio
Prefilled syringe
Aluminium
hydroxide
N/A
0.5 mL booster
dose every 10 years
Tritanrix-HB®
GlaxoSmithKline
Diphtheria,
Tetanus, Pertussis,
Hepatitis B
Single dose vial
Aluminium
salts
3 doses of 0.5 mL
4 weeks apart
From age 6 weeks
Babies born as
carriers of HBV
should also receive
Hepatitis B
immunoglobulin at
a different
injection site
COMBACT-HIB®
Sanofi-Pasteur
Haemophilus
influenzae type b,
Diphtheria,
Tetanus, Pertussis
Freeze-dried
preparation for
reconstitution
None
3 doses of 0.5 mL
4–8 weeks apart
From age 6 weeks
Booster at age
15–18 months
PENTAXIM®
Sanofi-Pasteur
Diphtheria,
Tetanus, Pertussis
(acellular),
Haemophilus
influenzae type b,
Inactivated Polio
Two formulations
produced with only
suspension
available in South
Africa
None
3 doses of 0.5 mL 4
weeks apart
From age 6 weeks
Booster dose at 18
months
Infanrix hexa®
GlaxoSmithKline
Diphtheria,
Tetanus, Pertussis
(acellular),
Haemophilus
influenzae type b,
Hepatitis B,
Inactivated Polio
Prefilled syringe
None
3 doses of 0.5 mL at
2, 3 and 4 months
OR
If HBV vaccine is
given at birth:
Administered at 6,
10 and 14 weeks
Booster dose at 18
months
Twinrix®
GlaxoSmithKline
Hepatitis A and B
Prefilled syringe
Purified diphtheria
toxin ≥ 2 IU
Tetanus toxoid ≥ 20 IU
Inactivated poliovirus
types 1–3 at 40, 8, 32
D-antigen units
Diphtheria
toxoid ≥ 30 IU
Tetanus toxoid ≥ 60 IU
Inactivated pertussis
bacteria (whole
cell) ≥ 4 IU
Recombinant HBsAg
10 mcg
Haemophilus b
polysaccharide 10 mcg
Diphtheria
toxoid ≥ 30 IU
Tetanus toxoid ≥ 60 IU
Inactivated B
pertussis ≥ 4 IU
Haemophilus b
polysaccharide 10 mcg
Diphtheria
toxoid ≥ 30 IU
Tetanus toxoid ≥ 40 IU
Pertussis toxoid
(acellular) 25 mcg
Inactivated poliovirus
1–3 at 40, 8, 32
D-antigen units
Diphtheria
toxoid ≥ 30 IU
Tetanus toxoid ≥ 40 IU
Pertussis toxoid
(acellular) 25 mcg
FHA 25 mcg
Pertactin 8 mcg
Recombinant
HBsAg ≥ 10 mcg
Inactivated poliovirus
1–3 at 40, 8, 32
D-antigen units
Purified capsular
polysaccharide of Hib
10 mcg
Hepatitis A antigen 720
ELISA units
Recombinant HBsAg
20 mcg
None
None
Morupar®
Biovac
Measles, Mumps,
Rubella
Prefilled syringe
Measles virus (Schwarz
strain in chick embryo
cell line)
Mumps virus (Urabe
AM9 strain in chick
embryo cell line)
Rubella virus (Wistar
RA27/3 strain)
None
Adults:
3 doses of 1 mL at
0, 1 and 6 months
Paediatric: (1–15
years)
2 doses of 1 mL at 0
and 6 months
Single dose of
0.5 mL
Booster at 4-6 year
follow up improves
protection
C42
A. Visser, A. Hoosen / Vaccine 30S (2012) C38–C44
Table 1 (Continued)
Pharmaceutical
name
Target pathogens
Formulation
Constituents
Adjuvant(s)
Primary
administration
Special instructions
Priorix®
GlaxoSmithKline
Measles, Mumps,
Rubella
Single dose vial
None
Single dose of
0.5 mL
Booster at 4-6 year
follow up improves
protection
Trimovax®
Sanofi-Pasteur
Measles, Mumps,
Rubella
Single dose vial
Measles virus (Schwarz
strain)
Mumps virus (RIT4385
strain)
Rubella virus (Wistar
RA 27/3)
Measles virus (Schwarz
strain in chick embryo
cell line)
Mumps virus (Urabe
AM9 strain in
embryonated hen eggs)
Rubella virus (Wistar
RA 27/3 strain in
human diploid cell
line)
None
Single dose of
0.5 mL
Booster at 4–6 year
follow up improves
protection
vaccines, OPV and Hepatitis B virus vaccine are not given at birth
in the private sector. Furthermore, Varicella-, Hepatitis A virusand MMR vaccines are included in the private schedule as opposed
to the public sector which only offers Measles vaccine [93]. It is
estimated that approximately 14% of the South African population
makes use of private health insurance [94]. Therefore, an estimated
40 million South Africans make use of the Government EPI. The
variability of National (Government) versus Extended (Private) EPI
vaccines and the impact on herd immunity has not been studied.
4. Effecting change in the South African EPI
The South African National Advisory Group on Immunization
(NAGI) was established in 1993 under instruction of the Ministry
of Health. Subsequently, the National EPI was established in 1995.
Prior to this, immunization programmes varied between various
regions and local governing bodies [75]. This group consists of
14 members, of which 9 are regular members, representing the
disciplines of paediatrics, neurology, community health, virology,
microbiology, infectious diseases, pulmonology, vaccinology and
medicines regulation. In addition, 3 ex officio members from the
Department of Health EPI programme is included, as well as a WHO
and UNICEF representative [95].
NAGI functions in an advisory capacity and has effected inclusion of Hib vaccine in 1999 [80] as well as the introduction of
rotavirus and pneumococcal vaccines [96]. These decisions are
based on various factors, including (in decreasing order of importance): mortality, disability-adjusted life years or quality-adjusted
life years lost, hospitalizations, equity, overall morbidity and epidemic potential. Economic issues are also taken into considerations,
to not only ensure affordability, but also sustainability. This does
not include formal economic evaluations by the group, but rather
use of data generated from local research units [95]. In addition,
issues like burden of disease and equity also play a major role in
decisions the EPI.
The final decision is taken by the Department of Health, and
NAGI therefore simply acts as an advisory board. Of note, over 75%
of suggestions formulated by NAGI has been implemented in the
local EPI [95].
5. Conclusion
South Africa shows great diversity in terms of socio-economic
development and infrastructure. These factors have been shown
to directly impact on timeliness of vaccination, where poorer
communities classically show lower coverage rates with reduced
timeliness [97]. This being said, combination vaccines have been
proposed as a cost-effective alternative that owing to its relative ease of administration, should theoretically improve on both
timeliness and therefore coverage rates [98]. Despite this, implementation of use in the South African setting at this point is still
limited, but it may offer an exciting avenue of expanding the
antigen repertoire without impacting on side effects, efficacy or
complexity of scheduling.
Conflict of interest statement
None declared.
References
[1] Global Alliance for Vaccines and Immunization. <http://www.gavialliance.org/
about/mission/impact/> [accessed 20.10.11].
[2] UNICEF. <http://www.childinfo.org/hiv aids.html> [accessed 28.12.11].
[3] Koslap-Petraco M, Judelsohn R. Societal impact of combination vaccines: experiences of physicians, nurses, and parents. J Pediatr Health Care 2008;22:
300–9.
[4] CDC. Pertussis. In: Atkinson W, Hamborsky J, Wolf C, editors. Epidemiology
and prevention of vaccine-preventable diseases. Washington, DC: Public Health
Foundation; 2006. p. 1–44.
[5] CDC.Combination vaccines for childhood immunization: recommendations
of the Advisory Committee on Immunization Practices (ACIP), the American
Academy of Pediatrica (AAP) and the American Academy of Family Physicians
(AAFP). MMWR Morb Mortal Wkly Rep 1999:1–15.
[6] Dagan R, Botujansky C, Watemberg N. Safety and immunogenicity in young
infants of Haemophilus b–tetanus protein conjugate vaccine, mixed in the
same syringe with diphtheria–tetanus-enhanced inactivated poliovirus vaccine. Pediatr Infect Dis J 1994;13:356–62.
[7] Decker M, Edwards K. Combination vaccines: problems and promise. J Pediatr
2000;137:291–5 [editorial].
[8] Halsey N, Blatter M, Bader G. Inactivated poliovirus vaccine alone or sequential
inactivated and oral poliovirus vaccine in 2-, 4-, and 6-month-old infant with
combination Haemophilus influenzae type b/hepatitis B vaccine. Pediatr Infect
Dis J 1997;16:675–9.
[9] Marcy S. Pediatric combination vaccines: their impact on patients, providers,
managed care organizations, and manufacturers. Am J Manag Care
2003;9:314–20.
[10] Decker M, Edwards K, Bogaerts H. Combination vaccines. In: Plotkin S, Orenstein W, Offit P, editors. Vaccines. 5th ed. Elsevier; 2008. p. 1069–101 [Chapter
38].
[11] Halsey N. Safety of combination vaccines: perception versus reality. Pediatr
Infect Dis J 2001;20:S40–4.
[12] Woodkin K, Rodewald L, Humiston S, Carges M, Schaffer S, Szilagyi P. Physician
and parent opinions: are children becoming pincushions from immunizations?
Arch Pediatr Adolesc Med 1995;149:845–9.
[13] Corbel M. Control testing of combined vaccines: a considerations of potential
problems and approaches. Biologicals 1994;22:353–60.
[14] Anthony B. FDA perspective on regulatory issues in vaccine development.
In: Williams J, Goldenthal K, Burns D, Lewis B, editors. Combined vaccines
and simultaneous administration: current issues and perspectives. New York:
Annals of the New York Academy of Sciences; 1995. p. 10–6.
[15] Insel R. Potential alterations in immunogenicity by combining or simultaneous
administering vaccine components. In: Williams J, Goldenthal K, Burns D, Lewis
B, editors. Combined vaccines and simultaneous administration: current issues
A. Visser, A. Hoosen / Vaccine 30S (2012) C38–C44
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
[42]
[43]
[44]
[45]
[46]
[47]
and perspectives. New York: Annals of the New York Academy of Sciences;
1995. p. 35–47.
Gellin B, Maibach E, Marcuse E. Do parents understand immunizations? A
national telephone survey. Pediatrics 2000;106:1097–102.
Meyerhoff A, Jacoba R, Greenberg D, Yagoda B, Castles C. Clinicians satisfaction with vaccination visits and the role of multiple injections, results from the
COVISE study (Combination Vaccines Impact on Satisfaction and Epidemiology). Clin Pediatr (Phila) 2004;43:87–93.
Meyerhoff A, Jocobs R. Do too many shots due lead to missed vaccination
opportunities? Does it matter? Prev Med 2005;41:540–4.
Hull B, McIntyre P. Timeliness of childhood immunisation in Australia. Vaccine
2006;24:4403–8.
Freed G, Cowan A, Clark S, Santoli J, Bradley J. Use of a new combined vaccine
in pediatric practices. Pediatrics 2006;118:e251–7.
Kalies H, Grote V, Verstaeten V, H.Essel L, Schmitt H, Kries Rv. The use of combination vaccines had improved timeliness of vaccination in children. Pediatr
Infect Dis J 2006;25:507–12.
Goldfarb N, Patel N, Clarke J. Improving quality by encouraging providers to use
pediatric combination vaccines. Manag Care 2005;6:3–12.
Development IBoRa, editor. World development report 1993. Washington, DC:
International Band of Reconstruction and Development; 1993.
World Health Organization. State of the world’s vaccines and immunization; 2012 [accessed 28.02.12] http://whqlibdoc.who.int/publications/
2009/9789241563864 eng.pdf.
Mahoney R, Ramachandran S, Xu Z. The introduction of new vaccines into
developing countries II. Vaccine financing. Vaccine 2000;18:2625–35.
Blecher M, Meheus F, Kollipara A, Hecht R, Cameron N, Pillay Y.
Financing vaccinations—the South African experience. Vaccine 2012;30
(Suppl. 3):C79–86.
Lydon P, Levine R, Makinen M, Brenzel L, Mitchell V, Milstien J, et al. Introducing new vaccines in the poorest countries: what did we learn from the GAVI
experience with financial sustainability? Vaccine 2008;26:6706–16.
Phoshoko S. Vaccine costing in SA, personal communication.
Hersh B, Tambini G, Nogueira A, Carrasco P, Quadros Cd. Review of regional
measles surveillance data in the Americas, 1996–99. Lancet 2000;355:
1943–8.
Edwards K, Decker M. Combination vaccines: hopes and challenges. Pediatr
Infect Dis J 1994;13:13.
Fabio JD, Quadros Cd. Considerations for combination vaccine development and
use in the developing world. Clin Infect Dis 2001;33:S340–5.
Hadler S, Dietz V, Okwo-Bele J, Cutts F. Immunization in developing countries.
In: Plotkin S, Orenstein W, Offit P, editors. Vaccines. 5th ed. Saunders Elsevier;
2008. p. 1542.
World Health Organization. Expanded programme on immunization (EPI).
<http://www.who.int/immunization delivery/en/> [accessed 25.01.12].
Dicko M, Oni A, Ganivet S, Kone S, Pierre L, Jacquet B. Safety of immunization in Africa: not simply a problem of logistics. Bull World Health Organ
2000;78:163–9.
Halsey N. Limiting infant exposure to thimerosal in vaccines and other sources
of mercury. JAMA 1999;282:1763–6.
Pichichero M, Latiolais T, Bernstein D. Vaccine antigen interaction after a
combination diphtheria–tetanus–toxoid-acellular pertussis/purified capsular
polysaccharide of Haemophilus infulenzae type b-tetanus toxoid vaccine in two-,
four- and six-month-old infants. Pediatr Infect Dis J 1997;16:863–70.
Schmitt H, Zepp F, Muschenborn S. Immunogenicity and reactogenicity of
a Haemophilus influenzae type b tetanus conjugate vaccine when administred separately or mixed with concomittant diphtheria–tetanus–toxoid and
aceullar pertussis vaccine for primary and for booster immunization. Eur J
Pediatr 1998;157:208–14.
Nakayama T, Aizawa C, Kuno-Sakai H. A clinical analysis of gelatin allergy
and determination of its causal relationship to the previous administration of
gelatin-containing acellular pertussis vaccine combined with diphtheria and
tetanus toxoids. J Allergy Clin Immunol 1999;103:321–5.
Berkovich S, Starr S. Effects of live type 1 poliovirus vaccine and other viruses
on the tuberculin test. N Engl J Med 1966;274:67–72.
Brickman H, Beardry P, Marks M. The timing of tuberculin tests in relation to
immunization with live viral vaccines. Pediatrics 1975;55:392–6.
Halsey N, Combination vaccines: defining and addressing current safety concerns. Clin Infect Dis 2001;33:S312–8.
Institute of Medicine, Division of Health Promotion and Disease Prevention.
Immunologic reactions. In: Stratton K, Howe C, Johnston R, editors. Adverse
events associated with childhood vaccines: evidence bearing on causality.
Washington, DC: National Academy Press; 1993. p. 59–66.
Pickering L, Siegelman M. Lymphoid tissues and organs. In: Paul W, editor.
Fundamental immunology. 4th ed. Philadelphia: Lippincott-Raven; 1999. p.
479–532.
Center for Biologics Evaluation and Research, US Food and Drug Administration.Guidance for industry for the evaluation of combination vaccines
for preventable disease: production, testing and clinical studies. Fed Reg
1997;62:17624–5.
Horne A, Lachenbruch P, Getson P, Hsu H. Analysis of studies to evaluate the
immune response to combination vaccines. Clin Infect Dis 2001;33:S306–11.
Ball L, Falk L, Horne A, Finn T. Evaluating the immune response to combination
vaccines. Clin Infect Dis 2001;33:S299–305.
Halsey N. A perspective on combination vaccines. Pediatr Infect Dis J
1998;17:653–4.
C43
[48] Harrison L, Tajkowski C, Croll J. Postlicensure effectiveness of the Haemophilus
influenzae type b polysaccharide-Neisseria meningitidis outer membrane
protein complex conjugate vaccine among Navajo children. J Pediatr
1994;125:571–6.
[49] US Code of Federal Regulations. Title 21, part 601.25(d)(2). Washington, DC:
US Government Printing Office; 2001.
[50] US Code of Federal Regulations. Title 21, part 610.17. Washington, DC: US
Government Printing Office; 2001.
[51] US Code of Federal Regulations. Title 21, part 601.25(d)(4). Washington, DC:
US Government Printing Office; 2001.
[52] US Code of Federal Regulations. Title 21, part 312.21. Washington, DC: US
Government Printing Office; 2001.
[53] Kuter B, Brown M, Hartzel J, Williams W, EvesiKaren A, Black S, et al. Safety
and immunogenicity of a combination measles, mumps, rubella and varicella
vaccine (ProQuad). Hum Vaccin 2006;2:205–14.
[54] Shinefield H, Black S, Staehle B, Adelman T, Ensor K, Ngai A, et al. Safety, tolerability and immunogenicity of concomitant injections in separate locations
of M-M-RII, VARIVAX and TETRAMUNE in healthy children vs. concomitant
injections of M-M-RII and TETRAMUNE followed six weeks later by VARIVAX.
Pediatr Infect Dis J 1998;17:980–5.
[55] Schmitt H, Steul K, Borkowski A, Ceddia F, Ypma E, Knuf M. Two versus
three doses of a meningococcal C conjugate vaccine concomitantly administered with a hexavalent DTaP-IPV-HBV/Hib vaccine in healthy infants. Vaccine
2008;26:2242–52.
[56] Tejedor J, Moro M, Ruiz-Contreras J, Castro J, Gómez-Campderá J, Navarro
M, et al. Immunogenicity and reactogenicity of primary immunization with
a hexavalent diphtheria–tetanus–acellular pertussis–hepatitis B-inactivated
polio-Haemophilus influenzae type B vaccine coadministered with two doses
of a meningococcal C-tetanus toxoid conjugate vaccine. Pediatr Infect Dis J
2006;25:713–20.
[57] Reisinger K, Brown M, Xu J, Sullivan B, Marshall G, Nauert B, et al. A combination
measles, mumps, rubella, and varicella vaccine (ProQuad) given to 4- to 6year-old healthy children vaccinated previously with M-M-RII and Varivax.
Pediatrics 2006;117:265.
[58] Arístegui J, Dal-Ré R, Díez-Delgado J, Marés J, Casanovas J, García-Corbeira
P, et al. Comparison of the reactogenicity and immunogenicity of a combined diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated polio
(DTPa-HBV-IPV) vaccine, mixed with the Haemophilus influenzae type b (Hib)
conjugate vaccine and administered as a single injection, with the DTPaIPV/Hib and hepatitis B vaccines administered in two simultaneous injections
to infants at 2, 4 and 6 months of age. Vaccine 2003;21:3593–600.
[59] CDC. Pertussis vaccination: use of acellular pertussis vaccines among infants
and young children. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1997;46:1–25.
[60] Granoff D, Rappuoli R. Are serological responses to acellular pertussis antigens
sufficient criteria to ensure that new combination vaccines are effective for
prevention of disease? Dev Biol Stand 1997;89:379–89.
[61] Clements-Mann M. Lessons for AIDS vaccine development from non-AIDS vaccines. AIDS Res Hum Retroviruses 1998;14:S197–203.
[62] Edsall G, Elliott M, Peebles T, Panaro R, Eldred M. Excessive use of tetanus toxoid
boosters. JAMA 1967;202:111–3.
[63] Peebles T, Levine L, Eldred M, Edsall G. Tetanus-toxoid emergency boosters: a
reappraisal. N Engl J Med 1969:280.
[64] Jacobs R, Lowe R, Lanier B. Adverse reactions to tetanus toxoid. JAMA
1982;247:40–2.
[65] Baraff L, Cody C, Cherry J. DTP-associated reactions: an analysis by injection
site, manufacturer, prior reactions, and dose. Pediatrics 1984;73:31–6.
[66] Jones A, Melville-Smith M, Watkins J, Seagroatt V, Rice L, Sheffield F. Adverse
reactions in adolescents to reinforcing dose of plain and adsorbed tetanus vaccines. Community Med 1985;7:99–106.
[67] American Academy of Pediatrics. Tetanus (Lockjaw). In: Peter G, editor. 1997
Red Book: report of the Committee on Infectious Diseases. 24th ed. Elk Grove
Village, IL: American Academy of Pediatrics; 1997. p. 518–23.
[68] CDC.Diphtheria, tetanus, and pertussis: recommendations for vaccine use and
other preventative measures. Recommendations of the Immunization Practice
Advisory Committee (ACIP). MMWR 1991;40:1–28.
[69] Sackett D, Rosenberg W, Gray J, Haynes R, Richardson W. Evidence based
medicine: what it is and what it isn’t. BMJ 1996;312:71–2.
[70] American Academy of Pediatrics. Pneumococcal infections. In: Peter G, editor.
1997 Red Book: report of the Committee on Infectious Diseases. 24th ed. Elk
Grove Village, IL: American Academy of Pediatrics; 1997. p. 410–9.
[71] World Health Organization. <http://www.int/countries/en/> [accessed
25.04.12].
[72] Ntombenhle J, Cameron N. The decision making process on new vaccine introduction in South Africa. Vaccine 2012;30(Suppl. 3):C9–13.
[73] Madhi S, Cutland C, Jones S, Groome M, Ortiz E. One-year post-primary antibody persistence and booster immune response to a DTaP-IPV//PRP-T vaccine
(Pentaxim) given at 18–19 months of age in South African children primed at
6, 10 and 14 weeks of age with the same vaccine. S Afr J Med 2011;101:879–83.
[74] Madhi S, Cutland C, Jones S, Groome M, Ortiz E. Immunogenicity and safety of an
acellular pertussis, diphtheria, tetanus, inactivated poliovirus, Hib-conjugate
combined vaccine (Pentaxim) and monovalent hepatitis B vaccine at 6, 10 and
14 weeks of age in infants in South Africa. S Afr J Med 2011;101:126–31.
[75] Ngcobo N. The impact of the immunisation programme on vaccine-preventable
diseases in South Africa: a review of progress over a 10- to 15-year period. S
Afr J Epidemiol Infect 2008;23:9–13.
C44
A. Visser, A. Hoosen / Vaccine 30S (2012) C38–C44
[76] Schoub B. Introduction of inactivated poio vaccine (IPV) into the routine immunization in South Africa. Vaccine 2012;30(Suppl. 3):C35–7.
[77] Griffiths U, Botham L, Schoub B. The cost-effectiveness of alternative polio
immunization policies in South Africa. Vaccine 2006;24:5670–8.
[78] National Institutes for Communicable Diseases. Polio paralyses child.
<http://www.nicd.ac.za/?page=alerts&id> [accessed 12.04.12].
[79] National Institute for Communicable Diseases. Annual review 2010–2011.
<http://www.nicd.ac.za/assets.files/> [accessed 12.04.12].
[80] Von Gottberg A, De Gouveia I, Madhi S. Impact of conjugate Haemophilus
influenzae type b (Hib) vaccine introduction in South Africa. Bull World Health
Organ 2006;84:811–8.
[81] Von Gottberg A, Cohen C, Whiteloaw A, Chhagan M, Flannery B, Cohen
A, et al. Invasive disease due to Haemophilus influenzae serotype b ten
years after routine vaccination, South Africa, 2003–2009. Vaccine 2012;30:
565–71.
[82] Huebner R, Klugman K, Matai U, Eggers R, Hussey G. Laboratory surveillance
for Haemophilus influenzae type b, meningococcal and pneumococcal disease.
Haemophilus Surveillance Working Group. S Afr Med J 1999;89:924–5.
[83] Hussey G, Hitchcock J, Schaaf H, Hanslo GC, Schalkwyk Ev, Pitout J, et al. Epidemiology of invasive Haemophilus influenzae infections in Cape Town, South
Africa. Ann Trop Paediatr 1994;14:97–103 [Abstract].
[84] Barnighausen T, Bloom D, Canning D, Friedman A, Levine O, O’Brien J, et al.
Rethinking the benefits and costs of childhood vaccination: the example of the
Haemophilus influenzae type b vaccine. Vaccine 2011;29:2371–80.
[85] John T, Muliyil J. Introducing pentavalent vaccine in EPI in India: issues
involved. Indian J Med Res 2010;132:450–5.
[86] Madhavi Y, Raghuram N. Pentavalent & other new combination vaccines: solution in search of problems. Indian J Med Res 2010;132:456–7.
[87] SAVIC. <http://www.savic.ac.za/news/newsarticles.php> [accessed 28.12.11].
[88] Du Toit G, Weinberg E. Egg allergy and MMR vaccination. S Afr J Med
2003;93:113–4.
[89] Cameron N. When should be introduce a combination measles–mumps-(MMR)
vaccine into the national childhood expanded immunization programme in
South Africa? Vaccine 2012;30(Suppl. 3):C58–60.
[90] Corcoran C, Hardie D. Seroprevalence of rubella antibodies among antenatal
patients in the Western Cape. S Afr J Med 2005;95:688–90.
[91] Robertson S, Cutts F, Samuel R, Diaz-Ortega J. Control of rubella and congenital
rubella syndrome (CRS) in developing countries. Part 2. Vaccination against
rubella. Bull World Health Org 1997;75:69–80.
[92] Fonn S, Sartorius B, Levin J, Likibi M. Immunisation coverage estimates by cluster sampling survey of children (aged 12–23 months) Gauteng province, 2003.
S Afr J Epidemiol Inf 2006;21:164–9.
[93] Paediatric Group. <http://www.paediatrician.co.za> [accessed 21.04.12].
[94] Mail and Guardian. Forty million South African without medical aid.
<http://www.mg.co.za/article/2009-07-07-forty-million-south-africanswithout-medical-aid> [accessed 21.04.12].
[95] Schoub B, Ngcobo N, Madhi S. The National Advisory Group on Immunization
(NAGI) of the Republic of South Africa. Vaccine 2010;28S:A31–4.
[96] Madhi S, Puren A, Kuwanda L, Jassat W, Jones S, Little T, et al. Long-term
immunogenicity and efficacy of a 9-valent conjugate pneumococcal vaccine
in human immunodeficient virus infected and non-infected children in the
absence of a booster dose of vaccine. Vaccine 2007;25:2451–7.
[97] Fadnes L, Jackson D, Engebretsen I, Zembe W, Sanders D, Sommerfelt H, et al.
Vaccination coverage and timeliness in three South African areas: a prospective
study. BMC Public Health 2011;11:404–14.
[98] Gentile A, Bhutta Z, Bravo L, Samy A, Garcia R, Hoosen A, et al. Pediatric disease
burden and vaccination recommendations: understanding local differences. Int
J Infect Dis 2010;14:e649–58.
Vaccine 30S (2012) C45–C51
Contents lists available at SciVerse ScienceDirect
Vaccine
journal homepage: www.elsevier.com/locate/vaccine
Review
An update after 16 years of hepatitis B vaccination in South Africa
Rosemary J. Burnett a,∗ , Anna Kramvis b , Carine Dochez c , André Meheus c
a
Department of Public Health, University of Limpopo, Medunsa Campus, Pretoria, South Africa
Hepatitis Virus Diversity Research Programme, Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
c
Department of Epidemiology and Social Medicine, University of Antwerpen, Belgium
b
a r t i c l e
i n f o
Article history:
Received 6 September 2011
Received in revised form
29 December 2011
Accepted 6 February 2012
Keywords:
Hepatitis B virus
Vaccination
South Africa
a b s t r a c t
Hepatitis B (HB) virus (HBV) infection is highly endemic with at least 65 million chronic HB surface
antigen (HBsAg) carriers in Africa, 25% of whom are expected to die from liver disease. Before the introduction of the HB vaccine, the prevalence of chronic carriage of HBV in black South Africans was 9.6%,
with 76% having been previously exposed to HBV. The major transmission route in South Africa is unexplained horizontal transmission between toddlers, with most transmission occurring before the age of 5
years. During adolescence and early adulthood, sexual transmission becomes the dominant route, while
healthcare workers (HCWs) are also at risk for parenteral/percutaneous transmission during occupational exposures. In 1995 the South African Department of Health (SADoH) incorporated the HB vaccine,
administered as a monovalent, into the Expanded Programme on Immunisation (EPI) at 6, 10, and 14
weeks of age, and studies conducted thereafter have found it to be safe and highly effective. Catch-up
vaccination for adolescents was not introduced and there is no schools-based vaccination programme.
The SADoH recommends HB vaccination of HCWs, but this is not mandatory and there is no national
policy, thus HB vaccination uptake in HCWs is sub-optimal. Since 1995, studies on children have found
that the prevalence of chronic HBsAg carriage has decreased, as has the incidence of paediatric hepatocellular carcinoma and HBV-related membranous nephropathy. The SADoH should focus their efforts on
attaining a high infant HB vaccine coverage, prepare for introducing a HB birth dose, and consider using a
hexavalent vaccine (DTaP-IPV-Hib-HepB). The department may also want to consider including targeted
HB vaccination for 12 year-olds, if their Road to Health Cards show they were not vaccinated as infants.
A national policy is needed for HCWs to ensure that they are fully vaccinated and protected against HBV
infection.
© 2012 Elsevier Ltd. All rights reserved.
1. Introduction
Hepatitis B (HB) virus (HBV) infection is a major public health
problem in sub-Saharan Africa. The virus is highly endemic (≥8%
HB surface antigen [HBsAg] prevalence) with at least 65 million
chronic HBV carriers in Africa [1], 25% of whom are expected to
die from liver disease including cirrhosis and hepatocellular carcinoma (HCC) [2]. Although anti-viral treatment for chronic HB can
Abbreviations: AEFI, adverse events following immunisation; Anti-HBc, antibody to hepatitis B core antigen; Anti-HBs, antibody to hepatitis B surface antigen;
DNA, deoxyribonucleic acid; EPI, Expanded Programme on Immunisation; GAVI,
Global Alliance for Vaccines and Immunisation; HBeAg, hepatitis B e antigen; HBsAg,
hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma;
HCW, healthcare worker; HIV, human immunodeficiency virus; SADoH, SA National
Department of Health; WHO, World Health Organization.
∗ Corresponding author at: Department of Public Health, PO Box 215, University
of Limpopo, Medunsa Campus, 0204 Pretoria, South Africa. Tel.: +27 12 521 3328;
fax: +27 86 612 2943.
E-mail addresses: rosemary [email protected], [email protected]
(R.J. Burnett).
0264-410X/$ – see front matter © 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.vaccine.2012.02.021
result in viral clearance, for most patients this is not the case, and
these treatments are unavailable to the majority of sub-Saharan
Africans. Nevertheless, HBV infection is vaccine-preventable, and
in 1992 the World Health Organization (WHO) recommended that
the highly efficacious HB vaccine should be incorporated into the
national Expanded Programmes on Immunisation (EPI) in all countries by 1997 [3]. The majority of African governments (45 of the
46 WHO African Region [AFRO] member states) had incorporated
the HB vaccine into their EPIs by December 2010, and the last one
(Equatorial Guinea) will do so in the coming months [4,5].
1.1. The prevalence of HBV in South Africa
Prior to the introduction of HB vaccination in South Africa, it
was estimated that the prevalence of HBsAg chronic carriage in
black South Africans was 9.6%, with 76% having been previously
exposed (positive for one or more HBV serological marker) to HBV
[2]. In stark contrast, Caucasians and Indians had a carrier rate
of 0.2% and a total exposure rate of 5%, whilst those of mixed
descent (European-African) had a carrier rate of 0.4–3%, and a total
exposure rate of 18–25%, and South Africans of Chinese descent had
C46
R.J. Burnett et al. / Vaccine 30S (2012) C45–C51
a carrier rate of 5.3% and a total exposure rate of 50% [6]. Generally,
prevalence rates vary between rural and urban populations, with
a prevalence of HBV chronic carriers in the rural former Transkei
(Eastern Cape) of 15.5%, while those in urban areas are much lower:
Durban, 7.4%, and Soweto, 1.3% [6]. Although both sexes are equally
exposed to HBV, HBsAg carriage is higher in males, with an average
male to female ratio of 2.6:1 [7]. It has been estimated that HBV
is responsible for approximately 60% of the country’s acute viral
hepatitis cases, while 94.2% of black men with HCC had previous
exposure to HBV, with 56.5% of them being HBsAg-positive [7].
1.2. Transmission of HBV in South Africa
Perinatal transmission (via percutaneous and permucosal exposure to the mother’s blood from 28 weeks of gestation up to 7 days
after birth, but occurring mainly at or near the time of birth) [8–10]
does occur in South Africa. This however is not the major transmission route in the country nor the region as a whole, because
of the relatively low frequency of HBe antigen (HBeAg) positivity
in HBsAg-positive pregnant women (0–18.6%) [6]. Because HBeAg
acts as a tolerogen [11,12], 70–90% of babies born to HBeAg-positive
mothers will become chronic carriers of the virus, in contrast
to only 10% of babies born to mothers who are HBeAg-negative
[13–17]. It was previously thought that breastfeeding may also play
a role, but more recent studies have shown this not to be the case
[10].
Horizontal transmission between toddlers (i.e. transmission
unrelated to recognised sexual, perinatal, or parenteral exposure
[18]) is the major route in South Africa [2,6,19,20]. Although this
mode of transmission is largely unexplained, ritual scarification
[2,6,19], weeping sores [19], and saliva [2,21] have been implicated.
About 20–30% of those horizontally infected before the age of 5
years progress to chronicity [15,16,22]. HBV exposure during childhood can lead to a large proportion of adolescents being infected by
the time they reach the age of sexual maturity [20]. Thereafter, in
adolescence and early adulthood, sexual transmission becomes the
dominant route of transmission [2,6,19,20,22], with 3–5% of those
infected at this age progressing to chronicity [15,16,23].
Parenteral/percutaneous transmission is another important
route of transmission. Worldwide, unsafe injections and contaminated blood transfusions are responsible for up to 21 million
HBV infections each year [24,25]. Most occur in regions of high
endemicity. This risk is greatly reduced in South Africa where
blood donations are routinely screened for HBV using individual
donor nucleic acid testing [26]. Moreover, South African healthcare
workers (HCWs) and their patients are at high risk for acquiring
HBV infections in the healthcare setting [20,27–29]. As with sexual transmission, parenteral transmission (mainly as a result of
intravenous drug use) is an important mode of HBV infection in
regions of low and intermediate endemicity, with infections occurring mainly in adolescents and young adults. Thus the mode of
transmission in South Africa differs from the mode seen in areas
of low endemicity.
2. The prevention and control of HBV
In May 2010, the 63rd World Health Assembly adopted a resolution prioritising the global prevention and control of viral hepatitis
[30], of which HBV is the major causative agent in sub-Saharan
Africa. A cheap, highly effective inactivated plasma-derived vaccine against HBV has been available since 1982 [3,31]. In 1986,
a more expensive recombinant HB vaccine, made by inserting
the HBsAg gene into yeasts or mammalian cell lines via plasmids, was introduced. The recombinant yeasts or cell lines are
cultured, and the resulting HBsAg proteins are then purified and
incorporated into the vaccine. In natural infections, HBsAg is the
protein that elicits host production of both neutralising antiHBs and HBsAg-specific cytotoxic T lymphocytes. Since their
introduction, recombinant HB vaccines have gradually replaced
plasma-derived HB vaccines, having an excellent immunogenicity
and safety profile with infrequent mild adverse events following immunisation (AEFIs) [23,32]. Immunisation strategies for the
prevention and control of HBV include routine infant immunisation; prevention of perinatal transmission; catch-up vaccination
for older age groups; and vaccination of high risk groups, including
HCWs [28,31].
If a good immune response was elicited after the primary
vaccination course, booster doses for healthy individuals are unnecessary and uneconomical [33–36]. Even if anti-HBs is lost and is
not detectable in the serum for 28–31 months post-vaccination,
a good anamnestic response is mounted when a previously successfully vaccinated person is exposed to HBV [35]. Furthermore,
immune memory has been shown to persist for at least 20 years
after successful primary vaccination [37].
2.1. Universal infant HB vaccination in South Africa
2.1.1. Integration of HB vaccination into the Expanded
Programme on Immunisation
Because chronic HBV carriage is mainly established in early
childhood in South Africa, infant immunisation against HBV has
been prioritised, with the South African National Department of
Health (SADoH) having introduced the HB vaccine into the national
EPI (EPI-SA) in April 1995 [38,39]. The first HB vaccine to be used
in the EPI-SA was the plasma-derived Hepaccine B vaccine (Cheil
Foods and Chemicals, Seoul, South Korea). Despite the excellent
safety record of this vaccine, EPI-SA followed global trends and
switched to genetically engineered recombinant HB vaccines. Currently, the Heberbiovac HB vaccine (Centre for Genetic Engineering
and Biotechnology, Havana, Cuba), which has been shown to be
more immunogenic than Hepaccine B in the South African setting
[40], or Engerix-B (GlaxoSmithKline, Belgium), are being used. As
in most countries in the region, the HB vaccine is given at 6, 10, and
14 weeks of age [17]. While the EPIs of GAVI-assisted countries in
the region administer the HB vaccine as part of the pentavalent vaccine against diphtheria, tetanus, pertussis, HBV, and Haemophilus
influenzae type b (DTPw-HepB-Hib), EPI-SA administers it as a
monovalent vaccine [41].
2.1.2. Effectiveness of HB vaccination in children
Various post-introduction South African studies have shown the
HB vaccine to be both highly immunogenic and effective. Children who were vaccinated as infants with Hepaccine B in 1995
and followed up for two to three years, had an initial seroprotection frequency of 93% (anti-HBs ≥10 mIU/ml). Of the original 186
children, 93 were tested in 1997, and 69 in 1998, with 75.3% and
76.8% still having protective levels of anti-HBs, respectively. None
of the children were positive for HBsAg, HBV DNA, or anti-HBc [42].
Field studies on children who, as infants, were vaccinated with
Hepaccine B as part of the routine EPI, have shown similar effectiveness. In an Eastern Cape cohort, none of 1213 fully vaccinated
(i.e. having received three doses of HB vaccine) 12–24 month-olds
born after 1995, were found to be HBsAg-positive, compared to
7.8% (39/498) of unvaccinated 12–24 month-olds born before 1995,
who were HBsAg-positive. Furthermore, only 0.3% (4/1213) of the
vaccinated cohort were found to be HBV DNA positive, compared
to 6.5% (30/459) of the HBsAg-negative unvaccinated cohort, and
84.6% (834/986) of the vaccinated cohort had protective levels of
anti-HBs [43]. A study on fully vaccinated 18 month-olds who had
been vaccinated in rural districts of all 9 provinces of South Africa,
found protective levels of anti-HBs in 87% (669/769), with only
R.J. Burnett et al. / Vaccine 30S (2012) C45–C51
0.4% (3/756) being HBsAg-positive [44]. Similarly, a study on 8–72
month-old children who had been vaccinated in Limpopo Province,
found protective levels of anti-HBs in 86.8% (519/598), with none
being positive for either HBsAg or HBV DNA [38]. Finally, the HB
vaccine has also been shown to be effective in human immunodeficiency virus (HIV)-positive babies, although somewhat less than
in HIV-negatives. A study on 5–24 month-old babies who had been
vaccinated as part of the routine EPI in Gauteng Province, found
protective levels of anti-HBs in 78.1% (57/73) of HIV-positives compared to 85.7% (197/230) of HIV-negatives, with 2.7% (2/73) and
0.4% (1/230), respectively being positive for HBsAg [45]. This finding is in agreement with a 2003 review which reported reduced
effectiveness of various vaccines in HIV-positive children, including
the HB vaccine [46].
2.1.3. HB vaccine coverage in under 1-year-olds
The coverage of the 3rd dose of HB vaccine (HB-3) in South
Africa rose from 74% in 1997 [17] to 88% in 2000 [47]. The latest official HB-3 coverage figure for 2010 is 97% [47], which
shows a vast improvement but may be an over-estimation [47].
According to the WHO, HB-3 coverage dropped to 56% in 2007,
and has not risen since. However, these coverage estimates are not
based on scientific surveys, and a high quality coverage survey has
been recommended [47].
2.2. Prevention of perinatal transmission
Recently, the WHO recommended that the EPI of all countries
should include a birth dose of HB vaccine, administered within 24 h
of birth to stop perinatal transmission [23]. At the time of this
recommendation, studies from countries where perinatal transmission is common, such as those in southeast Asia, had shown that
administering a birth dose of HB vaccine is highly effective in preventing HB infection in neonates born to HBeAg-positive mothers
[48]. However, in sub-Saharan Africa, including South Africa, horizontal transmission between infants and toddlers, and not perinatal
transmission, is the most common transmission route, thus adding
a birth dose to the current schedule is not immediately apparent as
epidemiologically justifiable.
There is concern though, that the relatively high prevalence of
HIV in the region may have changed this premise for two reasons: First, HIV and HBV co-infected individuals are more likely
to have active HBV infection, and pregnant women with active
HBV infection are more likely to infect their babies perinatally [20].
However, a study on 1420 South African antenatal women found
no increase in HIV-positives for either HBsAg (6.2% versus 5.8% in
HIV-negatives) or HBV DNA (2.4% versus 2.2%), although there was
a significant increase in the prevalence of HBV exposure in the HIVpositive group relative to the negative group (39.2% versus 30.1%)
[49].
Second, a more compelling reason is that there may be a lack
of transfer of maternal anti-HBs from immunosuppressed HIVinfected mothers. A recent South African study found that only
21% of HIV-exposed neonates had protective levels of anti-HBs
compared to 54% in HIV-unexposed neonates, a finding that was
statistically significant [50]. Thus almost 80% of babies born to
HIV-positive mothers have no protection against HBV until the first
dose of vaccine is received at 6 weeks of age, during which time the
infant may be horizontally infected [20]. However, since the CD4+
count for the initiation of highly active antiretroviral treatment
(HAART) has recently been raised to 350 cells/mm3 , it is hoped that
in the future a substantial proportion of HIV-positive pregnant
women will be placed on HAART (as opposed to dual antiretroviral
therapy for the prevention of mother-to-child transmission of
HIV). This will not only prevent HIV transmission, but also, by
reducing immunosuppression in the mothers, maternal anti-HBs
C47
levels may be conserved resulting in increased anti-HBs transfer
to their babies.
Clearly the current HB vaccination schedule is not preventing all
infant infections in South Africa, as a few breakthrough infections
have been reported, mainly in HIV-exposed/infected babies [44,45].
The most recent South African study found that only 1% (3/303) of
babies aged 5–24 months were positive for HBsAg, and although 2
of the 3 HBsAg-positive babies were HIV-positive, this finding was
not statistically significant [45]. The HIV status of the mothers in
this study was unknown.
It is not unreasonable to argue that a birth dose may prevent a
substantial proportion of these infections. But first, one must examine the programmatic challenges and opportunities. Administering
a HB vaccine birth dose within the EPI-SA is logistically feasible
because the current monovalent HB vaccine is suitable for the birth
dose and can be administered together with oral polio vaccine and
Bacille Calmette Guérin (BCG), which are already scheduled to be
administered at birth. However, the HB vaccine birth dose must
be given within 24 h of birth, whereas the time of administration
of the birth dose of both oral OPV and BCG is more flexible, and
therefore sometimes only given within 7 days or even 14 days after
birth. Moreover, BCG coverage figures in the more rural provinces of
KwaZulu-Natal and the Eastern Cape are relatively low at 79.1% and
70.6%, respectively [51]. This is probably because most rural babies
are born at home, and home births are generally not attended by
trained HCWs [52].
Next, one must examine the economic opportunities and challenges. In 2009, the EPI-SA cost of fully vaccinating a child was USD
148 in the public sector and USD 454 in the private sector for the
vaccines alone [53]. While South Africa is a middle income country
that has, since 1994, had the good fortune to have successive health
ministers who have all been fully committed to supporting EPI-SA,
there are many competing health priorities. For example, the burden of cervical cancer in South Africa is high, yet the country has
not yet introduced the highly effective vaccine against the human
papilloma virus (HPV) (the cause of cervical and other anogenital
cancers). It must also be established how effective the HB birth dose
will be at preventing neonatal infections, bearing in mind that birth
dose coverage will be lower (and is unlikely to be administered
within 24 h [52]) in the rural areas, where the prevalence of HBeAg
in HBsAg-positive black pregnant women is 12% [6]. On the other
hand, administering a HB birth dose in urban areas, where birth
dose coverage is expected to be higher, may in fact not be very costeffective considering that the carriage of HBeAg in HBsAg-positive
black pregnant women born and living in the urban township of
Soweto was previously found to be 0% [6].
Thus in light of programmatic challenges and the many competing health priorities in the country with limited resources, the
introduction of a HB birth dose, especially for home births in underresourced rural communities, may not be viewed as a priority at
present [52]. Since there are no South African studies which show a
reduction in HBsAg prevalence when the birth dose is used, further
studies are needed before any recommendations regarding this can
be made.
2.3. Catch-up vaccination programmes for adolescents
In regions highly endemic for HBV, the WHO places the most
emphasis on implementing universal infant immunisation with
high coverage, rather than on catch-up vaccination programmes
for adolescents. Only once high coverage rates of infants and young
children are achieved should catch-up vaccination for older children be considered in these regions [23]. This is a pragmatic
approach for sub-Saharan Africa, because transmission occurs
mostly before the age of 5 years in this region, and school immunisation programmes are largely non-existent. According to the most
C48
R.J. Burnett et al. / Vaccine 30S (2012) C45–C51
recently published EPI schedule, EPI-SA is meant to administer a Td
(tetanus and reduced strength diphtheria) vaccine to 12 year-olds
(Td-12y) [41], who are nearing completion of primary schooling.
However, there is no functional school-based immunisation programme through which this can be administered, and coverage for
Td-12y is extremely low (EPI-SA, personal communication). Currently, most children below 16 years of age should theoretically be
vaccinated as the HB vaccine was incorporated into EPI-SA in 1995,
thus it is also logical to consider HB vaccination during secondary
schooling at ≥16 years of age. However, by 2013 most children
born prior to 1995 should have completed their secondary education, thus there is a very small window of opportunity and it is
probably too late for the SADoH to consider this option. Thus, in
line with WHO recommendations, strengthening infant immunisation by increasing EPI coverage in sub-districts with sub-optimal
coverage should remain the priority for EPI-SA.
[20]. Unfortunately HBV DNA testing is not routinely conducted on
such cases.
Although the SADoH recommends HB vaccination for HCWs, it
has not been made mandatory [20,29,68]. An earlier study from
Gauteng, South Africa found that the majority of HCWs at high
risk for HBV are not vaccinated, with only 21.2% remembering ever
being vaccinated [68]. While current research has shown that the
situation has vastly improved, with HB vaccination being widely
available and 67.9% of Gauteng HCWs having received at least one
dose, only 19.9% had received all 3 doses [29]. Clearly, there is a
need for a national policy for the prevention and control of HBV in
HCWs to be developed and implemented in South Africa.
3. Impact of universal infant HB vaccination on the burden
of disease
3.1. Reduction in HBsAg prevalence in children
2.4. Vaccination of HCWs
HCWs are at high risk for HB infection, and HBV is acknowledged
as being a major cause of occupationally acquired viral hepatitis
in HCWs [20,27–29]. Conversely, nosocomial transmission of HBV
from infected HCWs to their patients can also occur [25,27]. Data
on the prevalence of HBsAg in sub-Saharan HCWs is scant. The few
studies that have been conducted have found HBsAg-positivity of:
25.7% in Nigerian surgeons (versus 15% in administrative staff) [54];
11% in Ugandan medical students [55]; 8.1–8.7% in Ugandan HCWs
[56,57], and 3.5% in South African HCWs (unpublished study).
In industrialised countries, which are largely in regions of low
HBV endemicity, there are policies aimed at preventing occupationally acquired and nosocomial transmission of HBV. For example, the
European Union (EU) requires all employers to provide information
and vaccination to at-risk HCWs [58–61], and it is official policy
in many EU countries to vaccinate all newly enrolled HCWs for
HBV [33,60,61]. Organisations such as the Viral Hepatitis Prevention Board endorsed this policy, and extended the recommendation
to include vaccination of students in their early years of study in
the health professions [62]. Similarly, the United States requires
that employers offer free vaccination to at-risk HCWs, as stipulated
in the Occupational Safety and Health Administration Blood-borne
Pathogen Standard [59,63]. When post-vaccination testing shows a
sufficient immune response, no booster doses are needed even after
subsequent loss of anti-HBs [34,36]. Revaccination of those who
fail to respond to the primary vaccination series is recommended,
because it has been shown that 30–69% of non-responders respond
to a second series [16,60].
In countries highly endemic for HBV, such as South Africa, the
occupational risk of contracting HBV is increased. HIV-positivity
is a risk factor for acquiring HBV infection; for reactivating HBV
infections that were previously cleared; and also for re-infection
with HBV in individuals who were previously immune through
clearance of natural infection [20]. HBV is about 100 times more
infectious than HIV, yet HCWs are generally more worried about
HIV, and seldom test for HBV infection after needle-stick injuries
or other occupational exposures [64]. In South Africa, it has been
estimated that 46% of hospital beds are occupied by patients with
HIV-related illnesses [65]. Of concern is that 63% (121/192) of
acquired immunodeficiency syndrome (AIDS) patients in a Gauteng
hospital had serological markers of past or present HBV infection,
and 40.6% (78/192) had active HBV infections (HBV DNA positive),
and were thus highly infectious [66]. A further concern is that
HBsAg-negative HBV infection is highly prevalent in HIV-positive
patients [20,66,67]. Thus unprotected HCWs exposed to the blood
or body fluids of such patients will not receive HBV post-exposure
prophylaxis (PEP) unless the source patient is tested for HBV DNA
Just over 20 years ago, a call was made for more research to be
conducted on the horizontal transmission of HBV in sub-Saharan
Africa, as it was felt that both the impending HIV epidemic and
the introduction of HBV vaccination would change the epidemiology of HBV to such an extent, that this information would be
lost forever [69]. As it turns out, this prediction has come true.
For example, a large South African study conducted just prior to
the introduction of the HB vaccine into the EPI, found that 8.1% of
0–6 month old babies, and 8.9% of 7–12 month old babies, were
HBsAg-positive; much higher rates than previously reported from
South Africa in these age groups [70]. It was speculated that this
increase may have been caused by an increased HIV prevalence in
pregnant women, resulting in either (a) increased HBV and HIV coinfection with a subsequent increase in perinatal HBV transmission,
or (b) immunosuppression in HIV mono-infected pregnant women
resulting in decreased transfer of anti-HBs to their offspring [20].
Fortunately the introduction of the HB vaccine in the EPI-SA in 1995
has reversed this trend, with all South African studies on vaccinated children finding low HBsAg carriage, ranging from 0.0% in
children with unknown HIV status, to 2.7% in HIV-positive children
[38,42,44,45].
3.2. Reduction in HCC
It is too early to measure the impact of HB vaccination on
the prevalence of HCC in South African adults. Although relatively
uncommon, HBV-associated HCC can present in children in subSaharan Africa. A recent South African national audit of children
≤14 years of age, found a decrease in the proportion of HCC in
malignant liver tumours between 1988–2003 and 1988–2006 from
35% (68/194) to 27% (77/274), with this reduction being attributed
to 10 years of universal infant immunisation [71,72]. The number of malignant liver tumours had increased by 80 cases, and the
incidence of HCC had increased by 9 cases over the 3 year period
(2004–2006), thus HCC accounted for only 11.3% of new cases. Also,
since 68 HCC cases had previously been recorded during 15 years,
13–14 cases would have been expected in these 3 years instead of
9. However, this is not a large reduction when compared to the dramatic reduction in HBsAg carriage found in younger children, and
this needs further investigation.
3.3. Reduction in extra-hepatic manifestations of chronic HBV
HBV-associated nephrotic syndrome (NS), particularly membranous nephropathy (MN) which accounts for 86% of HBV-associated
NS cases in KwaZulu-Natal, is one of the major extra-hepatic manifestations of chronic HB seen in South African children [73]. A
study conducted in a KwaZulu-Natal referral hospital, which is the
R.J. Burnett et al. / Vaccine 30S (2012) C45–C51
only public sector hospital in the province that provides paediatric
nephrology services, found an overall decrease in HBV-associated
MN in children ≤14 years old, from 1984 to 2001. The average annual incidence rate ratio (IRR) for the pre-immunisation
era (1984–1995) was 0.2/105 , while that for 2000–2001 was
0.03/105 . Although this decrease was not statistically significant
in ≤4 year-olds when comparing the average annual IRR for
1984–1995 (0.16/105 ) to that for 2000–2001 (0/105 ), the probability of finding no cases from 1998 to 2001 was statistically
significant (p = 0.01) when compared to finding 23 cases from 1984
to 1997. However, a statistically significant decrease was found in
the 5–9 year-old group, with an average annual IRR of 0.46/105 for
1984–1995 compared to 0.09/105 for 2000–2001. There was also
a decrease in the 10–14 year-old group (0.14/105 for 1984–1995
compared to 0/105 for 2000–2001), but this was not statistically
significant [73].
4. Discussion and conclusion
A number of studies have found the HB vaccine delivered
through the EPI-SA to be both highly immunogenic and effective,
and at current HB-3 coverage rates it is clear that HBsAg carriage
in young South African children will continue to be dramatically
reduced, if not eliminated. The high prevalence of HIV in pregnant
women does not seem to be having a major impact on HBV transmission in neonates and infants as previously feared. However, the
finding of 2.7% HBsAg carriage in HIV-positive babies [45] is of concern, even although this is significantly less than levels of above
8% found in a pre-vaccination study on babies of unknown HIV
status [70], and needs further investigation. An expedient strategy
would be to add HBV serology testing to any current study testing
the effectiveness of one of the newest vaccines (either rotavirus or
the pneumococcal conjugate vaccine) that have been added to the
EPI-SA, in HIV-positives.
While very little criticism can be directed towards HB vaccination within the EPI-SA, some recommendations can be made.
Currently infants are receiving 3 injections at weeks 6 and 14:
(DTaP [acellular pertussis]-IPV [inactivated poliovirus]-Hib, HepB,
and PCV13 [pneumococcal conjugate vaccine, which is only given
at 6 and 14 weeks, and then again at 9 months]). In order to
reduce the number of injections, the EPI-SA could strongly consider replacing the pentavalent (DTaP-IPV-Hib) with a hexavalent
(DTaP-IPV-Hib-HepB), which is available in South Africa [74]. A HB
birth dose is recommended when using combination vaccines, presumably because anti-HBs geometric mean titres (GMTs) with a
birth dose have been shown to be much higher than without [75].
However, a number of studies have shown good immunogenicity
and long-term anti-HBs memory when using a hexavalent (Infanrix Hexa, GlaxoSmithKline, Belgium) without a HB birth dose [75].
A recent South African study has found good seroprotection rates
(≥10 mIU/ml of anti-HBs) when administering an investigational
hexavalent (Hexaxim, Sanofi Pasteur, France) without a HB birth
dose (95.7%) and with a birth dose (99.0%). However, anti-HBs GMTs
were considerably lower without the birth dose (330 mIU/ml) than
with the birth dose (1913 mIU/ml) [76]. Heberbiovac HB, one of the
current HB vaccines used by EPI-SA, has a seroprotection rate of
97.8%, and a GMT of 1145 mIU/ml after 3 doses at 6, 10, and 14
weeks [40]. On the other hand, the first HB vaccine used in the EPISA (Hepaccine B) had a seroprotection rate of 93.0%, and a GMT of
only 258 mlU/ml when administered at the same schedule [77].
The investigational hexavalent performed better than Engerix-B
(administered together with DTP-Hib and OPV [oral polio virus] in
a third comparative arm of the Madhi et al. study), which elicited
a comparable seroprotection rate of 95.4%, but had a much lower
GMT of only 148 mIU/ml [76].
C49
When everything is taken into account, if high birth dose coverage of BCG (within 24 h) can be obtained in the rural areas of
South Africa, and if it is found that a HB birth dose is cost effective,
the best option may be to introduce a HB birth dose, and to use a
hexavalent vaccine. Further studies are required before this recommendation becomes policy. In the interim, the EPI-SA should focus
their efforts on attaining a high HB vaccine coverage in all districts
and sub-districts in the country, and prepare for introducing a HB
birth dose, if and when it can be done effectively and efficiently.
Now that 16 years have passed since the introduction of the HB
vaccine into the EPI-SA, it is too late to start a programme on mass
catch-up HB vaccination for adolescents. However, when a schoolbased immunisation programme is successfully implemented for
Td-12y, given that the WHO estimates HB-3 coverage to be only
56%, the EPI-SA may want to consider including targeted HB vaccination for 12 year-olds, if their Road to Health Cards show they
were not fully vaccinated as infants.
In light of the evidence presented here, it is strongly recommended that the SADoH develops a national policy for the
prevention and control of HBV in HCWs. This should include
testing for HBV status, and HB vaccination during the early years
of training, before student HCWs are exposed to patients [60,62].
Pre-vaccination testing will identify those who are protected
against HBV (anti-HBs ≥10 mIU/ml) through natural infection (i.e.
are also anti-HBc-positive), thus avoiding unnecessary vaccinations. Anti-HBs negative HCWs should be tested for HBsAg, and all
chronic HB carriers should be counselled about selecting a career
path which precludes them from performing exposure-prone
procedures that put patients at risk of HBV transmission [60], and
educated about the need to report all HCW-to-patient exposures
so that exposed patients can be given PEP for HBV in good time.
The remaining unexposed HCWs should be given a full 3 dose
course of HB vaccination, and be tested one month after receiving
the final dose [33,60]. Non-responders should be re-vaccinated
with another 3 doses. Boosters are not necessary if HCWs have
an adequate immune response of ≥10 mIU/ml anti-HBs [33–36],
although some authors recommend that a booster dose should
be given to HCWs with <100 mIU/ml [60]. While mandatory HB
vaccination and HBV testing may not be realistic in the South
African setting, the national policy should clearly place the onus on
the health education institution/employer to ensure that all HCWs
are educated about HBV transmission in the healthcare setting,
and are offered vaccination, testing, and appropriate counselling
or career guidance where necessary.
In conclusion, despite the gaps identified here, the introduction
of the HB vaccine into the EPI-SA in 1995 has been a resounding
success for the SADoH. Those responsible are to be congratulated
for their vision and foresight in making the prevention and control
of HBV a priority on the health agenda of the first democratically
elected government of South Africa.
Conflict of interest statement
None declared.
References
[1] Kramvis A, Kew MC. Epidemiology of hepatitis B virus in Africa, its genotypes
and clinical associations of genotypes. Hepatol Res 2007;37(s1):S9–19.
[2] Kiire CF. The epidemiology and prophylaxis of hepatitis B in sub-Saharan Africa:
a view from tropical and subtropical Africa. Gut 1996;38(Suppl. 2):S5–12.
[3] World Health Organization. Immunization, vaccines and biologicals: hepatitis B; 2008 [accessed August 2011] http://www.who.int/immunization/
topics/hepatitis b/en/index.html.
[4] World Health Organization Regional Office for Africa. Sixtieth session, Malabo,
Equatorial Guinea, 30 August–3 September 2010. Correlation between the
work of the Regional Committee, the Executive Board, and the World Health
Assembly. AFR/RC60/19.
C50
R.J. Burnett et al. / Vaccine 30S (2012) C45–C51
[5] Davis R. Africa 2010 in retrospect: hits and misses. Pan Afr Med J 2010;7(22).
[6] Kew MC. Progress towards the comprehensive control of hepatitis B in Africa:
a view from South Africa. Gut 1996;38(Suppl. 2):S31–6.
[7] Kew MC. Hepatitis B virus infection: the burden of disease in South Africa. S Afr
J Epidemiol Infect 2008;23(1):4–8.
[8] Beasley RP, Hwang LY. Postnatal infectivity of hepatitis B surface antigencarrier mothers. J Infect Dis 1983;147(2):185–90.
[9] Viral Hepatitis Prevention Board. Prevention and control of perinatal hepatitis
B virus (HBV) transmission in the WHO European region – a VHPB symposium
report – Istanbul, Turkey, March 15–17, 2006; December 2006, vol. 15, no. 1.
[10] Jonas MM. Hepatitis B and pregnancy: an underestimated issue. Liver Int
2009;29(Suppl. 1):133–9.
[11] Chen MT, Billaud JN, Sällberg M, Guidotti LG, Chisari FV, Jones J, et al. A function
of the hepatitis B virus precore protein is to regulate the immune response to
the core antigen. Proc Natl Acad Sci USAU S A 2004;101(41):14913–8.
[12] Chen M, Sällberg M, Hughes J, Jones J, Guidotti LG, Chisari FV, et al. Immune
tolerance split between hepatitis B virus precore and core proteins. J Virol
2005;79(5):3016–27.
[13] Edmunds WJ, Medley GF, Nokes DJ, O’Callaghan CJ, Whittle HC, Hall AJ. Epidemiological patterns of hepatitis B virus (HBV) in highly endemic areas. Epidemiol
Infect 1996;117(2):313–25.
[14] Wilson JN, Nokes DJ, Carman WF. The predicted pattern of emergence of vaccine-resistant hepatitis B: a cause for concern? Vaccine
1999;17(7–8):973–8.
[15] André F. Hepatitis B epidemiology in Asia, the Middle East and Africa. Vaccine
2000;18(Suppl 1):S20–2.
[16] Lin KW, Kirchner JT. Hepatitis B. Am Fam Phys 2004;69:75–82.
[17] François G, Dochez C, Mphahlele MJ, Burnett R, Van Hal G, Meheus A. Hepatitis B vaccination in Africa: mission accomplished. S Afr J Epidemiol Infect
2008;23:24–8.
[18] Davis LG, Weber DJ, Lemon SM. Horizontal transmission of hepatitis B virus.
Lancet 1989;1(8643):889–93.
[19] Mphahlele MJ, François G, Kew MC, Van Damme P, Hoosen AA, Meheus A. Epidemiology and control of hepatitis B: implications for eastern and southern
Africa. S Afr J Epidemiol Infect 2002;17(1,2):12–7.
[20] Burnett RJ, François G, Kew MC, Leroux-Roels G, Meheus A, Hoosen AA,
et al. Hepatitis B virus and human immunodeficiency virus co-infection in
sub-Saharan Africa: A call for further investigation. Liver Int 2005;25(2):
201–13.
[21] Heiberg IL, Hoegh M, Ladelund S, Niesters HG, Hogh B. Hepatitis B virus DNA
in saliva from children with chronic hepatitis B infection: Implications for
saliva as a potential mode of horizontal transmission. Pediatr Infect Dis J
2010;29(5):465–7.
[22] Ayoola EA. Viral hepatitis in Africa. In: Zuckerman AJ, editor. Viral hepatitis and
liver disease. New York: Alan R Liss; 1988. p. 161–9.
[23] World Health Organization. Hepatitis B vaccines. WHO position paper.
Wkly Epidemiol Rec 2009;40(84):405–20 [accessed August 2011]
http://www.who.int/wer/2009/wer8440.pdf.
[24] Simonsen L, Kane A, Lloyd J, Zaffran M, Kane M. Unsafe injections in the developing world and transmission of bloodborne pathogens: a review. Bull World
Health Organ 1999;77(10):789–800.
[25] World Health Organization. WHO best practices for injections and related
procedures toolkit; 2010 [accessed August 2011] http://whqlibdoc.who.
int/publications/2010/9789241599252 eng.pdf.
[26] Vermeulen M, Dickens C, Lelie N, Walker E, Coleman C, Keyter M, et al. Hepatitis
B virus transmission by blood transfusion during 4 years of individual-donation
nucleic acid testing in South Africa: estimated and observed window period
risk. Transfusion 2011, doi:10.1111/j.1537-2995.2011.03355.x [Epub ahead of
print].
[27] Hollinger FB. Hepatitis B virus. In: Fields BN, Knipe DM, Howley PM, et
al, editors. Fields virology. 3rd ed. Philadelphia: Lippincott-Raven; 1996.
p. 2739–90.
[28] François G, Hallauer J, Van Damme P. Hepatitis B vaccination: how to reach risk
groups. Vaccine 2002;21(1–2):1–4.
[29] Burnett RJ, François G, Mphahlele MJ, Mureithi JG, Africa PN, Satekge MM, et al.
Hepatitis B vaccination coverage in healthcare workers in Gauteng Province,
South Africa. Vaccine 2011;29(25):4293–7.
[30] World Health Organization. Viral hepatitis. Sixty-third World Health Assembly; 2010, March [accessed August 2011] http://apps.who.int/gb/ebwha
/pdf files/WHA63/A63 15-en.pdf.
[31] World Health Organization. Introduction of hepatitis B vaccine into childhood immunization services: Management guidelines, including information
for health workers and parents. WHO/V&B/01.31; 2001 [accessed August 2011]
http://www.who.int/vaccines-documents/DocsPDF01/www613.pdf.
[32] François G, Kew MC, Van Damme P, Mphahlele MJ, Meheus A. Mutant hepatitis
B viruses: a matter of academic interest only or a problem with far-reaching
implications. Vaccine 2001;19:3799–815.
[33] Kane M, Banatvala J, Da Villa G, Esteban R, Franco E, Goudeau A, et al. Are booster
immunisations needed for lifelong hepatitis B immunity? European Consensus
Group on HB Immunity. Lancet 2000;355(9203):561–5.
[34] Banatvala J, Van Damme P, Van Hattum J. Boosters for hepatitis B. European Consensus Group on Hepatitis B Immunity. Lancet 2000;356(9226):
337–8.
[35] Banatvala J, Van Damme P, Oehen S. Lifelong protection against hepatitis B: the role of vaccine immunogenicity in immune memory. Vaccine
2000;19(7–8):877–85.
[36] Banatvala JE, Van Damme P. Hepatitis B vaccine – do we need boosters? J Viral
Hepat 2003;10(1):1–6.
[37] Poovorawan Y, Chongsrisawat V, Theamboonlers A, Leroux-Roels G, Kuriyakose
S, Leyssen M, et al. Evidence of protection against clinical and chronic hepatitis
B infection 20 years after infant vaccination in a high endemicity region. J Viral
Hepat 2011;18(5):369–75.
[38] Tsebe KV, Burnett RJ, Hlungwani NP, Sibara MM, Venter PA, Mphahlele MJ.
The first five years of universal hepatitis B vaccination in South Africa:
evidence for elimination of HBsAg carriage in under 5-year-olds. Vaccine
2001;19(28–29):3919–26.
[39] Ngcobo JN, Cameron NA. The decision making process on new vaccines introduction in South Africa. Vaccine 2012;30(Suppl. 3):C9–13.
[40] Mphahlele MJ, Burnett RJ, Kyaw T, Schoeman HS, Aspinall S. Immunogenicity
and safety of yeast-derived recombinant hepatitis B vaccine (Heberbiovac HB)
in South African children. S Afr Med J 2004;94(4):280–1.
[41] South African Department of Health. Expanded Programme on Immunisation – EPI (SA) revised Childhood Immunisation Schedule from April 2009.
http://www.doh.gov.za/docs/epi-f.html [accessed August 2011].
[42] Mphahlele MJ, Tshatsinde EA, Burnett RJ, Aspinall S. Protective efficacy and
antibody follow-up of hepatitis B vaccine within the South African expanded
programme on immunisation. S Afr Med J 2002;92(8):612–3.
[43] Hino K, Katoh Y, Vardas E, Sim J, Okita K, Carman WF. The effect of introduction
of universal childhood hepatitis B immunization in South Africa on the prevalence of serologically negative hepatitis B virus infection and the selection of
immune escape variants. Vaccine 2001;19(28–29):3912–8.
[44] Schoub BD, Matai U, Singh B, Blackburn NK, Levin JB. Universal immunization
of infants with low doses of a low-cost: plasma-derived hepatitis B vaccine in
South Africa. Bull World Health Organ 2002;80(4):277–81.
[45] Simani OE, Leroux-Roels G, François G, Burnett RJ, Meheus A, Mphahlele MJ.
Reduced detection and levels of protective antibodies to hepatitis B vaccine in
under 2-year-old HIV positive South African children at a paediatric outpatient
clinic. Vaccine 2009;27:146–51.
[46] Moss WJ, Clements CJ, Halsey NA. Immunisation of children at risk of infection with human immunodeficiency virus. Bull World Health Organ 2003;81:
61–70.
[47] World Health Organization. Immunization profile – South Africa; 2011
[accessed November 2011] http://apps.who.int/immunization monitoring
/en/globalsummary/countryprofileresult.cfm?C=‘zaf’.
[48] Lee C, Gong Y, Brok J, Boxall EH, Gluud C. Effect of hepatitis B immunisation in
newborn infants of mothers positive for hepatitis B surface antigen: systematic
review and meta-analysis. BMJ 2006;332(7537):328–36.
[49] Burnett RJ, Ngobeni JM, François G, Hoosen AA, Leroux-Roels G, Meheus A, et al.
Increased exposure to hepatitis B virus infection in HIV-positive South African
antenatal women. Int J STD AIDS 2007;18(3):152–6.
[50] Jones CE, Naidoo S, De Beer C, Esser M, Kampmann B, Hesseling AC. Maternal
HIV infection and antibody responses against vaccine-preventable diseases in
uninfected infants. JAMA 2011;305(6):576–84.
[51] Health Systems Trust. The District Health Barometer 2008/09. Part
A: Indicator comparison by districts. Chapter 3. Output indicators:
immunisation; 2010 [accessed August 2011] http://www.hst.org.za/
uploads/files/DRAFTdhb0708 31.pdf.
[52] Kramvis A, Clements CJ. Implementing a birth dose of hepatitis B vaccine for
home deliveries in Africa – Too soon? Vaccine 2010;28:6408–10.
[53] Ngcobo NJ, Cameron NA. Introducing new vaccines into the childhood immunisation programme in South Africa. S Afr J Epidemiol Infect 2010;25(4):
3–4.
[54] Belo AC. Prevalence of hepatitis B virus markers in surgeons in Lagos: Nigeria.
East Afr Med J 2000;77(5):283–5.
[55] Pido B, Kagimu M. Prevalence of hepatitis B virus (HBV) infection among Makerere University medical students. Afr Health Sci 2005;5(2):92–8.
[56] Braka F, Nanyunja M, Makumbi I, Mbabazi W, Kasasa S, Lewis RF. Hepatitis B
infection among health workers in Uganda: evidence of the need for health
worker protection. Vaccine 2006;24(47–48):6930–7.
[57] Ziraba AK, Bwogi J, Namale A, Wainaina CW, Mayanja-Kizza H. Sero-prevalence
and risk factors for hepatitis B virus infection among health care workers in a
tertiary hospital in Uganda. BMC Infect Dis 2010;10:191.
[58] European Union. Directive 2000/54/EC of the European Parliament and of
the Council of 18 September 2000 on the protection of workers from risks
related to exposure to biological agents at work (seventh individual directive within the meaning of Article 16(1) of Directive 89/391/EEC). Official J
L 17/10/2000;262:0021–45.
[59] Bonanni P, Bonaccorsi G. Vaccination against hepatitis B in health care workers.
Vaccine 2001;19:2389–94.
[60] Gunson RN, Shouval D, Roggendorf M, Zaaijer H, Nicholas H, Holzmann H, et al.,
European Consensus Group. Hepatitis B virus (HBV) and hepatitis C virus (HCV)
infections in health care workers (HCWs): guidelines for prevention of transmission of HBV and HCV from HCW to patients. J Clin Virol 2003;27(3):213–30.
[61] De Schryver A, Claesen B, Meheus A, van Sprundel M, François G. European
survey of hepatitis B vaccination policies for healthcare workers. Eur J Public
Health 2011;21(3):338–43.
[62] FitzSimons D, François G, De Carli G, Shouval D, Prüss-Üstün A, Puro V, et al.
Hepatitis B virus, hepatitis C virus and other blood-borne infections in healthcare workers: guidelines for prevention and management in industrialised
countries. Occup Environ Med 2008;65:446–51.
[63] Viral Hepatitis Prevention Board. Viral hepatitis. Viral Hepatitis Newsl 1996,
July;5(1).
R.J. Burnett et al. / Vaccine 30S (2012) C45–C51
[64] De Villiers HC, Nel M, Prinsloo EAM. Occupational exposure to bloodborne
viruses amongst medical practitioners in Bloemfontein, South Africa. South Afr
Fam Pract 2007;49(3):14.
[65] Colvin M. Impact of AIDS – the health care burden. In: Abdool Karim SS, Abdool
Karim Q, editors. HIV/AIDS in South Africa. Cape Town: Cambridge University
Press; 2005. p. 338.
[66] Lukhwareni A, Burnett RJ, Selabe SG, Mzileni MO, Mphahlele MJ. Increased
detection of HBV DNA in HBsAg-positive and HBsAg-negative South African
HIV/AIDS patients enrolling for highly active antiretroviral therapy at a tertiary
hospital. J Med Virol 2009;81(3):406–12.
[67] Bell TG, Makondo E, Martinson NA, Kramvis A. Hepatitis B virus infection in
human immunodeficiency virus infected southern African adults: occult or
overt – that is the question. J Viral Hepat, submitted for publication.
[68] Vardas E, Ross MH, Sharp G, McAnerney J, Sim J. Viral hepatitis in South African
healthcare workers at increased risk of occupational exposure to blood-borne
viruses. J Hosp Infect 2002;50(1):6–12.
[69] Hudson CP. How AIDS forces reappraisal of hepatitis B virus control in subSaharan Africa. Lancet 1990;336(8727):1364–7.
[70] Vardas E, Mathai M, Blaauw D, McAnerney J, Coppin A, Sim J. Preimmunization
epidemiology of hepatitis B virus infection in South African children. J Med
Virol 1999;58(2):111–5.
C51
[71] Moore SW, Millar AJ, Hadley GP, Ionescu G, Kruger M, Poole J, et al. Hepatocellular carcinoma and liver tumors in South African children: a case for increased
prevalence. Cancer 2004;101(3):642–9.
[72] Moore SW, Davidson A, Hadley GP, Kruger M, Poole J, Stones D, et al. Malignant liver tumors in South African children: a national audit. World J Surg
2008;32(7):1389–95.
[73] Bhimma R, Coovadia HM, Adhikari M, Connolly CA. The impact of the
hepatitis B virus vaccine on the incidence of hepatitis B virus-associated
membranous nephropathy. Arch Pediatr Adolesc Med 2003;157(10):
1025–30.
[74] Visser A, Hoosen AA. Combination vaccines for South Africa. Vaccine
2012;30(Suppl. 3):C38–44.
[75] Dhillon S. DTPa-HBV-IPV/Hib Vaccine (Infanrix hexa): A Review of its Use as
Primary and Booster Vaccination. Drugs 2010;70(8):1021–58.
[76] Madhi SA, Mitha I, Cutland C, Groome M, Santos-Lima E. Immunogenicity and
safety of an investigational fully liquid hexavalent combination vaccine versus
licensed combination vaccines at 6: 10, and 14 weeks of age in healthy South
African infants. Pediatr Infect Dis J 2011;30(4):e68–74.
[77] Aspinall S, Kocks DJ. Immunogenicity of a low-cost hepatitis B vaccine in
the South African Expanded Programme on Immunisation. S Afr Med J
1998;88(1):36–9.
Vaccine 30S (2012) C52–C57
Contents lists available at SciVerse ScienceDirect
Vaccine
journal homepage: www.elsevier.com/locate/vaccine
Review
Haemophilus influenzae type b conjugate vaccines – A South African perspective
Adele Visser a,∗ , Anwar Hoosen b
a
b
Department Medical Microbiology, Division Clinical Pathology, University of Pretoria, National Health Laboratory Services, Tshwane Academic Division, South Africa
Department Medical Microbiology, University of Pretoria, National Health Laboratory Services, Tshwane Academic Division, South Africa
a r t i c l e
i n f o
Article history:
Received 15 February 2012
Received in revised form 3 June 2012
Accepted 8 June 2012
Keywords:
Haemophilus influenzae type b
HIV-1
Introduction of vaccines
a b s t r a c t
Introduction of Hib vaccine is known to positively impact on reduction of both morbidity and mortality
in children less than 5 years of age. Incorporation of this vaccine into a National EPI, however, does come
at a significant cost, which is especially important in non-GAVI funded countries. Compounded reduction
in response in certain patient populations and possible indication of booster doses further impacts on
cost-benefit analyses. Despite these issues, South Africa has supplied Hib vaccine as part of the National
EPI in the form of a combination vaccine, Pentaxim® , which combines Hib with Diphtheria, Tetanus,
acellular Pertussis (DTP) and Poliomyelitis since 2009. Prior to this, another combination vaccine was
utilized containing Hib and DTP. This has subsequently lead to a significant reduction in invasive Hib
disease post-introduction, therefore largely justifying utilization.
© 2012 Elsevier Ltd. All rights reserved.
1. Introduction
Historically, Haemophilus influenzae type b (Hib) was considered
the most common severe invasive infection in children younger
than 5 years of age [1,2] in industrialized countries [3], causing in excess of 8 million serious infections worldwide [4]. The
peak incidence among unvaccinated individuals varies from 6 to 7
months in developing countries [5], to slightly older in developed
countries [6]. Hib-related mortality is attributed to meningitis and
pneumonia, but invasive disease may also present as epiglottitis,
osteomyelitis, septic arthritis, septicemia, cellulitis and pericarditis [6]. Worldwide studies conducted prior to the introduction of
Hib vaccines amongst almost 4000 patients showed that in excess
of 90% of patients presented with one of six clinical syndromes. Of
these, meningitis accounted for more than half, but other clinical
manifestations included bacteremic pneumonia, epiglottitis, septicemia, cellulitis and osteoarticular disease (with septic arthritis
more common than osteomyelitis) [7]. Invasive disease represented only part of the clinical implication, as meningitis is often
complicated with hearing impairment, seizure disorders, cognitive
and developmental delay, and various other permanent neurological sequelae [8]. Introduction of Hib vaccination has had a
major impact on invasive disease in both developing [9–12] and
industrialized countries [7,13,14] despite the fact that disease epidemiology differs in these settings (Table 1).
South Africa was the first African country to introduce Hib vaccine as part of the National Expanded Program on Immunization
∗ Corresponding author. Tel.: +2782 780 1051; fax: +2712 329 7777.
E-mail address: [email protected] (A. Visser).
0264-410X/$ – see front matter © 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.vaccine.2012.06.022
(EPI) in 1999 [15]; the estimated coverage in 2004 was 92% [6].
Comparison of pre- and post-vaccination burden of diseases data
is not possible as a national laboratory-based surveillance system
for invasive Hib disease was established simultaneously with the
introduction of Hib vaccine in 1999 [15]. However, a study from
Cape Town in the pre-immunization era performed at an academic
hospital reported an incidence rate of invasive Hib disease of 169
and 47 per 100,000 population for children less than 1 and less than
5 years of age, respectively [17]. Based on the national laboratorybased surveillance (which yields only a fraction of the real burden)
reported rates of invasive Hib disease in the first year following
vaccination were 6.2 and 1.9 per 100,000 population in less than
1 year and less than 5 years old, respectively. Over the period of
2000–2004 rates of invasive Hib disease decreased significantly, by
65% and 71% in less than 1 year old and less than 5 year old [16],
indicating the impact of the Hib vaccine introduction in 1999.
Since 2003, the laboratory surveillance system become an active
system including enhanced surveillance conducted at sentinel sites
in each of the 9 provinces; detection rates of invasive Hib disease
remains low, but from 2003 to 2009 the detection rate increased
from 0.7 to 1.3 cases per 100,000 population in children less than
5 years old. Most of these cases were in fully vaccinated children
(primary series of 3 doses at 6, 10 and 14 weeks of age) [18].
These findings supported the decision to add since November 2010
a booster dose of Hib at 18 months of age as part of the a new
pentavalent vaccine [18].
The World Health Organization (WHO) Strategic Advisory
Group of Experts recommended worldwide implementation of
Hib vaccination, in 2006. They further stated exception from
this only if “robust epidemiologic evidence exists of low disease burden, lack of benefit, or overwhelming impediments to
A. Visser, A. Hoosen / Vaccine 30S (2012) C52–C57
C53
Table 1
Differential epidemiology of Hib disease in Africa versus the Americas described in children younger than 5 years of age and expressed per 100,000 population.
African population
Age of disease
Clinical features (number of cases) [12]
Death rate
6–7 months [6]
Meningitis
Pneumonia
60 (40–85)
American population
46 (31–52)
1724 (1574–2817)
12 months [5]
Meningitis
Pneumonia
11 (7–15)
25 (16–30)
510 (466–834)
Adapted from Ref. [4].
implementation” [19]. Despite convincing evidence collected over
more than twenty years, indicating vaccine efficacy [20,21], only
42% of children worldwide had received this vaccine by 2010 [22].
Two main obstacles have been cited for this; firstly the lack of
accurate epidemiological data due to various practical issues surrounding disease identification (discussed in text) and secondly,
the high vaccine cost [23].
2. Development of Hib conjugate vaccines
Development of the first polysaccharide Hib vaccines started in
the 1970s with the only field studies performed in Finland [24]. This
was achieved by utilizing the polyribosylribitol phosphate (PRP)
subunits of the bacterial capsule [25]. This vaccine showed an 90%
efficacy (95% confidence interval of 55–98%) specifically in children older than 18 months [24]. Efficacy in younger children is
markedly lower due to the T-cell independent nature of the vaccine response. These formulations were only licensed for use in
the United States (US) [26], Canada [27] and parts of Saudi Arabia
[28], where more than 10 million doses were administered from
1985 to 1989 in the US alone [13]. By the late 1980s, conjugate
vaccines were being developed against Hib disease, and following
this, combination formulations were developed containing these
Hib conjugate vaccines [29]. These conjugate vaccines were proven
to be superior to PRP vaccines as the PRP-only vaccines were poorly
immunogenic in children under the age of 18 months [24], lacked
a booster response [30] and did not show any reduction in nasal
carriage [31]. This was by and large due to the T-cell-independent
nature of the immune response to polysaccharides. Based on disease epidemiology where severe infection is typically noted in
younger children, an alternative was needed to improve immunogenicity in this target group [6]. The first Hib conjugate vaccine
introduced to the market was a diphtheria toxoid conjugate (PRPD), thereafter altered to the mutant diphtheria toxin conjugate
(PRP-HbOC) [7]. Later on, conjugates were developed containing
the outer membrane protein of Neisseria meningitides (PRP-OMP)
and tetanus toxoid (PRP-T) [32,33] (Table 2). The first vaccines to
be commercially produced were formulated as PRP-HbOC, PRP-D
or PRP-OMP and effectiveness was established by extensive clinical trials [34]. Subsequently, PRP-T formulations were produced
and efficacy and licensing were based on demonstrating equivalent serum antibody levels compared to PRP-OMP and PRP-HbOC.
Of note, most formulations currently utilized, conjugate to tetanus
Table 2
Conjugate vaccines developed to improve immunogenicity of Hib vaccines.
Corynebacterium
diphtheriae
Neisseria meningitides
Clostridium tetani [34]
Subunit utilized
Licensing
Modified non-toxic
fragment of diphtheria
toxin (PRP-HbOC)
Diphtheria toxoid
(PRP-D)
Outer membrane
protein
(PRP-OMP)
Tetanus toxoid
(PRP-T)
Vaccine efficacy
clinical trials [14,34]
Vaccine efficacy
clinical trials [14]
Equivalence studies
[31,32]
toxoid, as the conjugation technology is not protected by patent
laws [6]. PRP-D formulations are no longer in clinical use as these
vaccines have been shown to have inferior effectiveness, especially
in high prevalence disease populations [35].
In December 2007, a voluntary recall of specific Hib conjugate vaccine lots (PRP-OMP Pedvax HIB® and Combax® ) by
Merck & Co., Inc. (West Point, USA) indirectly lead to generalized reduction in vaccine coverage. The recall was purely
precautionary following identification of Bacillus cereus in vaccine
manufacturing equipment [36], and subsequent surveillance did
not reveal any contaminated vaccine lots [37] or clinical cases of
vaccine-associated B. cereus infection to recipients [36]. Subsequent
recommendations were to simply omit use of the booster dose,
but to continue vaccination otherwise. Despite this, a generalized
reduction in vaccine coverage was noted. This finding highlights
the importance of clearly communicated guidelines once a change
in national policy is necessary [38].
3. Cost, distribution and delivery
Hib vaccine is more expensive than most of the other EPI vaccines. Costs were estimated to be as much as seven times that of
measles, polio, Bacillus Calmette–Guérin (BCG), diphtheria, tetanus
and pertussis vaccine in 2005 [23] but current prices are 3 to 9 times
the cost (S. Phoshoko, Personal communication). By the end of 2004,
the WHO reported that only ten countries in Africa included Hib
conjugate vaccine as part of their EPI. These countries are Burundi,
The Gambia, Ghana, Kenya, Madagascar, Malawi, Rwanda, South
Africa, Uganda and Zambia [39]. However, the current state of Hib
vaccine use in Africa seems promising as only Equatorial Guinea,
Nigeria, Tunisia, Botswana and Somalia are not including Hib in
their routine EPI [40]. In January 2000, the Global Alliance for Vaccines and Immunization (GAVI) was launched, with the mission
statement, to provide access to vaccines to the 70 poorest countries
in the world [41]. Subsequently, this was expanded to the poorest
76 countries [23,42]. The strategy aims to provide these vaccines
through collaboration between the WHO, UNICEF, the World Bank,
the Bill & Melinda Gates Foundation, donor governments, international development and finance organizations, the pharmaceutical
industry, as well as from the developing countries themselves [41].
By the end of 2010, an additional 91 million children had received
a full course of Hib vaccines, they would otherwise not have had
access to [43]. One of the requirements for GAVI support is proof
of burden of disease [44]. This has been an issue in the past in the
Indian subcontinent, where inadequate surveillance data existed to
motivate for provision of vaccines [45]. Fortunately, this has fueled
research in this field, confirming mortality due to Hib meningitis to
be as high as 11% with 30% of survivors suffering subsequent major
neurological sequelae [45].
Despite formal inclusion in the respective EPI’s, vaccine coverage varies significantly from as low as 50% (Madagascar) [39] and
more recently, Central African Republic (58%), to 99% in Burkina
Faso [46]. Evaluation of rates of invasive Hib disease is dependent
on National Surveillance systems. Several countries do not make
use of this, and those who do, report significantly variable rates.
These vary from no reported cases (Congo, Gambia, Guinea-Bissau,
C54
A. Visser, A. Hoosen / Vaccine 30S (2012) C52–C57
Lesotho, Rwanda, Suriname and Zambia) in excess of 6000 Hib
meningitis cases (Burkina-Faso) [46].
4. Mechanism of vaccine protection
Initial efforts to develop a vaccine utilized polysaccharide
antigens. This elicits a T-cell independent response, classically characterized by lower antibody titers, low affinity antibodies with
the absence of immune memory. Subsequent efforts to conjugate vaccines to proteins, significantly improved the protective
response [47]. Clinically, the improved immunogenicity is of particular importance in children under the age of 18 months [24].
It has been established through PRP vaccine studies [48], that
antibody levels in excess of 0.15 ␮g/mL and 1 ␮g/mL in serum is
indicative of short- and long-term protection, respectively [49].
This is due to both the opsonic activity of antibodies [50–52], as well
as complement-mediated bactericidal activity [51,53]. In addition,
the vaccine offered indirect protection by delaying nasopharyngeal carriage and asymptomatic colonization amongst vaccinated
infants [54–57]. This provides an additional level of herd immunity
[58,59]. For this reason, Hib vaccine is considered to have effectiveness greater than reported efficacy [6]. Various studies have
described community settings where unvaccinated children show
significant disease reduction, as a byproduct of vaccination of their
peers [9,60–63]. Intermittent colonization, however, is associated
with development of natural immunity [64,65] and is likely the
cause of the natural decline in incidence of invasive disease with
age amongst unvaccinated children [66].
HIV-1 positive patients generally do not launch the same degree
of immune response to vaccines as their HIV-negative counterparts
in terms of antibody titer production [49]. In addition, presence of
anti-PRP antibodies may not confer protection within this population group, as in some instances, antibodies have been shown
to be functionally impaired [67]. This quantitative and qualitative
impairment seems to correlate with degree of HIV-1 disease progression [67,68].
5. Vaccine efficacy and effectiveness
Epidemiologically, Hib vaccine effectiveness is considered as a
measure of reduction in invasive disease. Invasive disease is confirmed by culture of H. influenzae type b from blood or cerebrospinal
fluid (CSF). However, invasive disease is generally considered as a
poor indicator of overall Hib disease. In addition, there a relatively
small fraction of children with other invasive disease forms like
Hib pneumonia will be bacteremic. Furthermore, false laboratory
negative results may occur due to inherent difficulties in bacterial
culture. Hib is a fastidious organism and is highly sensitive to variables pertaining to sampling after initiation of antibiotic therapy,
transport delay and incubation conditions [7]. For these reasons
using this case definition, the number of clinical cases, may be
significantly underestimated [6]. Various authors have suggested
alternative diagnostic and epidemiological means, to overcome this
problem, including antigen detection methods [69,70] as well as
vaccine-probe study designs [71]. Laboratory parameters focusing
on both quantitative and qualitative antibody characteristics have
been suggested as markers of protection against disease [72–76].
This is in light of the fact that immunoglobulin quantity [77], subtype [73,76] and avidity [72–75] all contribute to the protective
effect.
The WHO advocates that all countries should measure the
impact of Hib vaccination in their setting, if practically permitted
[78]. The aim with this is not only to determine the vaccine performance under field conditions in general, but specifically within
certain population groups. Of particular interest is HIV-1 positive
individuals, as vaccine efficacy may be reduced [79]. Proof of effectiveness within a specific population aids in justifying use of these
vaccines as part of national guidelines, seeing as this vaccine is in
general more costly than most other vaccines included in the EPI. To
determine effectiveness of Hib vaccine, a high-quality populationbased surveillance system is required to be in place, to collect data
from both pre-vaccine and post-vaccine periods [78]. The South
African National Surveillance system was established the same year
as introduction of Hib vaccine into the EPI in 1999 [18]. Therefore, pre-vaccination data is restricted to studies not performed
on national level [17]. Of note, all countries that have included Hib
vaccines as part of the national vaccination schedule have shown
a significant reduction in invasive disease [14,21,80]. As part of an
extensive meta-analysis performed by O’Loughlin et al. [78], vaccine efficacy against invasive disease was found to be 95% (95% CI
82–99). This corresponds well with a Cochrane review on this matter [81], as well as various geographically diverse studies [9,82–87].
6. Hib vaccination and HIV-1 populations
At present, there are an estimated 3,4 million HIV-infected
children under the age of 15 years, with 390,000 children newly
infected per annum [88]. Of these, less than 10% receive the ART
they require [89]. Amongst these patients, one in three children
will demise before one year of age, from various causes, including serious bacterial infection [90]. HIV-infected children are at a
significantly higher risk of developing bacteremic pneumonia than
their HIV-negative counterparts [91]. In the absence of ART, use of
co-trimoxazole prophylaxis has been shown to reduce mortality
by as much as 43% [92]. It is postulated that is due to prevention of invasive bacterial infection [93]. This practice, however,
requires daily administration of antibiotics for prolonged periods
of time, and therefore preventative vaccines may have a major
impact in reducing mortality in this respect [93]. The WHO recommends use of all routine vaccines in HIV-infected patients with
some notable alterations [94]; firstly evaluation of risk for disseminated BCG [95], and secondly earlier administration of measles
vaccine owing to reduced maternal antibody levels for placental
transfer [96]. Additionally, due to the inherent immunosuppression noted in HIV-infected individuals, effectiveness of vaccines, in
general, has been described to be reduced [79], often necessitating
booster doses [93].
Very limited data is available on Hib vaccine effectiveness within
settings with a high HIV-1 seroprevalence. Attempts to study vaccine performance have been published from Malawi [84] and Kenya
[97], showing either very low patient numbers or low HIV-1 seroprevalence, respectively. Most of our currently understanding of
Hib vaccine in this population, comes from a study performed in
South Africa. In this study, it is evident that vaccine effectiveness
is reduced amongst HIV-infected patients, although still showing
moderate activity (55% disease reduction versus 91% amongst HIV1 negative patients). The HIV-1 rate used in this study was obtained
from antenatal clinic attendee data, and therefore, vaccine efficacy
may have been underestimated [93]. Furthermore, the risk of vaccine failure was estimated to be 35 fold higher (95% CI 14.6–84.6)
for HIV-infected patients [67]. The reason for this seems to be due
to a reduction in both quantity and quality of Hib antibodies [67].
In the South African study, HIV-infected children not only had a
statistically significantly lower geometric mean antibody concentration 1-month post-immunization, but also lower rates of HibPS
antibody concentrations to enable a 50% serum bactericidal activity
[67]. Notably, booster doses of Hib vaccine have shown a subsequent improvement of antibody titers to protective levels [98,99],
and some authors advocate this practice, although optimal timing of vaccination has not been established. However, the use of
A. Visser, A. Hoosen / Vaccine 30S (2012) C52–C57
antibody level as a marker of protection within this patient population has been questioned by some authors [93] and more extensive
studies are therefore warranted [93].
7. Hib vaccines and South Africa
South Africa is not included as one of the GAVI funded nations
[43]. Despite this, it was the first African country to self-finance
inclusion of Hib conjugate vaccines as part of the EPI since 1999
[16]. Furthermore, the most recent EPI schedule, as implemented
in 2009, also includes a booster dose at 18 months [100] as part of
the pentavalent vaccine (Pentaxim® ) [101].
From introduction to the South African EPI in 1999, Hib vaccine was administered as part of a combination formulation with
Diphtheria, Tetanus and whole cell Pertussis (DTP). Although
monovalent formulations of the Hib vaccine are available, various combination vaccines offer the advantage of fewer injections
without compromising on the number of antigens administered
[102]. The Centers for Disease Control and Prevention recommends
two (PRP-OMP) to three (PRP-T) primary doses, in monovalent
or combination form, with a booster dose at 12–15 months.
Licensed vaccines may be used interchangeably, in order to complete the vaccination series. Of note, the Hiberix® formulation
(GlaxoSmithKline, Bryanston, South Africa) is only registered for
use as a booster, and not for primary vaccination [102]. The EPI
currently in effect, as stipulated in April 2009 utilizes the Sanofi
Pasteur vaccine, Pentaxim® , which is a combination vaccine for
DTP (acellular formulation), Hib and Poliomyelitis. Since first being
marketed in 1997, more than 100 million doses have been administered in over 100 countries, of which 23 have included it as part of
the local EPI [103]. GAVI-supported countries use the pentavalent
formulation, which contains Diphtheria, Tetanus, whole-cell Pertussis, H. influenzae type b and Hepatitis B virus. This formulation
is less expensive but does have a worse side-effect profile owing to
use of whole-cell as opposed to acellular Pertussis [42].
There has been a significant reduction in cases of invasive Hib
disease since the introduction of the Hib vaccine. This trend is most
obvious within the below one year of age population group. Risk
factors for developing invasive Hib disease were identified as HIV-1
infection and incomplete vaccination. Despite the clear correlation
between HIV-infection and risk of vaccine failure [67], vaccine failures have not been described in other high HIV-1 seroprevalence
settings [104]. The changes made within the national vaccination
recommendations, are also supported by an improved surveillance
system. This laboratory-based surveillance system identified that
the incidence of non-typable H. influenzae was higher amongst
HIV-1 infected patients, and laboratory tested antimicrobial resistance was becoming increasingly important [16]. It did not allude to
the bimodal vaccine failure pattern described previously in South
Africa amongst HIV-infected patients [91,105]. The introduction of
the booster dose was prompted by resurgence of invasive Hib disease, which was ascribed to vaccine failure [18]. It will, however be
interesting to observe the impact of the booster dose, as introduced
in 2009, on the epidemiology of invasive Hib disease amongst HIV-1
infected and uninfected children.
8. Conclusion
The global acceptance of Hib vaccines has led to major reduction in global disease burden, directly impacting on morbidity and
mortality [7]. As the relatively high cost of incorporating this vaccine into any national immunization schedule invariably becomes
an important determinant for use, external funding to poorer countries is essential to ensure adequate vaccine coverage to effect the
same disease reduction to all.
C55
The high sero-prevalence of HIV-1 in South Africa compounds
issues surrounding Hib disease prevention, as HIV-infected children seem to show a more rapid waning immunity as compared
to their HIV negative counterparts. This, combined with a higher
risk of invasive Hib disease in HIV-infected individuals, is cause for
concern. The impact of the booster dose of Hib vaccine administered at 18 months remains to be seen as the hope is that this will
provide benefit not only to partially vaccinated patients, but also
unvaccinated individuals by providing an additional vaccination
opportunity in the second year of life [18].
Conflict of interest statement
None declared.
References
[1] CDC. Notice to readers. Haemophilus influenzae type b vaccine. MMWR Morb
Mortal Wkly Rep 1988;36:832.
[2] CDC. Progress toward elimination of Haemophilus influenzae type b invasive
disease among infants and children – United States, 1998– 2000. MMWR
Morb Mortal Wkly Rep 2002;51:234–7.
[3] Cochi S, O’Mara D, Preblud S. Progress in Haemophilus influenzae type b
polysaccharide vaccine use in the Unites States. Pediatrics 1988;81:166–9.
[4] Watt J, Wolfson L, O’Brien K, Henkle E, Deloria-Knoll M, McCall N, et al. Burden
of disease caused by Haemophilus influenzae type b in children younger than
5 years: global estimates. Lancet 2009;374:903–11.
[5] Claesson B. Epidemiology of invasive Haemophilus influenzae type b disease
in Scandinavia. Vaccine 1993;11:S30–3.
[6] Morris S, Moss W, Halsey N. Haemophilus influenzae type b conjugate vaccine
use and effectiveness. Lancet Infect Dis 2008;8:435–43.
[7] Peltola H. Worldwide Haemophilus influenzae type b disease at the beginning
of the 21st century: global analysis of the disease burden 25 years after the
use of the polysaccharide vaccine and a decade after the advent of conjugates.
Clin Microbiol Rev 2000;13:302–17.
[8] Broome D. Epidemiology of Haemophilus influenzae type b infections in the
United States. Pediatr Infect Dis J 1987;6:779–82.
[9] Adegbola R, Secka O, Lahai G, Lloyd-Evans N, Njie A, Usen S. Elimination
of Haemophilus influenzae type b (Hib) disease from The Gambia after the
introduction of routine immunization with the Hib conjugate vaccine: a
prospective study. Lancet 2005;366:144–50.
[10] Martin M, Casellas J, Madhi S, Urquhart T, Delport S, Ferrero F. Impact
of Haemophilus influenzae type b conjugate vaccine in South Africa and
Argentina. Pediatr Infect Dis J 2004;23:842–7.
[11] Wenger J, DiFabio J, Landaverde J, Levine O, Gaafar T. Introduction of Hib
conjugate vaccines in the non-industrialized world: experience in four ‘newly
adopting’ countries. Vaccine 1999;18:736–42.
[12] Wilson N, Mansoor O, Wenger J, Martin R, Zanardi L, O’Leary M. Estimating
the Haemophilus influenzae type b (Hib) disease burden and the impact of Hib
vaccine in Fiji. Vaccine 2003;21:1907–12.
[13] Adams W, Deaver K, Cochi S, Plikaytis B, Zell E, Broome C. Decline of childhood Haemophilus influenzae type b (Hib) disease in the Hib vaccine era. JAMA
1993;269:264–6.
[14] Heath P, McVernon J. The UK Hib vaccine experience. Arch Dis Child
2002;86:396–9.
[15] Huebner R, Klugman K, Matai U, Eggers R, Hussey G. Laboratory surveillance
for Haemophilus influenzae type b, meningococcal and pneumococcal disease.
Haemophilus Surveillance Working Group. S Afr Med J 1999;89:924–5.
[16] Von Gottberg A, De Gouveia I, Madhi S. Impact of conjugate Haemophilus
influenzae type b (Hib) vaccine introduction in South Africa. Bull World Health
Organ 2006;84:811–8.
[17] Hussey G, Hitchcock J, Schaaf H, Hanslo GC, Van Schalkwyk E, Pitout J, et al.
Epidemiology of invasive Haemophilus influenzae infections in Cape Town,
South Africa. Ann Trop Paediatr 1994;14:97–103.
[18] Von Gottberg A, Cohen C, Whitelow A, Chhagan M, Flannery B, Cohen A, et al.
Invasive disease due to Haemophilus influenzae serotype b ten years after
routine vaccination, South Africa, 2003–2009. Vaccine 2012;30:565–71.
[19] World Health Organization. Conclusions and recommendations from the
Strategic Advisory Group of Experts to the Department of Immunization,
vaccines and biologicals. Wkly Epidemiol Rec 2006;81:1–12.
[20] Bisgard K, Kao A, Leake J, Strebel P, Perkins B, Wharton M. Haemophilus influenzae invasive disease in the United States, 1994–1995: near disappearance of
a vaccine-preventable childhood disease. Emerg Infect Dis 1998;4:229–37.
[21] Murphy T, White K, Pastor P. Declining incidence of Haemophilus influenzae
type b disease since introduction of vaccination. JAMA 1993;269:246–8.
[22] World Health Organization. Global Immunization Data; Accessed at:
http://www.who.int/immunization monitoring/Global Immunization Data.
pdf [accessed on 20.10.11].
[23] World Health Organization. Haemophilus influenzae vaccine (HiB) Accessed
at: http://www.who.int/immunization delivery/vaccines/en/ [accessed on
25.1.12].
C56
A. Visser, A. Hoosen / Vaccine 30S (2012) C52–C57
[24] Peltola H, Kayhty H, Virtanen M, Makela P. Prevention of Haemophilus influenzae type b bacteraemic infections with the capsular polysaccharide vaccine.
N Engl J Med 1984;310:1561–6.
[25] Anderson P, Peter R, Johnston B, Wetterlow L, Smith D. Immunization of
humans with polyribosylphosphate, the capsular antigen of Haemophilus
influenzae, type b. J Clin Invest 1972;51:39–44.
[26] American Academy of Pediatrics Committee on Infectious Diseases.
Haemophilus influenzae type b polysaccharide vaccine. Pediatrics
1985;76:322–4.
[27] Canada Diseases Weelkly Report. Statement on Haemophilus influenzae type
b polysaccharide vaccine. Can Dis Weekly 1986;12:33–5.
[28] Narchi H, Kulaylat N. Regional Haemophilus influenzae type b immunization program: a success or a false sense of security. Saudi Med J 1997;18:
155–7.
[29] Anderson P. Antibody responses to Haemophilus influenzae type b and diphtheria toxin induced by conjugates of oligosaccharides of the type b capsule
with the nontoxic protein CRM197. Infect Immun 1983;39:233–8.
[30] Makela P, Peltola H, Kayhty H, Jousimies H, Pettay O, Ruoslahti E, et al.
Polysaccharide vaccines of group A Neisseria meningitidis and Haemophilus
influenzae type b: a field trial in Finland. J Infect Dis 1977;136:S43–50.
[31] Takala A, Eskola J, Leinonen M, Kayhty H, Nissinen A, Pekkanen E, et al.
Reduction of oropharyngeal carriage of Haemophilus influenzae type b
(Hib) in children immunized with an Hib conjugate vaccine. J Infect Dis
1991;164:982–6.
[32] Decker M, Edwards K, Bradley R, Palmer R. Comparative trial in infants of four
conjugate Haemophilus influenzae type b vaccines. J Pediatr 1992;120:184–9.
[33] Granoff D, Anderson E, Osterholm M, Holmes S, McHugh J, Belshe R, et al. Differences in immunogenicity of three Haemophilus influenzae type b conjugate
vaccines in infants. J Pediatr 1992;121:187–94.
[34] Heath P. Haemophilus influenzae type b conjugate vaccines: a review of efficacy data. Pediatr Infect Dis J 1998;17:S117–22.
[35] Ward J, Brenneman G, Letson G, Heyward W. Limited efficacy of a Haemophilus
influenzae type b conjugate vaccine in Alaska Native infants. The Alaska H
influenzae Vaccine Study Group. N Engl J Med 1990;323:1393–401.
[36] Huang W, Chang S, Miller E, Woo E, Hoffmaster A, Gee J, et al. Safety assessment of recall Haemophilus influenzae type b (Hib) conjugate vaccines – United
States, 2007–2008. Pharmacoepidemiol Drug Saf 2010;19:306–10.
[37] CDC. Interim recommendations for the use of Haemophilus influenzae type
b (Hib) conjugate vaccines related tot he recall of certain lots of Hibcontaining vaccines (PedvaxHIB and Comvax). MMWR Morb Mortal Wkly
Rep 2007;56:1318–20.
[38] White K, Pabst L, Cullen K. Up-to-date Haemophilus influenzae type b vaccination coverage during a vaccine shortage. Pediatrics 2011;127:e707–12.
[39] Arevshatian L, Clements C, Lwanga S, Misore A, Ndumbe P, Seward J, et al. An
evaluation of infant immunization in Africa: is a transformation in progress?
Bull World Health Organ 2007;85:449–57.
[40] World Health Organization. Global Immunization Data. Accessed at:
http://www.who.int/immunization monitoring/Global Immunization Data.
pdf [accessed on 11.10.11].
[41] GAVI. Accessed at: http://www.gavialliance.org/about/mission/what/
[accessed on 20.10.11].
[42] GAVI. Accessed at: http://www.gavialliance.org/ [accessed on 20.4.12].
[43] GAVI. Accessed at: http://www.gavialliance.org/about/mission/impact/
[accessed on 20.10.11].
[44] GAVI.
Accessed
at:
http://www.gavialliance.org/about/governance/
programme-policies [accessed on 26.4.12].
[45] Vashishtha V. Introduction of Hib containing pentavalent vaccine in national
immunization program of India: the concerns and the reality! Indian Pediatr
2009;46:781–2.
[46] World
Health
Organization.
Accessed
at:
http://apps.who.int/
immunization monitoring/en/globalsummary/countryprofileresult.cfm?C
=bfa [accessed on 25.4.12].
[47] Siegrist C. Vaccine immunology. In: Plotkin S, Orenstein W, Offit P, editors.
Vaccines. Fifth ed. Elsevier; 2008. p. 17–36.
[48] Peltola H, Kayhty H, Sivonen A, Makela P. Haemophilus influenzae type b capsular polysaccharide vaccine in children: a double-blind field study of 100,000
vaccines 3 months to 5 years of age in Finland. Pediatrics 1977;60:730–7.
[49] Kayhty H, Peltola H, Karanko V, Makela P. The protective level of serum antibodies to the capsular polysaccharide of Haemophilus influenzae type b. J Infect
Dis 1983;147:1100.
[50] Cates K, Marsh K, Granoff D. Serum opsonic activity after immunization of
adults with Haemophilus influenzae type b-diptheria toxoid conjugate vaccine.
Infect Immun 1985;48:183–9.
[51] Johnston R, Anderson P, Rosen F, Smith D. Characterization of human antibody
to polyribophosphate, the capsular antigen of Haemophilus influenzae type B.
Clin Immunol Immunopathol 1973;1:234–40.
[52] Newman S, Waldo B, Johnston R. Separation of serum bactericidal and
opsonizing activities for Haemophilus influenzae type b. Infect Immun
1973;8:488–90.
[53] Anderson P, Johnston R, Smith D. Human serum activities against Haemophilus
influenzae, type b. J Clin Invest 1972;51:31–8.
[54] Barbour M. Conjugate vaccines and the carriage of Haemophilus influenzae
type b. Emerg Infect Dis 1996;2:176–82.
[55] Heath P, Booy R, Azzopardi H, Slack M, Bowen-Morris J, Griffiths H, et al. Antibody concentration and clinical protection after Hib conjugate vaccination in
the United Kingdom. J Am Med Assoc 2000;284:2334–40.
[56] McVernon J, Howard A, Slack M, Ramsay M. Long-term impact of vaccination on Haemophilus influenzae type b (Hib) carriage in the United Kingdom.
Epidemiol Infect 2004;132:765–7.
[57] Murphy T, Pastor P, Medley F, Osterholm M, Granoff D. Decreased
Haemophilus colonization in children vaccinated with Haemophilus influenzae type b conjugate vaccine. J Pediatr 1993;122:517–23.
[58] Barbour M, Mayon-White R, Coles C, Crook D, Moxon E. The impact of conjugate vaccine on carriage of Haemophilus influenzae type b. J Infect Dis
1995;171:93–8.
[59] Mohle-Boetani J, Ajello G, Breneman E. Carriage of Haemophilus influenzae
type b in children after widespread vaccination with conjugate Haemophilus
influenzae type b vaccines. Pediatr Infect Dis J 1993;12:589–93.
[60] Dagan R, Fraser D, Roitman M. Effectiveness of a nationwide infant immunization program against Haemophilus influenzae type b. The Israeli Pediatric
Bacteremia and Meningitis group. Vaccine 1999;17:134–41.
[61] Garpenholt O, Hugosson S, Fredlud H, Giesecke J, Olcen P. Invasive disease
due to Haemophilus influenzae type b during the first six years of general
vaccination of Swedish children. Acta Paediatr 2000;89:471–4.
[62] Hviid A, Melbye M. Impact of routine vaccination with a conjugate
Haemophilus influenzae type b vaccine. Vaccine 2004;22:378–82.
[63] Peltola H, Kilpi T, Anttila M. Rapid disappearance of Haemophilus influenzae type b meningitis after routine childhood immunization with conjugate
vaccines. Lancet 1992;340:592–4.
[64] Hall D, Lum M, Knutson L, Heyward W, Ward J. Pharyngeal carriage and
acquisition of anticapsular antibody to Haemophilus influenzae type b in
a high-risk population in southwestern Alaska. Am J Epidemiol 1987;126:
1190–7.
[65] Michaels R, Norden C. Pharyngeal colonization with Haemophilius influenzae type b: a longitudinal study of families with a child with meningitis or
epilottitis due to H influenzae type b. J Infect Dis 1977;136:222–8.
[66] Anderson P, Smith D, Ingram D, Wilkins J, Wehrle P, Howie V. Antibody to polyribophosphate of Haemophilus influenzae type b in infants
and children: effects of immunization with Polyribophosphate. J Infect Dis
1977;136:S57–62.
[67] Madhi S, Kuwanda I, Saarinen L, Cutland C, Mothupi R, Kayhty H, et al.
Immunogenicity and effectivenss of Haemophilus influenzae type b conjugate vaccine in HIV infected and uninfected African children. Vaccine
2005;23:5517–25.
[68] Peters V, Sood S. Immunity to Haemophilus influenzae type b polysaccharide
capsule after vaccination with the complete series of oligosaccharide CRM197
conjugate vaccine in infants with human immunodeficiency virus infection.
J Pediatr 1996;128:363–5.
[69] Kennedy W, Chang S, Purdy K. Incidence of bacterial meningitis in Asia using
enhanced CSF testing: polymerase chain reaction, latex agglutination and
culture. Epidemiol Infect 2007;135:1217–26.
[70] Saha S, Baqui A, Areefin S. Detection of antigenuria for diagnosis of invasive
Haemophilus influenzae type b disease. Ann Trop Paediatr 2006;26:326–9.
[71] Mulholland E. Use of vaccine trials to estimate burden of disease. J Health
Popul Nutr 2004;22:257–67.
[72] Amir J, Liang X, Granoff D. Variability in the functional activity of
vaccine-induced antibody to Haemophilus influenzae type b. Pediatr Res
1990;27:358–64.
[73] Amir J, Scott M, Nahm M, Granoff D. Bactericical and opsonic activity of IgG1
and IgG2 anticapsular antibodies to Haemophilus influenzae type b. J Infect Dis
1990;162:163–71.
[74] Lucas A, Granoff D. Functional differences in idiotypical defined IgG1
anti-polysaccharide antibodies elicited by vaccination with Haemophilus
influenzae type b polysaccharide–protein conjugates. J Immunol 1995:154.
[75] Schlesinger Y, Granoff D. Avidity and bactericidal activity of antibody elicited
by different Haemophilus influenzae type b conjugate vaccines. The Vaccine
Study Group. JAMA 1992;267:1489–94.
[76] Schreiber J, Barrus V, Cates K, Siber G. Functional characterization of human
IgG, IgM and IgA antibody directed to the capsule of Haemophilus influenzae
type b. J Infect Dis 1986;153:8–16.
[77] Granoff D. Assessing Efficacy of Haemophilus influenzae type B combination
vaccines. Clin Infect Dis 2001;33:S278–87.
[78] O’Loughlin R, Edmond K, Mangtani P, Cohen A, Shetty S, Hajjeh R, et al.
Methodology and measurement of the effectiveness of Haemophilus influenzae type b vaccine: systematic review. Vaccine 2010;28:6128–36.
[79] Moss W, Clements C, Halsey N. Immunization of children at risk of
infection with human immunodeficiency virus. Bull World Health Organ
2003;81:61–70.
[80] Ribeiro G, Reis J, Cordeiro S, Lima J, Gouveia E, Petersen M. Prevention of
Haemophilus influenzae type b (Hib) meningitis and emergence of serotype
replacement with type and strains after introduction of Hib immunization in
Brazil. J Infect Dis 2003;187:109–16.
[81] Swingler G, Fransman D, Hussey G. Conjugate vaccines for preventing Haemophilus influenzae type b infections. CDS Rev 2007;2:CD001729
[review].
[82] Baqui A, Arifeen SE, Saha S, Persson I, Zaman K, Gessner B. Effectiveness of
Haemophilus influenzae type b conjugate vaccine on prevention of pneumonia
and meningitis in Bangladeshi children: a case-control study. Pediatr Infect
Dis J 2007;26:565–71.
[83] Bower C, Condon R, Payne J, Burton P, Watson C, Wild B. Measuring the impact
of conjugate vaccines on invasive Haemophilus influenzae type b infection in
Western Australia. Aust N Z J Public Health 1998;22:67–72.
A. Visser, A. Hoosen / Vaccine 30S (2012) C52–C57
[84] Daza P, Banda R, Misoya K, Katsulukuta A, Gessner B, Katsande R. The impact
of routine infant immunization with Haemophilus influenzae type b conjugate
vaccine in Malawi, a country with high human immunodeficiency virus prevalence. Vaccine 2006:24.
[85] Jafari H, Adams W, Robinson K, Plikaytis B, Wenger J. Efficacy of Haemophilus
influenzae type b conjugate vaccines and persistence of disease in disadvantaged populations. The Haemophilus influenzae Study Group. Am J Public
Health 1999;89:364–8.
[86] Lee E, Corcino M, Moore A, Garib Z, Pena C, Sanchez J. Impact of Haemophilus
influenzae type b conjugate vaccine on bacterial meningitis in the Dominican
Republic. Rev Panam Salud Publica 2008:24.
[87] Lee E, Lewis R, Makumbi I, Kekitiinwa A, Ediamu T, Bazibu M. Haemophilus
influenzae type b conjugate vaccine is highly effective in the Ugandan routine immunization program: a case-control study. Trop Med Int Health
2008;13:495–502.
[88] The United Nations Children’s Fund. Accessed at: www.childinfo.
org/hiv aids.html [accessed on 28.12.11].
[89] The United Nations Children’s Fund. Children and AIDS: a stocktaking report.
Geneva: UNICEF; 2007, pp.1–40.
[90] Newell M, Coovadia H, Cortina-Borja M, Rollins N, Gaillard P, Dabis F. Mortality
of infected and uninfected infants born to HIV-infected mothers in Africa: a
pooled analysis. Lancet 2004;364:1236–43.
[91] Madhi S, Petersen K, Madhi A, Khoosal M, Klugman K. Increased disease burden and antibiotic reisstance of bacteria causing severe community-acquired
lower respiratory tract infection in human immunodeficiency virus type-1
infected children. Clin Infect Dis 2000;31:170–6.
[92] Mulenga V, Ford D, Walker A, Mwenya D, Mwansa J, Sinyinza F. Effect of
cotrimoxazole on causes of death, hospital admission and antibiotic use in
HIV-infected children. AIDS 2007;21:77–84.
[93] Mangtani P, Mulholland K, Madhi S, Edmond K, O’Laughlin R, Hajjeh R.
Haemophilus influenzae type b disease in HIV-infected children: a review of
the disease epidemiology and effectiveness of Hib conjugate vaccines. Vaccine
2010;28:1677–83.
C57
[94] Mphahlele M, Mda S. Immunizing the HIV infected child: a view from subSaharan Africa. Vaccine 2012;30(Suppl. 3):C61–5.
[95] World Health Organization. Revised BCG vaccination guidelines for infants at
risk for HIV infection. Wkly Epidemiol Rec 2007;82:193–6.
[96] World Health Organization. Measles vaccine: WHO position paper. Bull World
Health Organ 2004;79:130–42.
[97] Cowgill K, Ndiritu M, Nyiro J, Slack M. Effectiveness of Haemophilus influenzae
type b conjugate vaccine introduction into routine childhood immunization
in Kenya. JAMA 2006;296:671–8.
[98] Read J, Frasch C, Rich K, Fitzgerald G, Clemens J, Pitt J. The immunogenicity of
Haemophilus influenzae type b conjugate vaccines in children born to human
immunodeficiency virus-infected women. Women and Infants Transmission
Study Group. Pediatr Infect Dis J 1998;17:391–7.
[99] Rutstein R, Rudy B, Cnaan A. Response of human immunodeficiency virusexposed and -infected infants to Haemopilus influenzae type b conjugate
vaccine. Arch Pediatr Adolesc Med 1996;150:838–41.
[100] Visser A, Moore D, Whitelaw A, Lowman W, Kantor G, Hoosen A, et al. Part
VII: interventions. SAMJ 2011;101:587–95.
[101] SAVIC. Accessed at: www.savic.ac.za/news/newsarticles.php [accessed on
28.12.11].
[102] CDC. Chapter 2: Haemophilus influenzae Type b Invasive Disease. Accessed at:
http://www.cdc.gov/vaccines/pubs/surv-manual/chpt02-hib.pdf [accessed
on 17.10.11].
[103] Sanofi Pasteur Accessed at: www.sanofipasteur.com/sanofi-pasteur2/
articles/201-sanofi-pasteur-launches-pentaximu-first-5-in-1-combinationvaccine-in-china.html [accessed on 28.10.11].
[104] Daza P, Banda R, Misoya K, Katsukukuta A, Gessner B, Katsande R, et al. The
impact of routine infant immunization with Haemophilus influenzae type b
conjugate vaccine in Malawi, a country with high human immunodeficiency
virus prevalence. Vaccine 2006;24:37–9.
[105] Madhi S, Madhi A, Petersen K, Khoosal M, Klugman K. Impact of human
immunodeficiency virus type 1 infection on the epidemiology and outcome of
bacterial meningitis in South African children. Int J Infect Dis 2001;5:119–25.
Vaccine 30S (2012) C58–C60
Contents lists available at SciVerse ScienceDirect
Vaccine
journal homepage: www.elsevier.com/locate/vaccine
Review
When, and how, should we introduce a combination measles–mumps–rubella
(MMR) vaccine into the national childhood expanded immunization programme
in South Africa?
Neil A. Cameron ∗
University of Stellenbosch/Western Cape Provincial Health Department, South Africa
a r t i c l e
i n f o
Article history:
Received 6 November 2011
Received in revised form 24 February 2012
Accepted 29 February 2012
Keywords:
Immunization programmes
MMR vaccine
Elimination of measles and rubella
Congenital rubella syndrome
a b s t r a c t
This article briefly reviews the history and epidemiology of measles, mumps and rubella disease and the
case for introducing combination measles–mumps–rubella (MMR) vaccine into the national childhood
immunization schedule in South Africa. Despite adopting the World Health Organization’s Measles Elimination strategy in 1996 and achieving a significant decrease the incidence of measles, added effort is
needed in South and southern Africa to reach the goal to eliminate endogenous spread measles. Mumps
is still common disease of childhood and while there are few sequelae, even the rare complications are
important in large populations. Congenital rubella syndrome is seldom reported, but it is estimated that
of the million or so children born every year in South Africa over 600 infants are affected to some degree
by rubella infection. The naturally acquired immunity to rubella in women of childbearing age in South
Africa has been estimated at over 90%, so that introducing a rubella containing vaccine in childhood may
paradoxically increase the proportion of girls reaching puberty still susceptible to rubella. The elimination
of endogenous measles and rubella is being achieved in many countries in South America, and despite
the recent measles epidemic, must still be seriously considered for South and southern Africa. Current
constraints and potential steps needed to reach the goal in South Africa are discussed.
© 2012 Elsevier Ltd. All rights reserved.
1. Introduction
After polio eradication the one of the most sought after goals in
child health is the elimination and eradication of measles together
with rubella and eventually mumps. The achievements of the World
Health Organization, of the Pan American Health Organization
and many other country immunization programmes, of UNICEF,
of Rotary, of the vaccine manufacturers, of the researchers and of
the major donor organizations over the past three to five decades
gives good cause to hope, that elimination and eradication of these
four diseases within the next three to five decades is indeed more
likely than it is not. MMR vaccine is one of the keys to such success.
2. Measles
“Count your children after the measles has passed” is an old Arabic proverb. The disease was described as distinct from small pox by
the Persian physician Rhazes in the 10th century as “more dreaded
than smallpox” [1]. The devastating nature of measles in previously
∗ Tel.: +27 21 9389 440; fax: +27 21 9389 116.
E-mail address: [email protected]
0264-410X/$ – see front matter © 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.vaccine.2012.02.082
unexposed populations, also in the Cape Colony in the 18th century,
as described by Drutz and Morley, confirms this observation [2,3].
In the pre-vaccination era measles was estimated to cause six
million deaths per year mostly in developing countries [4]. More
recently WHO estimates of measles deaths globally have dropped
from 733 000 in 2000 to 164 000 in 2008 and the aim to eliminate
measles in six out of five WHO regions by 2020 does seem feasible
[5].
Measles vaccine was officially introduced into the national
immunization programme in South Africa in September 1975 and
MMR vaccine into the private sector about the same time. From
1981 to 1990 there were between 15 000 and 22 000 clinical cases,
and between 250 and 500 deaths, notified annually. In 1990 the
Health Department at the time undertook a mass measles campaign and in 1991 the cases dropped to 4777 and the deaths to
29. In 1992, however, the number of measles cases rebounded,
in slightly older children, with almost 23 000 cases and 53 deaths
[6].
Following a WHO assisted review of the national immunization programme in South Africa in December of 1993 there was
a significant strengthening of the whole of this programme which
became known as the Expanded Programme of Immunization (EPI
SA) [7]. The global polio eradication strategy and the measles elimination strategy were adopted, and a combined polio and measles
N.A. Cameron / Vaccine 30S (2012) C58–C60
mass immunization campaign was launched in 1996 involving all
children 6 months to under 15 years. This was followed by similar campaigns in 2000, 2004 and 2007 in all children 6 months to
under 5 years. The incidence of measles dropped dramatically, with
almost no cases or deaths being notified in 1997 and from 1998 to
2003 an average 30 cases a year, and no deaths, were reported.
Between 2003 and 2005 there were several outbreaks of measles
in the provinces of Gauteng, KwaZulu-Natal and the Eastern Cape
with a few cases in the Cape Town area. A total of 1676 cases
and 27 deaths were reported [8]. In 2006, 2007 and 2008, there
were, respectively, 83, 30 and 40 measles cases were confirmed
but no deaths reported to the National Institute for Communicable
Diseases [9].
After the first mass campaign in 1996 most young health professionals in the country had never seen a case of measles, until about
half way through 2009, when a scattering of reported cases around
Pretoria and Johannesburg became a full blown epidemic, peaking
in Gauteng in mid-October 2009 and in the rest of the country in
mid-April 2010. Professor Lucille Blumberg of the National Institute of Infectious diseases in Johannesburg reported that at least
one young doctor was admitted to intensive care with complications of measles. This was the first major country-wide measles
epidemic in almost 17 years, with a total of over 18 000 laboratory
confirmed cases reported by the time the epidemic tailed out in the
middle of 2010 [10].
The response to this epidemic was to move forward the planned
mass campaign for measles and polio firstly in Gauteng then to the
other provinces, and as older age groups were involved, to include
the age groups 6 months to 15 years. The case fatality rate from
measles in this epidemic reported by the Western Cape Provincial Health Department on March 16th 2010 was about 1% (8/765)
[11]. As part of a review of the epidemic and campaign at the
National Institute for Communicable Diseases (NICD) in Johannesburg in May 2011 it was recommended more work was needed
to expand immunization coverage, to ensure effective information,
education and communication and to strengthen surveillance and
contact tracing, especially in informal areas around the towns and
cities [12].
3. Mumps
Hippocrates described parotitis and orchitis in 500 BC [1]. In
the pre-vaccine era, mumps epidemics were reported usually
from schools, prisons, ships and military barracks about every 2–5
years. The sero-prevalence of mumps antibodies in pre-vaccine
era was between 50 and 90% globally. The introduction of MMR
vaccine dropped the incidence of mumps dramatically, though
in recent years several epidemics of mumps were reported in
university students in the UK and the USA [13,14]. McIntyre and
Keen reported on 11 360 cases of viral meningitis investigated in
Cape Town between 1981 and 1989 and found that 9% were due
to mumps. The average age in this series was 3 years [15]. Complications from mumps such as orchitis (20–50%) and encephalitis
(15%) are common but usually with full recovery. Permanent
deafness occurs in 1:20 000 cases and is permanent [1]. Mumps is
inconvenient and uncomfortable, and costly if admitted to hospital
and while the sequelae of mumps maybe rare, in large populations
these become significant especially if preventable [13].
4. Rubella
Rubella was first identified as distinct from measles by German physicians in the early 19th century. Rubella like mumps
tends to occur in periodic epidemics in pre-adolescent children
[1]. Congenital rubella syndrome (CRS) was recognised for the first
C59
time in 1940 in Sydney Australia by an ophthalmologist, Norman
Gregg, who after overhearing mothers of infants with congenital
cataracts share in the waiting room that they had had rubella while
pregnant, did a record review and linked an unusual increase of
congenital cataracts, and later of congenital heart disease and deafness in infants, to an epidemic of rubella which had spread to the
population from a local army camp [16].
The global toll of CRS in 2000 was estimated at 100 000 cases
per year [17]. In South Africa, it has been estimated that of the
million or so children born in 2005, 654 or 16 to 69/100 000 live
births were affected to some degree by congenital rubella infection [18]. Diagnosing congenital rubella is difficult. Those who are
picked up early, tend to have a congenital cataract or a serious
heart lesion. Sometimes a CRS related defect is only suspected
when a child finds school work difficult [19]. So that even if not
of widespread public concern, introducing MMR vaccine into the
South African immunization programme seems to make sense both
from a humanitarian and a cost perspective [20].
Replacing measles vaccine with MMR should not pose significant logistic or health budget problems. Even though the current
public tender price for measles vaccine is about US$0.30 a dose
in a 10 dose measles vial, and whole sale cost of single dose
MMR vaccine to the private sector is currently about US$14.30, the
government tender the prices should be closer to UNICEF tender
prices—currently between US$1 and US$2 a dose [21]. And despite
MR vaccine being half the price of MMR, it seems sensible to use
MMR vaccine to avoid both the disease and the rare sequelae. And
with more manufacturers starting to make the newer vaccines, the
tender prices for rotavirus and pneumococcal vaccines in South
Africa are likely to decrease, so that the cost of MMR should not
have health budget implications.
Almost 70% (130/193) of other WHO member states have
replaced measles vaccine with the combination measles, mumps,
rubella (MMR) or measles–rubella (MR) vaccine, the question
must be asked, “If there are relatively inexpensive MR or MMR
vaccines have been introduced into the childhood immunization
programme of majority of countries, why hasn’t South Africa?” [22].
The problem is that unless routine immunization programmes
can demonstrate the ability to consistent achieve a high national
immunization coverage for measles vaccine in all sub-districts,
introducing rubella vaccine to the childhood immunization schedule is likely sooner or later to lead to an increase of congenital
rubella syndrome, as has indeed happened in Greece and Brazil
[23,24]. Thus demonstrating in practice that partial immunization
coverage with rubella vaccine results in an increase in CRS. Schoub
et al. have expressed concern that the incomplete coverage of MMR
in the private sector will result in more young women susceptible to
rubella than before, because the natural spread of the virus is inhibited. They provided serological evidence that the immunity gap for
rubella in women of childbearing age using private sector health
care, was about 11% compared to 5% in those using the public sector
health care, and found that only about 60% of MMR doses needed to
cover the estimated 100 000 children who had access private health
care were distributed in South Africa in 2007 [18]. Vynnycky et al.
have expressed similar concerns about the availability of MMR in
the private sector [25].
When introducing a vaccine such as MMR, which has caused
controversy in a number of countries, Larson et al. have pointed out
that good communication about the science, efficacy and safety of
vaccines may not alleviate the anxieties many parents have about
immunization [26]. Leach and Fairhead argue that often the need
is not primarily about providing appropriate information or even
the building of trust, but of learning to engage effectively with parents and communities, and to appreciate that such dialogue is more
likely to facilitate than constrain efforts to promote the acceptance
of vaccines [27].
C60
N.A. Cameron / Vaccine 30S (2012) C58–C60
So the question should really be: when and how should
South Africa introduce rubella containing measles vaccine? Schoub
et al. have recommended that the introduction be preceded by a
targeted programme especially for schoolgirls, supported by serosurveillance and be repeated annually for least for the 5 years [18].
In South American, where elimination of endogenous measles has
been achieved and there is excellent progress on the elimination of
endogenous rubella, the Pan American Health Organization (PAHO)
recommends a similar approach: (1) starting off with mass campaign of both males and females (the target group depending on
the epidemiology of rubella in the country), reaching coverage levels close to 100%; (2) ensuring the highest political commitment
and, through intensive social mobilization, and by encouraging full
population participation; (3) careful local micro-planning with a
practical information system; (4) capacity to detect and rapidly
respond to safety and supply concerns and other emerging issues
during campaigns [28].
Once measles vaccine coverage over 85% uniformly in all
provinces has been verified for a period long enough to be considered sustainable, measles vaccine should be replaced with MMR
vaccine in the childhood immunization schedule at 9 and 18
months, preceded by the kind of process shown to be successful
in South America.
While efforts to achieve a uniformly high sustained coverage of
measles and other vaccines in South Africa should be continued to
be enthusiastically implemented, the following actions should be
considered:
1. That a surveillance system for congenital rubella syndrome (CRS)
is setup in South Africa, along the lines recommended by WHO
[29].
2. That the Southern African Development Community (SADC)
should continue strengthen measles control efforts so that the
Region can, sooner rather than later, move to a strategy to eliminate the endogenous spread of measles and rubella and mumps
based on the South American model [28].
3. That the education, information and communication efforts
around measles, rubella and mumps be strengthened and
sustained, especially the information that families using private sector health care maybe more susceptible to congenital
rubella—needs to be more clearly and effectively communicated
[18,25,28].
4. That consideration should be given to adding a MMR vaccine to
the national immunization schedule around entry to high school,
regardless whether MMR or measles vaccine was given as an
infant [18,23].
5. That tertiary educational institutions where large numbers of
young people gather, one dose of MMR vaccine should be
strongly encouraged for all students irrespective of immunization history [18,23].
Despite the recent measles epidemic, the goal we set ourselves
in South Africa in 1996 to eliminate measles is not that far off.
With the new vision to develop a more effective community based
primary health care approach, the time does seem right to renew
efforts to reach this goal in time to report positively on measles
elimination in time for the Millennium Development Goals 2015,
and to be well on our way to achieving the same for rubella [30].
Conflict of interest statement
None declared.
References
[1] Centers for Disease Control and Prevention. In: Atkinson W, Wolfe S,
Hamborsky J, editors. Epidemiology and prevention of vaccine-preventable
diseases. 12th ed. Washington, DC: Public Health Foundation; 2011.,
http://www.cdc.gov/vaccines/pubs/pinkbook.
[2] Drutz JE. Measles: its history and its eventual eradication. Semin Pediatr Infect
Dis 2001;12(4):315–22.
[3] Morley DC. Severe measles in the tropics. 1. BMJ 1969;(1):297–300.
[4] Heyman DL, editor. Control of communicable disease manual. 18th ed. APHA;
2004.
[5] World Health Organization, Global Eradication of Measles. Report by the secretariat sixty-third world health assembly A63/18. Provisional agenda item
11.15; 25 March 2010.
[6] Küstner HGV, Radloff AM. The measles strategy revisited—what happened? Epidemiol Comments 1993;20(9):2–22. Department of Health, South
Africa.
[7] National review of the South African National Immunization Programme.
Epidemiol Comments 1994;21(10):204–15. Department of Health, South
Africa.
[8] McMorrow ML, van den Heever J. Measles outbreak in South Africa, 2003–2005.
S Afr Med J 2009;99:314–9.
[9] Communicable Diseases Surveillance Bulletins of the National Institute for
Communicable Diseases. Compiled from tables: provisional listing of laboratory confirmed cases of disease reported respectively for the years 2006,
2007 and 2008 in the March edition of the Bulletin of the following year.
http://www.nicd.ac.za/assets/files/CommDisBull.
[10] Measles. National Institute for Communicable Disease, Communiqué May
2011(2) http://www.nicd.ac.za/assets/files/NICD-NHLS Communiqué-May
2011(2) [Accessed July 2011].
[11] Measles and Diarrhoea Death Toll Hits 16. Cape Argus 15 March 2010
http://allafrica.com/stories/201003160074.html [accessed November 2011].
[12] Volmink H, Ihekweazu C. Report on symposium to review the recent measles
outbreak in South Africa 2009–2011. National Institute for Communicable Diseases; 2011, 19 May 2011.
[13] Galazka AM, Robertson SE, Kraigher A. Mumps and mumps vaccine: a global
review. Bull World Health Organ 1999;77(1):3–14.
[14] Hviid A, Rubin S, Mühlemann K. Mumps. Lancet 2008;371(9616):932–44.
[15] McIntyre JP, Keen G. Laboratory surveillance of viral meningitis by examination of cerebrospinal fluid in Cape Town, 1981–9. Epidemiol Infect
1993;111:357–71.
[16] Australian dictionary of biography, vol. 14. Melbourne University Press;
1996. p. 325–7. http://adbonline.anu.edu.au/biogs/A140370b.htm [Accessed
July 2011].
[17] Rubella vaccines, World Health Organization. Wkly Epidemiol Rec
2000;75:161–9.
[18] Schoub BD, Harris BN, McAnerney J, Blumberg LS. Rubella in South Africa: an
impending Greek tragedy. S Afr Med J 2009;99:515–9.
[19] Menser MA, Forrest JM. Rubella—high incidence of defects in children considered normal at birth. Med J Aust 1974;1(5):123–6.
[20] Hinman AR, Irons B, Lewis M, Kandola K. Economic analysis of rubella and
rubella vaccines: a global review. Bull World Health Organ 2002;80:264–70.
[21] UNICEF tender prices http://www.unicef.org/supply/index 57476.html
[Accessed July 2011].
[22] Reef SE, Strebel P, Dabbagh A, Gacic-Dobo M, Cochi S. Progress towards the
control of rubella and prevention of congenital rubella syndrome—worldwide
2009. J Infect Dis 2011;204(Suppl. 1).
[23] Panagiotopoulos T, Antoniadou I, Valassi-Adam E. Increase in congenital rubella
occurrence after immunisation in Greece: retrospective survey and systematic
review. Br Med J 1999;319:1462–7.
[24] Lanzieri TM, Segatto TC, Siqueira MM, Marilda M, Santos EC, De Oliveira
MD, et al. Burden of congenital rubella syndrome after a community-wide
rubella outbreak, Rio Branco, Acre, Brazil, 2000 to 2001. Pediatr Infect Dis J
2003;22:323–9.
[25] Vynnycky E, Gay NJ, Cutts FT. The predicted impact of private sector
MMR vaccination on the burden of congenital rubella syndrome. Vaccine
2003;21(21–22):2708–19.
[26] Larson HJ, Cooper LZ, Eskola J, Katz SL, Ratzan S. Addressing the vaccine confidence gap. Lancet 2011;378(August):26–35.
[27] Leach M, Fairhead J. Vaccine anxieties, global sciences, child health and society.
Earth Scan 2007. ISBN-13:978-1-84407-370-2.
[28] Rubella
watch
(PAHO)
January–April
2011.
http://new.paho.org/hq/dmdocuments/2011/NL RubellaWatch2011 01e.pdf
[accessed August 2011].
[29] World Health Organization. Recommended standards for surveillance
of selected vaccine-preventable diseases. http://www.who.int/vaccinesdocuments/DocsPDF06/843.pdf [accessed April 2011].
[30] Re-Engineering Primary Health Care. Speech by the Minister of Health
at the Launch of the SA/EU Primary Health Care Sector Policy Support
Programme. 14 September 2011 http://www.doh.gov.za/show.php?id=3067
[Accessed February 2012].
Vaccine 30S (2012) C61–C65
Contents lists available at SciVerse ScienceDirect
Vaccine
journal homepage: www.elsevier.com/locate/vaccine
Review
Immunising the HIV-infected child: A view from sub-Saharan Africa
M. Jeffrey Mphahlele a,∗ , Siyazi Mda b
a
b
Department of Virology, Medunsa Campus, University of Limpopo/NHLS Dr George Mukhari Tertiary Laboratory, Pretoria, South Africa
Department of Paediatrics and Child Health, University of Limpopo, Medunsa Campus, Pretoria, South Africa
a r t i c l e
i n f o
Article history:
Received 7 September 2011
Received in revised form 13 February 2012
Accepted 16 February 2012
Keywords:
Immunocompromised
HIV
Immunisation
Childhood vaccines
Live-attenuated vaccines
BCG
a b s t r a c t
The HIV-infected children are prone to multitude of infections. In sub-Saharan Africa, HIV/AIDS is certainly an important acquired immunodeficiency and is more likely to negatively impact on immunisation
programmes than other forms of immunodeficiencies. Although HIV infection is generally not a contraindication for immunisation, high background HIV prevalence in the region may result in lower rates
of vaccine immunogenicity, efficacy and population immunity. Nevertheless, vaccination is still better
than natural infection; the risk of vaccination far outweighs the risk of infection with the pathogen. The
primary focus of this review is to discuss the lessons learned in vaccinating HIV-infected children particularly with key live-attenuated vaccines in Africa such as Bacille Calmette-Guérin (BCG), measles, oral
polio vaccine (OPV), yellow fever and rotavirus. Immunisation against influenza virus, a common cause of
respiratory illness, is also discussed as multiple guidelines recommend influenza vaccination for number
of groups at high risk such as patients infected with HIV.
© 2012 Elsevier Ltd. All rights reserved.
1. Introduction
HIV-infected children are prone to infectious diseases and every
effort should be taken to protect such vulnerable populations from
vaccine preventable diseases (VPDs). HIV/AIDS is of utmost importance in sub-Saharan Africa and is more likely to negatively impact
on immunisation programmes. Although evidence is accumulating
that most children from HIV-infected mothers are born HIV-free
due to effective mother-to-child transmission (MTCT) programmes
in HIV endemic countries, there is still a high rate of MTCT of HIV
in the region [1–3]. Globally, HIV affects an estimated 33.2 million (30.6–36.1 million) people and nearly 90% of the 2.5 million
children with HIV worldwide are in sub-Saharan Africa [3]. The
overwhelming majority of these children are infected through the
MTCT [1,2].
With some notable exceptions, vaccines are generally safe
and beneficial for immunocompromised persons, although their
immunogenicity and effectiveness may be less optimal. The two
major issues in vaccinating the immunocompromised include the
safety and efficacy of the vaccines [4,5]. Several concerns regarding safety of vaccines have been previously reported [4]. These
include adverse events (AEs) or severe adverse events (SAEs) following immunisation especially with live-attenuated vaccines, and
in the case of HIV-infected persons, increase in HIV viral load as
∗ Corresponding author. Tel.: +27 12 521 4569/4227; fax: +27 12 521 5794.
E-mail addresses: [email protected], [email protected] (M.J.
Mphahlele).
0264-410X/$ – see front matter © 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.vaccine.2012.02.040
a result of immune activation and proliferation. Live-attenuated
vaccines of concern include Bacille Calmette-Guérin (BCG), oral
polio vaccine (OPV), measles-mumps-rubella (MMR), varicella,
measles-mumps-rubella-varicella (MMRV) and yellow fever. All
inactivated vaccines can be administered safely to persons with
altered immunocompetence, whether the vaccine is a killed whole
pathogen, recombinant subunit, toxoid, polysaccharide, or polysaccharide protein-conjugate vaccine (Table 1). If inactivated vaccines
are indicated for persons with altered immunocompetence, the
usual doses and schedules are recommended. With respect to efficacy, concerns are often associated with immunogenicity, quality
and quantity of antibody titre, duration of protective antibodies, protection against the disease and duration of protection
against the disease [4]. Unlike vaccine safety, efficacy is of concern
whether vaccination is performed with killed whole pathogen, toxoid, polysaccharide, or polysaccharide protein-conjugate, subunit,
or live-attenuated vaccine.
There are number of reasons why HIV-infected children should
be vaccinated. In high HIV prevalence regions, the accumulation
of susceptible hosts may compromise efforts to control infectious
diseases; thus vaccinating HIV-infected children is important in
maintaining population herd immunity. Also, HIV damages the
immune system and it usually takes a short time for the immune
system to be weakened or destroyed; and children are more susceptible to common infections or unusual opportunistic infections
(OIs) and progress to AIDS more rapidly. For example, before
the era of highly active antiretroviral therapy (HAART), some
of the most common OIs among children in the United States
were serious bacterial infections (most commonly pneumonia)
C62
M.J. Mphahlele, S. Mda / Vaccine 30S (2012) C61–C65
Table 1
Summary of recommendations on common vaccines in HIV-infected individuals.
Vaccine
Type
BCG
Live attenuated
OPV
Measles
Live attenuated
Live attenuated
Yellow fever
Live attenuated
Rotavirus
DTwP/DTaP
IPV
Hepatitis B
H. influenzae type b
Pneumococcal
Meningococcal
Human papilloma
Live attenuated
Inactivated
Inactivated
Inactivated/subunit
Inactivated/subunit
Inactivated/subunit
Inactivated/subunit
Inactivated/subunit
[6]. Thus, non-immunised HIV-infected children will be exposed
to multitude of infections including VPDs. This review is dedicated to discussing vaccination of HIV-infected children with key
live-attenuated vaccines in Africa; namely BCG, measles, OPV, yellow fever and rotavirus. Immunisation against influenza virus, a
common cause of respiratory illness, is also discussed. However,
the safety, immunogenicity and efficacy of additional important
vaccines such as Haemophilus influenzae type b, Streptococcus pneumoniae, hepatitis B virus and human papilloma virus, are not the
subject of this review as they are comprehensively covered elsewhere in this issue (Burnett et al. [7], Botha and Dochez [8]; Mahdi
et al. [9] – for cross referencing later).
Recommendations
Asymptomatic HIV
Symptomatic HIV
Yes [depends on risk-benefit
analysis]
Yes
Yes [vaccinate at 6, then 9 and 18
months]
Yes
[CD4+ > 200 cells/mm3 ]
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
No [give IPV if available]
No
No
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
are underway to improve immunogenicity and efficacy of vaccines in children receiving HAART. It has been noted that those
initiating HAART experience immune reconstitution which often
improves responses to vaccines and this could be one of the strategies aimed to enhance results of immunisation [11]. On the other
hand, immune reconstitution in children is mainly through the generation of naïve T-cells as opposed to the expansion of memory
T-cells. It is therefore probable that revaccination may be beneficial in HIV-infected children receiving HAART [12]. Thus, vaccine
recommendations for those with HIV infection require continual
updating as additional research becomes available.
3. Lessons learned in vaccinating HIV-infected children
2. Immunological challenges of immunising HIV-infected
persons
Most HIV-infected children have the capacity to mount both cellular and humoral immune responses during the first two years
of life, or when they are still relatively healthy. Studies of the
immunogenicity of Expanded Programme on Immunisation (EPI)recommended vaccines have shown satisfactory seroconversion
rates in the early stages of HIV infection [4,7–10], supporting that
vaccination benefits HIV-infected African children attending the
EPI clinics below the age of 2 years [10]. Although seroconversion
rates are generally satisfactory, the immune response is generally
sub-optimal to most EPI vaccines and as a result, antibody levels or
seroprotection rates induced by most EPI vaccines tend to be lower
in HIV-infected individuals and fall more rapidly over time than in
non-infected persons. In addition, the proportion of vaccine responders decreases with progression from HIV infection to AIDS due to
decline in cellular and humoral immune responses. The deterioration of immune response occurs rapidly due to a number of factors.
These include, but not limited to: (1) defective antigen processing (macrophages, dendritic cells and CD+ Th cells), (2) defective
immunological memory (failure to prime memory cells or failure
of primed B cells to differentiate into memory cells), (3) defective
primary response due to attrition of CD4 cells, (4) early loss of protective antibodies and (5) loss of immunological memory of T and
B cells after priming [4].
It is important to note that the majority of HIV-infected infants
are immunologically normal at the beginning, but in the absence
HAART, they develop progressive HIV infection that leads to the
destruction of all aspects of their immune system [4]. This observation is important for continued protection of children against
VPDs, taking into account advancing programmes on ARVs, which
bring hope to HIV endemic regions by improving the immune status and prolonging survival of most HIV-positive persons. Efforts
Certain live-attenuated vaccines are of major safety concern in
HIV-infected persons in that a defective immune system is less
able to respond adequately to attenuated vaccine strains, or in rare
cases, the vaccine strain may revert to virulence. In both cases,
the vaccine strain could multiply to undesirable levels and cause
systemic infections with SAEs. With the exception of BCG, asymptomatic HIV-infected children should be immunised according to
standard schedules. Thus, the WHO-UNICEF position on vaccination of HIV-infected children supports the routine immunisation of
these children with the exception of BCG and yellow fever vaccines
(for symptomatic HIV infection) [13,14]. Other live-attenuated vaccines such as MMR and varicella should be administered with
caution or avoided in symptomatic HIV persons. Some of the new
live-attenuated vaccines such as rotavirus have been evaluated and
appear to be well tolerated in HIV-infected individuals [15,16].
3.1. BCG in HIV-infected children
BCG is still one of the most widely given vaccines in developing
countries and has proven safe in immunocompetent individuals. Recent evidence demonstrated that HIV-infected infants who
were routinely given a birth dose of BCG at the time they were
asymptomatic, and who later developed AIDS, were at high risk
of developing local and disseminated BCG disease (estimated
incidence 407–1300 per 100,000) [17,18]. A South African surveillance study reported 32 cases of disseminated BCG over a 3-year
period, estimating the risk of disseminated BCG to be 992 per
100,000 vaccinations in HIV-infected children [17]. The AEs and
SAEs of BCG in HIV-infected babies include severe inflammation
or abscess formation at the site of injection, immobility of the
arm, lymphadenopathy, disseminated BCG infection requiring clinical management, death from disseminated BCG infection resulting
in multisystem disease. BCG vaccine is not contra-indicated in
M.J. Mphahlele, S. Mda / Vaccine 30S (2012) C61–C65
HIV-infected children, its administration should however take into
account risk-benefit analysis [13] (Table 1). WHO currently recommends that BCG should not be given in two scenarios: (1) when
risks outweigh benefits such as infants who are known to be HIV
infected with or without signs, and (2) when risks usually outweigh
benefits for infants born to HIV-positive mothers whose HIV infection status is unknown but who have signs or reported symptoms
suggestive of HIV infection. The latter guideline is applicable only
to children who have not yet received BCG in the first few weeks
of life, since clinical manifestations typically occur after 3 months
of age. Alternatively, BCG vaccination should be delayed until confirmation of HIV status is established usually at 6 months of age
[13].
Unfortunately, countries with high prevalence of HIV often have
the greatest burden of TB, and uninfected children will benefit
from the use of BCG vaccine. There are a number of programmatic challenges in diagnosing and identifying HIV-infected babies
around the time (i.e. birth dose) of BCG administration in Africa.
Clinical diagnosis is almost impossible in the majority of cases
as HIV-infected babies are asymptomatic at birth. Definitive laboratory diagnosis of HIV is based on the detection of the viral
nucleic acid by polymerase chain reaction (PCR) assay, a technology which is not always available in many diagnostic centres of the
region. The sensitivity of the PCR has also been shown to be low
in the first 48 hours of life [19]. The other challenge is that most
children from HIV-infected mothers are born HIV-free due to effective PMTCT programmes in HIV endemic countries. For example, a
South African PMTCT cross-sectional study designed to assess HIV
transmission in infants at their first immunisation visit (4–8 weeks
of age) reported a dramatic drop in infant HIV infections to 3.5%
[20]. This observation confirms that the majority of infants born to
mothers on PMTCT programmes in countries with high burdens of
HIV and TB will benefit from the use of BCG as recommended by
WHO.
3.2. Measles vaccine in HIV-infected children
Infection with HIV is likely to increase susceptibility and severity
of measles infection as HIV infection results in immune suppression and a poor nutritional status. Indeed studies from Zambia have
shown that the case fatality rate is higher in HIV-infected children
than that in HIV-uninfected children [21,22]. In Zaire (now Democratic Republic of Congo), the case fatality rate was marginally
higher in HIV-positive children than in HIV-negative children;
however this difference did not reach statistical significance [23].
However, the relationship between the degree of immune suppression due to HIV and severity of measles does not seem to be well
established. Vaccinated HIV-infected children have been found to
have lower measles antibody levels and they tend to have a more
rapid decline in measles antibodies compared with HIV-uninfected
children in a number of studies [24–28]. This poorer response to
measles vaccination appears to be related to the degree of HIV
immune suppression as measured by CD4 counts [29,30]. Conversely, a study conducted among Ugandan children failed to show
this association [31].
HIV-infected children are prone to be infected with measles at
an earlier age as placental transfer of maternal antibodies including antibodies to measles is impaired [32,33]. These antibodies
normally interfere with measles vaccination in infants younger
than 9 months; however in HIV-infected children early immunisation may be beneficial as maternal antibodies are likely to be low
and HIV-induced immune suppression may not have sufficiently
progressed to influence response to immunisation. Accordingly,
WHO has recommended that infants at high risk for developing
measles before 9 months of age, including HIV-infected asymptomatic infants, should receive measles vaccination at 6 and 9
C63
months of age [34]. Ideally, the vaccine should be offered as early
as possible in the course of HIV infection. The vaccine is generally
recommended for individuals with moderate immunodeficiency
if there is a risk of contracting wild measles from the community. A systematic review of literature on measles vaccination in
HIV-infected children suggested that vaccination is safe in these
children [35]. Another systematic review reported that from 39
studies that involved >1200 HIV-infected children no deaths related
to measles vaccine were observed and only a case of serious
adverse event that was possibly related to measles vaccination
was noted [36]. Generally, measles vaccine is contra-indicated
where there is advanced AIDS. Similarly, MMR or MMRV vaccines
can be considered for HIV-infected children who are not severely
immunosuppressed (i.e., those with age-specific CD4 cell percentages of ≥15%) [6].
3.3. OPV in HIV-infected children
The use of OPV (Sabin strains) has contributed greatly to the success of polio eradication globally, which was the vaccine of choice
for the EPI since 1974 for a number of reasons: affordability and ease
of administration, provision of long-term and herd immunity, and
superiority to inactivated polio vaccine (IPV) in inducing intestinal mucosal immunity [37]. The efficacy of OPV in HIV-infected
children is satisfactory, with over 90% of such vaccines developing protective antibody titres. There has been few reported cases of
vaccine-related paralytic polio in Romania [38] and Zimbabwe [39],
flaccid paralysis with vaccine polio 2 [38], and paralysis of right leg
two weeks post administration of the second dose [39]. In cases
with severe immunodeficiency, inactivated polio vaccine (IPV), if
available, is a preferred alternative.
The immunocompromised may also be the source of infection
following vaccination due to prolonged shedding of the vaccine strain to other immuno-compromised susceptibles of the
same household. For example, the OPV (Sabin) strains replicate in
the human gut and are excreted for several weeks after immunisation in immunocompetent children. This phenomenon may
contribute to herd immunity. In a few instances, the excretion
could be prolonged in immunodeficient individuals, particularly
in severely congenitally humorally immunodeficient individuals.
During excretion period, the mutations associated with attenuation of the vaccine strains can revert. This may, in rare cases, cause
vaccine-associated paralytic poliomyelitis (VAPP) in vaccines or
result in immunodeficient VDPV (iVDPV) strains which could be
excreted for several decades. Outbreaks of poliomyelitis caused
by circulating vaccine-derived poliovirus (cVDPV) have recently
occurred in communities with long-term incomplete immunisation coverage [40–43].
3.4. Rotavirus vaccine in HIV-infected children
The current rotavirus vaccines comprise live-attenuated viruses.
Data on natural rotavirus infection in HIV-infected children demonstrated that there are no major safety or efficacy concerns related
to the administration of rotavirus vaccine [15]. Similarly, one study
evaluated the safety, reactogenicity, and immunogenicity of Rotarix
vaccine in asymptomatic or mildly symptomatic (clinical stages I
and II according to WHO classification) HIV-infected South African
infants [16]. All symptoms (solicited and unsolicited) occurred
at a similar frequency in both groups. Six fatal serious adverse
events in the vaccine group and 9 in placebo group were reported.
In the vaccine group, satisfactory immune response was elicited
without aggravating the immunologic or HIV condition [16]. Thus,
rotavirus vaccine appears to be well tolerated in HIV-infected individuals.
C64
M.J. Mphahlele, S. Mda / Vaccine 30S (2012) C61–C65
3.5. Yellow fever vaccine in HIV-infected children
Yellow fever is a vectorborne disease resulting from the transmission of yellow fever virus to a human from the bite of an infected
mosquito, and the disease is endemic to sub-Saharan Africa and
tropical South America [44]. It is estimated to cause 200,000 cases
of clinical disease and 30,000 deaths annually [44]. There is no treatment for yellow fever disease, thus prevention through vaccination
is critical to lower disease risk and mortality. The yellow fever vaccine provides long-lasting immunity [45]. However, rare serious
adverse events after vaccination include neurologic or viscerotropic
syndromes or anaphylaxis.
WHO recommends that all people aged ≥9 months travelling to or living in areas of South America and Africa in which
a risk exists for yellow fever transmission should be vaccinated
[13]. However, the vaccine is contraindicated for people who
are severely immunocompromised. A recent systematic review of
adverse events associated with yellow fever vaccination in vulnerable populations which included nine studies in infants and
children as well as nine studies in HIV-infected individuals found
yellow fever vaccine to be safe and effective [45]. Only very small
numbers of cases of yellow fever vaccine-associated viscerotropic
disease, yellow fever vaccine-associated neurotropic disease, and
anaphylaxis in persons ≥60 years were identified [45].
To minimise the risk for serious adverse events, yellow fever
vaccine is not recommended for symptomatic HIV-positive children [13]. The immunogenicity and safety of yellow fever vaccine
in HIV-infected are scarce but show consistent immunogenicity in
those with CD4 counts >200 cells/mm3 [13]. Published studies in
HIV-positive people are limited to small studies and case reports,
mainly of travellers with CD4 > 200 cells/mm3 . With the exception
of 1 case of fatal meningoencephalitis, these studies did not detect
any other serious adverse events among HIV-positive individuals
[13].
live-attenuated vaccine remain and a large number of guidelines
suggest that the use of live-attenuated vaccine is contraindicated
and recommend that trivalent subunit vaccine should be given
instead [54,55]. Finally, there has been some concerns that immunisation with the influenza vaccine leads to transient increases in
HIV viral replication and decreases in CD4 cell counts; however,
these effects do not seem to be significant [55].
4. Conclusions
Vaccines are generally safe and SAEs are uncommon. All inactivated vaccines can be administered safely to persons with
altered immunocompetence whether the vaccine is a killed whole
pathogen or a recombinant, subunit, toxoid, polysaccharide, or
polysaccharide protein-conjugate vaccine. If inactivated vaccines
are indicated for persons with altered immunocompetence, the
usual doses and schedules are recommended. However, the effectiveness of such vaccinations might be suboptimal. Live-attenuated
vaccines have potential safety concerns in HIV-infected persons.
In this case, the vaccine strain could multiply unrestricted by the
immune system and cause systemic disease with SAEs. With the
exception of BCG, asymptomatic HIV-infected children should be
immunised according to standard schedules. Other live-attenuated
vaccines such as yellow fever, measles, MMR and varicella should
be administered with caution or avoided in symptomatic HIV persons. It should be noted that the benefits of vaccination in the great
majority of cases still far outweighs the risks of vaccination even in
the immunocompromised child.
Conflict of interest
None.
3.6. Influenza vaccines in HIV-infected individuals
References
Influenza virus is a common cause of respiratory illness in
individuals of all ages with or without HIV co-infection [46,47].
Patients who are immunosuppressed are at risk of serious influenza
associated complications. As a result, multiple guidelines recommend influenza vaccination for number of groups at high risk
such as patients infected with HIV and those who received either
solid-organ transplants, haemopoietic stem-cell transplants, or
patients on haemodialysis [47,48]. In addition, a number of health
authorities such as CDC and WHO recommend annual influenza
vaccination for HIV-infected individuals [49,50]. Influenza is more
severe in HIV-infected children as there is an eight-fold greater risk
of hospitalisation and death from pneumonia [51]. Children over
6 months of age could benefit from the vaccine on annual basis.
Several vaccines are available for seasonal influenza (some also
protect against pandemic H1N1). The two main types of influenza
vaccines in use include trivalent subunit vaccine which is given
intramuscularly and the live-attenuated vaccine which is administered intranasally. The efficacy and effectiveness of both vaccines
have shown to be adequate.
Influenza vaccines have been observed to be moderately effective in reducing the incidence of influenza in HIV-infected persons;
however, studies in children are limited [52]. Administration
of seasonal and pandemic H1N1 vaccines are strongly recommended in HIV-infected adults with CD4 counts above 100 cells/␮l
or HIV-infected children with CD4 count >15%, although the
immunogenicity and efficacy may be sub-optimal [48,50]. Both
trivalent subunit and live-attenuated vaccines appear to be
safe in stable HIV-infected children (CD4 count >15%) receiving
antiretroviral therapy [53]. Nonetheless, concerns about using the
[1] Davis LG, Weber DJ, Lemon SM. Horizontal transmission of hepatitis B virus.
Lancet 1989;1(8643):889–93.
[2] Dabis F, Ekpini ER. HIV-1/AIDS and maternal and child health in Africa. Lancet
2002;359(9323):2097–104.
[3] UNAIDS Report on the Global AIDS Epidemic 2010. <http://www.unaids.org/
en/media/unaids/contentassets/documents/unaidspublication/2010/
20101123 globalreport en.pdf> [accessed 10.08.11].
[4] Moss WJ, Clements CJ, Halsey NA. Immunisation of children at risk of
infection with human immunodeficiency virus. Bull World Health Organ
2003;81(1):61–70.
[5] Thio CL. Hepatitis B in human immunodeficiency virus infected patients: epidemiology, natural history, and treatment. Semin Liver Dis 2003;23(2):125–36.
[6] Centres for Disease Control and Prevention. Guidelines for the prevention and
treatment of opportunistic infections among HIV-exposed and HIV-infected
children: recommendations from CDC, the National Institutes of Health, the
HIV Medicine Association of the Infectious Diseases Society of America, the
Pediatric Infectious Diseases Society, and the American Academy of Pediatrics.
MMWR Recomm Rep 2009;58(September (RR-11)):1.
[7] Burnett RJ, Kramvis A, Dochez C, Meheus A. An update after 16 years of hepatitis
B vaccination in South Africa. Vaccine 2012;30(Suppl. 3):C45–51.
[8] Botha MH, Dochez C. Introducing human papillomavirus vaccines into clinical
practice in South Africa. Vaccine 2012;30(Suppl. 3):C28–34.
[9] Mahdi SA, Cohen C, von Gottberg A. Introduction of pneumococcal conjugate
vaccine into the public immunization program in South Africa: testimony to
success in translating research into policy. Vaccine 2012;30(Suppl. 3):C21–7.
[10] Simani OE, Leroux-Roels G, François G, Burnett RJ, Meheus A, Mphahlele MJ.
Reduced detection and levels of protective antibodies to hepatitis B vaccine in
under 2-year-old HIV positive South African children at a paediatric outpatient
clinic. Vaccine 2009;27(January (1)):146–51.
[11] Crane HM, Dhanireddy S, Kim HN, Ramers C, Dellit TH, Kitahata MM, et al.
Optimal timing of routine vaccination in HIV-infected persons. Curr HIV/AIDS
Rep 2009 May;6(2):93–9.
[12] Sutcliffe CG, Moss MJ. Do children infected with HIV receiving HAART need to
be revaccinated? Lancet Infect Dis 2010;10(September (9)):630–42.
[13] World Health Organisation. Weekly Epidemiological Record, 2007; 82 (21):
186–96. http://www.who.int/wer.
[14] World Health Organisation. Weekly Epidemiological Record, 2011; 86 (5):
37–44. http://www.who.int/wer.
M.J. Mphahlele, S. Mda / Vaccine 30S (2012) C61–C65
[15] Steele AD, Cunliffe N, Tumbo J, Madhi SA, De Vos B, Bouckenooghe A. A review
of rotavirus infection in and vaccination of human immunodeficiency virusinfected children. J Infect Dis 2009;200(November (Suppl. 1)):S57–62.
[16] Steele AD, Madhi SA, Louw CE, Bos P, Tumbo JM, Werner CM, et al. Safety,
reactogenicity, and immunogenicity of human rotavirus vaccine RIX4414 in
human immunodeficiency virus-positive infants in South Africa. Pediatr Infect
Dis J 2011;30(February (2)):125–30.
[17] Hesseling AC, Cotton MF, Fordham von Reyn C, Graham SM, Gie RP, Hussey
GD. Consensus statement on the revised World Health Organization recommendations for BCG vaccination in HIV-infected infants. Int J Tuberc Lung Dis
2008;12(December (12)):1376–9.
[18] Azzopardi P, Bennett CM, Graham SM, Duke T. Bacille Calmette-Guérin vaccinerelated disease in HIV-infected children: a systematic review. Int J Tuberc Lung
Dis 2009;13(November (11)):1331–44.
[19] Zhang Q, Wang L, Jiang Y, Fang L, Pan P, Gong S, et al. Early infant Human
immunodeficiency virus type 1 detection suitable for resource-limited settings with multiple circulating subtypes by use of nested three-monoplex
DNA PCR and dried blood spots. J Clin Microbiol 2008;46(February (2)):
721–6.
[20] Goga A, Dinh T-H, Jackson D. Results of an evaluation of effectiveness of the
National PMTCT Programme at six weeks postpartum, South Africa. In: 5th
South African AIDS conference. 2011.
[21] Oshitani H, Suzuki H, Mpabalwani ME, Mizuta K, Numazaki Y. Measles case
fatality by sex, vaccination status, and HIV-1 antibody in Zambian children.
Lancet 1996;348(9024):451.
[22] Moss WJ, Fisher C, Scott S, Monze M, Ryon JJ, Quinn TC, et al. HIV type 1 infection
is a risk factor for mortality in hospitalized Zambian children with measles. Clin
Infect Dis 2008;46(4):523–7.
[23] Sension MG, Quinn TC, Markowitz LE, Linnan MJ, Jones TS, Francis HL, et al.
Measles in hospitalized African children with human immunodeficiency virus.
Am J Dis Child 1988;142(12):1271–2.
[24] Breña AE, Cooper ER, Cabral HJ, Pelton SI. Antibody response to measles
and rubella vaccine by children with HIV infection. J Acquir Defic Syndr
1993;6(10):1125–9.
[25] Jason J, Murphy J, Sleeper LA, Donfield SM, Warrier I, Arkin S, et al. Immune
and serologic profiles of HIV-infected and noninfected hemophilic children and
adolescents Hemophilia Growth and Development Study Group. Am J Hematol
1994;46(1):29–35.
[26] Moss WJ, Scott S, Mugala N, Ndhlovu Z, Beeler JA, Audet SA, et al. Immunogenicity of standard-titer measles vaccine in HIV-1-infected and uninfected Zambian
children: an observational study. J Infect Dis 2007;196(3):347–55.
[27] Helfand RT, Witte D, Fowlkes A, Garcia P, Yang C, Fudzulani R, et al. Evaluation of
the immune response to a 2-dose measles vaccination schedule administered at
6 and 9 months of age to HIV-infected and HIV-uninfected children in Malawi.
J Infect Dis 2008;198(10):1457–65.
[28] Nair N, Moss WJ, Scott S, Mugala N, Ndhlovu ZM, Lilo K, et al. HIV-1 infection in Zambian children impairs the development and avidity of measles
virus-specific immunoglobulin G after vaccination and infection. J Infect Dis
2009;2006(7):1031–8.
[29] Palumbo P, Hoyt L, Demasio K, Oleske J, Connor E. Population-based study
of measles and measles immunization in human immunodeficiency virusinfected children. Pediatr Infect Dis J 1992;11(12):1008–14.
[30] Arpadi SM, Markowitz LE, Baughman AL, Shah K, Adam H, Wiznia A, et al.
Measles antibody in vaccinated human immunodeficiency virus type 1infected children. Pediatrics 1996;97(5):653–7.
[31] Waibale P, Bowlin SJ, Mortimer Jr EA, Whalen C. The effect of human immunodeficiency virus-1 infection and stunting on measles immunoglobulin-G
levels in children vaccinated against measles in Uganda. Int J Epidemiol
1999;28(2):341–56.
[32] Embree JE, Datta P, Stackiw W, Sekla L, Braddick M, Kreiss JK, et al. Increased
risk of early measles in infants of human immunodeficiency virus type 1seropositive mothers. J Infect Dis 1992;165(2):262–7.
[33] Scott S, Moss WJ, Cousens S, Beeler JA, Audet SA, Mugala N, et al. the influence
of HIV-1 exposure on levels of passively acquired antibodies to measles virus
in Zambian infants. Clin Infect Dis 2007;45(11):1417–24.
C65
[34] World Health Organisation. Weekly Epidemiological Record No. 14, 2004:
130–42. http://www.who.int/wer.
[35] Moss WJ, Cutts F, Griffin DE. Implications of the human immunodeficiency virus epidemic for control and eradication of measles. Clin Infect Dis
1999;29(1):106–12.
[36] Scott P, Moss WJ, Gilani Z, Low N. Measles vaccination in HIV-infected children:
systematic review and meta-analysis of safety and immunogenicity. J Infect Dis
2011;204(Suppl. 1):S164–78.
[37] World Health Organisation. Polio vaccines and polio immunization in the preeradication era: Weekly Epidemiological Record, WHO position paper. No. 23,
2010; 85: 213–28.
[38] Ion-Nedelcu N, Dobrescu A, Strebel PM, Sutter RW. Vaccine-associated paralytic
poliomyelitis and HIV infection. Lancet 1994;343:51–2.
[39] Chitsike I, van Furth R. Paralytic poliomyelitis associated with live oral
poliomyelitis vaccine in child with HIV infection in Zimbabwe: case report.
BMJ 1999;318:841–3.
[40] Sangrujee N, Cáceres VM, Godni SL. Cost analysis of post-polio certification
immunisation policies. Bull World Health Organ 2004;82:9–15.
[41] Halsey NA, Pinto J, Espinosa-Rosales F, Faure-Fontenla MA, da Silva E, Khan AJ,
et al. Search for poliovirus carriers among people with primary immune deficiency diseases in the United States, Mexico, Brazil, and the United Kingdom.
Bull World Health Organ 2004;82:3–8.
[42] Schoub BD. Will the three steps for containment of poliovirus be enough to
convince policy-makers? Bull World Health Organ 2004;82:63.
[43] Schatzmayr HG. Poliovirus vaccine strains will continue to circulate long after
wild strains have been eradicated. Bull World Health Organ 2004;82:65.
[44] Staples JE, Gershman M, Fischer M, Centers for Disease Control and Prevention (CDC). Yellow fever vaccine: recommendations of the Advisory Committee
on Immunization Practices (ACIP). MMWR Recomm Rep 2010;59(July (RR7)):1–27.
[45] Thomas RE, Lorenzetti DL, Spragins W, Jackson D, Williamson T. The safety
of yellow fever vaccine 17D or 17DD in children, pregnant women, HIV+
individuals, and older persons: systematic review. Am J Trop Med Hyg
2012;86(February (2)):359–72.
[46] Klein MB, Lu Y, DelBalso L, Cote S, Boivin G. Influenza virus infection is a primary
cause of febrile respiratory illness in HIV infected adults, despite vaccination.
Clin Infect Dis 2007;45:234–40.
[47] Kunisaki KN, Janoff EN. Influenza in immunosuppressed populations: a review
of infection frequency, morbidity, mortality, and vaccine responses. Lancet
Infect Dis 2009;9(August (8)):493–504.
[48] Green RJ, Feldman C, Schoub B, Richards BA, Madhi SA, et al. Influenza guideline
for South Africa – update 2008. S Afr Med J 2008;98:223–30.
[49] Centres for Disease Control and Prevention. General recommendations on
immunization: recommendations of the Advisory Committee on Immunization
Practices (ACIP). Morb Mortal Wkly Rep 2006;55(RR15).
[50] World Health Organisation. http://www.who.int/csr/disease/swineflu/en/
index.html [accessed 10.08.11].
[51] Glesby MJ, Hoover DR, Farzadegan H, Margolick JB, Saah AJ. The effect
of influenza vaccination on human immunodeficiency virus type 1
load: a randomized, double-blind, placebo-controlled study. J Infect Dis
1996;174(6):1332–6.
[52] Atashili J, Kalilani L, Adimora AA. Efficacy and clinical effectiveness in reducing
the incidence of influenza in HIV-infected individuals: a meta-analysis. BMC
Infect Dis 2006;September:38.
[53] Levin MJ, Song LY, Fenton T, Nachman S, Patterson J, Walker R, et al.
Shedding of live vaccine virus, comparative safety, and influenza-specific
antibody responses after administration of live attenuated and inactivated
trivalent influenza vaccines to HIV-infected children. Vaccine 2008;26(August
(33)):4210–7.
[54] Giannatassio A, Lo Vecchio A, Albano F, Giacomet V, Barbarino A, Guarino A. Flu
and pneumococcal immunisations in HIV-infected: methodological quality of
current recommendations. BMJ Qual Saf 2011;20(May (5)):432–9.
[55] Skiest DJ, Machala T. Comparison of the effects of acute influenza infection
and influenza vaccination on HIV viral load and CD4 cell counts. J Clin Virol
2003;26(April (3)):307–15.
Vaccine 30S (2012) C66–C71
Contents lists available at SciVerse ScienceDirect
Vaccine
journal homepage: www.elsevier.com/locate/vaccine
Review
Meeting the need for advocacy, social mobilisation and communication in the
introduction of three new vaccines in South Africa – Successes and challenges
Adele F. Baleta a,∗ , Johann van den Heever b , Rosemary J. Burnett c
a
b
c
Independent Science Writer, Communication’s Consultant, 4 Park Road, Rosebank, Cape Town 7700, South Africa
Expanded Programme on Immunisation (EPI), South African Department of Health, South Africa
Department of Public Health, University of Limpopo, Medunsa Campus, Pretoria, South Africa
a r t i c l e
i n f o
Article history:
Received 22 October 2011
Received in revised form 6 June 2012
Accepted 12 June 2012
Keywords:
Advocacy
Social mobilisation
Communication
Vaccine
South Africa
a b s t r a c t
Advocacy, social mobilisation and communication are key components of the successful introduction
of new vaccines into childhood immunisation schedules. The development of many new vaccines and
the innovation of finance mechanisms, means more efficacious vaccines are becoming available to children in developing countries. At the same time, communication technology is developing at a rapid
rate, and with the dramatic decrease in vaccine-preventable diseases over the past few decades, the
public have become increasingly exposed to confusing and conflicting information about the need for
vaccination. The science of vaccines has become more complex, making effective, clear and consistent
communication for healthcare workers and caregivers critical to the uptake of and adherence to lifesaving vaccination. The introduction of two new vaccines, the 7-valent pneumococcal conjugate vaccine
and the rotavirus vaccine together with the new pentavalent vaccine, which includes inactivated polio
vaccine and replaced the former combination vaccine with four antigens, into the South African Expanded
Programme on Immunisation over a short period of time, has been met with a number of challenges, some
of which led to a lowering of confidence in the Department of Health to deliver on its promises. Had consistent advocacy, social mobilisation and communication efforts not been in place, efforts to make an
impact on the burden of disease may not have been as successful. This paper focuses on the lessons
learned about effective advocacy with decision makers, social mobilisation, communication with parents and caregivers, and training healthcare workers regarding the introduction of the new vaccines.
© 2012 Elsevier Ltd. All rights reserved.
1. Introduction
Immunisation has moved to centre stage as one of the driving
forces behind efforts to meet the millennium development goals
(MDGs) – especially goal 4 which aims to reduce the under 5 years
of age mortality rate (U5MR) [1].
Abbreviations: AEFI, adverse events following immunisation; DTwP-Hib, diphtheria, tetanus, whole-cell pertussis, Haemophilus influenzae type b; DTaP-IPV/Hib,
diphtheria, tetanus, acellular pertussis, inactivated polio, Haemophilus influenzae
type b; EPI-SA, Expanded Programme on Immunisation of South Africa; GAVI, Global
Alliance for Vaccines and Immunisation; GIVS, Global Immunisation Vision and
Strategy; HCWs, healthcare workers; IPV, inactivated polio vaccine; MDG, millennium development goals; MoH, Minister of Health; NAGI, National Advisory Group
on Immunisation; PPP, public private partnership; PCV7 , 7-valent pneumococcal
conjugate vaccine; RTHC, Road to Health Card; RV, rotavirus vaccine; SA-DoH, South
African Department of Health; U5MR, under 5 years of age mortality rate; WHO,
World Health Organization.
∗ Corresponding author. Tel.: +27 82899 7071; fax: +27 21 6856961.
E-mail address: [email protected] (A.F. Baleta).
0264-410X/$ – see front matter © 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.vaccine.2012.06.033
Although worldwide mortality in children younger than 5 years
has dropped from 11.9 million deaths in 1990 to 7.7 million deaths
in 2010, almost half of these deaths (49.6%) occur in sub-Saharan
Africa [2]. In 1990, South Africa’s U5MR was estimated at 62 per
1000 live births, but mainly because of a failure to prevent maternal
to child transmission of human immunodeficiency virus (HIV), by
2002 it had risen to above 80 per 1000. By 2009 the U5MR had
dropped back to 62, which while encouraging, makes it particularly
challenging for South Africa to reach the MDG target of 20 per 1000
by 2015 [3].
In developing countries, more vaccines have become available
and more lives are being saved. For the first time in documented
history the number of children dying every year has fallen below
10 million – the result of improved access to clean water and
sanitation, increased immunisation coverage, and the integrated
delivery of essential health interventions [1]. More funding is
available for vaccines and new vaccines have been developed
with others in the late stages of clinical trials, making this decade
the most productive in the history of vaccine advancement.
Significantly, pneumococcal and rotavirus vaccines are now also
A.F. Baleta et al. / Vaccine 30S (2012) C66–C71
available to Global Alliance for Vaccines and Immunisation (GAVI)
– eligible countries, preventing a large fraction of two of the
leading causes of child mortality – pneumonia and diarrhoea. Their
introduction provides an opportunity to scale up interventions
for the prevention and treatment of pneumonia and diarrhoea to
achieve better overall disease control [1].
2. Vaccine introduction in South Africa
South Africa is a middle income country and does not qualify for
GAVI assistance. However, in its quest to turn the tide on childhood
morbidity and mortality, it has stepped up to the mark, initially
introducing the 7-valent pneumococcal conjugate vaccine (PCV7 )
and then rotavirus vaccine (RV) into the Expanded Programme on
Immunisation of South Africa (EPI-SA) within a year (between 2008
and 2009).
It was the first country in Africa to do so, in its push to achieve
MDG 4, while addressing the World Health Organization’s (WHO)
Global Immunisation Vision and Strategy (GIVS) to introduce a
range of newly available vaccines and technologies [4].
The pentavalent vaccine (diphtheria, tetanus, acellular pertussis, inactivated polio, and Haemophilus influenzae type b
(DTaP-IPV/Hib)) was also introduced at the same time during
2008–2009. This replaced the former four-antigen vaccine, diphtheria, tetanus, whole cell pertussis and H. influenzae type b
(DTwP-Hib). The introduction of these vaccines was no easy feat
for a country with nine provinces, 52 districts and more than 3500
health facilities, including those in remote areas. To its credit South
Africa, using its own resources, was also the first country on the
African continent to have introduced H. influenzae type b vaccine
into the primary childhood immunisation schedule in 1999 [5] and
among the first three to launch hepatitis B vaccine on the continent
in 1995 [6].
C67
4. Burden of disease and advocacy
The rigorous decision-making process goes through at least four
protracted stages [9]. Against a high background rate of HIV/AIDS,
tuberculosis and elevated child mortality from diarrhoea and pneumonia, the EPI-SA and the ministerial committee, the National
Advisory Group on Immunisation (NAGI), began advocating for the
introduction of PCV7 (which was available at the time) and RV. In
February 2008, the EPI-SA recommended to the former Minister of
Health (MoH) that PCV7 be introduced by 2010, allowing a 2-year
gap for proper planning. The recommendation for a DTaP-IPV/Hib
vaccine, the switch-over from DTwP-Hib, had already been submitted in 2007. All submissions were based on the epidemiology of the
diseases, and the efficacy and cost-effectiveness of the vaccines. The
NAGI recommendations to the South African Department of Health
(SA-DoH) supported the WHO position papers on the introduction
of PCV7 and RV vaccines, and the switch from oral polio vaccine to
IPV [10,11].
5. Political commitment
In April 2008 there was a spike in child deaths in the rural
Ukhahlamba District of the Eastern Cape Province, with 70% of
140 deaths reportedly due to gastroenteritis, pneumonia and malnutrition. Rather than any specific disease outbreak, the deaths
were mainly attributable to weaknesses in the health system [12].
Widespread media coverage prompted the MoH to travel to the area
on the border of Lesotho to attend to the crisis and offer support.
Propelled by the Ukhahlamba deaths, public concern and advocacy efforts to get government to financially and politically commit
to the introduction of the vaccines, the MoH announced to the 61st
World Health Assembly in May 2008 in Geneva, that the vaccines
against pneumococcal and rotavirus disease would be introduced
within 3 months [13]. Instead of a 2-year lead in, the plan had to be
fast-tracked to meet the deadlines and this had huge financial and
programmatic implications as both vaccines would be introduced
sooner and simultaneously with the new pentavalent vaccine.
3. Advocacy and communication
6. Social mobilisation and cold chain capacity
Advocacy and communication together comprise one of the five
operational components of any immunisation system and need to
be part of plans for the successful introduction of new vaccines.
The other four components for a healthy immunisation system
listed by the WHO, are (a) vaccine supply and quality, (b) logistics and cold chain, (c) service delivery and (d) surveillance and
data [7]. The three basic elements of the immunisation system are
adequate management, sustainable financing and strengthening of
human and institutional resources, including teaching and training
of healthcare workers (HCWs).
The WHO guidelines on the introduction of new vaccines,
advises that advocacy begins at the start of the decision-making
process to ensure that funding is made available and political commitment is provided for the new vaccines. According to these
guidelines, advocacy is best characterised as any effort to influence
policy and decision-makers, to fight for social change, to transform public perceptions and attitudes, to modify behaviour, or to
mobilise human and financial resources [8].
There are several steps to take in order to conduct an effective
advocacy and communication effort namely: (i) gathering information; (ii) building a plan; (iii) creating messages and material;
(iv) building a strong coalition; (v) engaging policy and decisionmakers; (vi) informing and involving the public; (vii) working with
mass media; and (viii) monitoring and evaluation. With foresight,
and in spite of the enormous challenges, these guidelines were
followed by the EPI-SA.
It was decided that the vaccines would be introduced to coincide with the new health budget announced in April 2008 and to be
implemented in 2009. Apart from financing issues, it was acknowledged that training and social mobilisation, as well as cold chain
capacity had to be assessed and strengthened before the vaccines
could be introduced. Social mobilisation is a process of gaining and
sustaining the involvement of all stakeholders to take action or to
attain a common goal [14] – in this case the immunisation of children with three new life-saving vaccines. The audits of all primary
healthcare facilities were submitted as part of the tender process
and the companies built in funds for training, social mobilisation
and refrigerator capacity (which had to increase by over 450%).
The national health promotion team submitted a plan to the
MoH requesting finance for the design and printing of promotional
material. With the assistance of the vaccine manufacturers, the EPISA schedule was updated and reprinted to include the new vaccines
without disrupting the existing 6, 10, 14 weeks and 9 month clinic
visit as well as the existing 18 month visit with regard to DTaPIPV/Hib, thus ensuring greater adherence and acceptability of the
vaccines. Posters of the new schedule were designed, printed and
distributed.
Underscoring government support and in the interests of
national social mobilisation, it was agreed the MoH would be
present at the national launch of the PCV7 and RV vaccines in the
Eastern Cape, and it was planned that the heads of health of each
of the nine provinces would be involved in the launch in their
C68
A.F. Baleta et al. / Vaccine 30S (2012) C66–C71
Fig. 1. A consumer pamphlet with information on the 7-valent pneumococcal conjugate vaccine. ©SA Department of Health.
areas of jurisdiction. A communication task team was formed which
involved relevant stakeholders including WHO representatives,
national EPI, national Health Promotion and Communications, the
Public Private Partnership (PPP) – in which the government has a
51% stake, and which procures the vaccines on behalf of the SA-DoH
– and the three vaccine companies which were awarded tenders for
the supply of the new vaccines.
7. Communication plan
Following WHO guidelines, a communication plan was developed with the objectives, target audiences, activities, messages and
indicators, channels of communication, time frames and budget
laid out for the national roll-out of the vaccines.
8. Training of HCWs
Initial training of HCWs was conducted with the assistance of the
vaccine companies and the PPP in the Eastern Cape’s Ukhahlamba
District from 25 to 28 August 2008. Thereafter training of HCWs
was rolled out countrywide with two sessions in each of the nine
provinces with representatives from every district. The trainees
were instructed to cascade the training to all HCWs in primary
healthcare clinics before implementation. All the aspects of the
new vaccines were communicated to HCWs including: what they
are indicated for, the disease burden, efficacy, schedules, delivery routes, dosages, the potential side effects and possible adverse
events following immunisation (AEFIs), procurement, ordering,
vaccine management, and risk benefit communications as well as
how to communicate in the event of any AEFIs.
9. Communication materials, channels and tools
The national EPI collated materials with the financial and
logistical assistance from the vaccine companies. These materials,
including brochures and posters, which had to be translated into the
various languages were printed and delivered to all the facilities.
Varied communication channels were used to ensure wide
publicity. These included: the print (local, regional and national
newspapers, journals, women and baby magazines) and electronic
media (local and national radio, television and internet). Various
tools were used to reach the media including press releases, fact
sheets, media scripts, advertorials in newspapers and magazines,
radio adverts, consumer pamphlets (Fig. 1), loud hailers, community road shows (edu-mobiles) and banners (Fig. 2) were used to get
the pro-immunisation messages across and to answer the public’s
questions and concerns about the introduction of the new vaccines.
Paediatricians in the private sector as well as health scientists were
reached via journal articles and meetings.
An example of one of the radio jingles aired on national and
regional radio is as follows:
Man’s voice: Pneumococcal diseases such as pneumococcal meningitis, pneumonia, ear and blood infections can be harmful to your
baby.
Woman’s voice: When your baby is 6-weeks old visit your local
clinic and ask about pneumococcal vaccination to help protect
your baby.
Child’s voice: All we want to do is to grow up happy. Don’t Wait.
Vaccinate!
Man’s voice: A national immunisation programme brought to you
by the Department of Health supported by (the name of a pharmaceutical company supplied).
A.F. Baleta et al. / Vaccine 30S (2012) C66–C71
Fig. 2. A banner used for social mobilisation during the introduction of new vaccines
in South Africa. ©SA Department of Health.
Although the vaccine companies contributed to the design
and the wording of various promotional materials, the SA-DoH
conducted the campaign with consistent messages about both the
risks and benefits of the vaccines. Messages included that:
• Vaccination is the most cost-effective medical intervention to
date.
• All medicines have side effects, and while vaccines can have
adverse events these are mostly mild local reactions and temperature peaks indicating an immune response.
• Serious or fatal reactions from vaccines are extremely rare, much
rarer than the incidence of vaccine-preventable diseases.
• The benefits of vaccinations far outweigh the risk of adverse
events. When considering a vaccination for ourselves or our children, it is natural to think about the potential negative effects
of that vaccination. But you have to balance the risk against the
benefits.
• Vaccination is different from giving medicine to an ill child to
make them better. Vaccinations protect children against serious
illness.
• Deciding not to vaccinate your child puts them at risk of catching
a range of potentially serious, even fatal, diseases.
• In reality, having a vaccination is much safer than not having
one. They are not 100% effective in every child, but they are the
best defence against epidemics that can potentially kill or permanently disable millions of children and adults.
• All vaccine companies have put their vaccines through randomised clinical trials, to test for safety and effectiveness before
they can be registered for use.
• All vaccine company trials are subjected to ethical review.
• All vaccine companies have to include possible or expected AEFIs
with their product insert.
10. Vaccine launch
The MoH duly launched the PCV7 and RV at Upper Telle village,
in the Senqu sub-district of Ukhahlamba on 12 September 2008
with local, national and international coverage from the media, all
of whom had been invited [15]. Upper Telle village was selected
for the launch because it is part of the Ukhahlamba District where
there had been numerous deaths reportedly due to gastroenteritis, pneumonia and malnutrition. The MoH also wanted to show
C69
Fig. 3. The late and former Minister of Health Mantho Tshabalala-Msimang prepares
to vaccinate a child at the Upper Telle Village vaccine launch. ©SA Department of
Health.
political support and the SA-DoH’s commitment to reaching people, irrespective of where they live and the challenges they face.
Upper Telle is difficult to access, situated in a remote, mountainous
area on the border with Lesotho and the Free State Province. The
Upper Telle clinic staff are also under enormous pressure, having to
deal with cross-border clients as well as locals who are mostly poor.
Bisected by a river from Lesotho, the area has water and sanitation
challenges.
After the launch, the vaccines were rolled out district-by-district
in the Eastern Cape until the planned countrywide introduction in
April 2009.
Build-up activities for community mobilisation were held in
Upper Telle Village in the week before the launch. A team of health
officials, community HCWs and volunteers conducted a door-todoor campaign in the sub-district to inform community members
about the launch. Schools and community meetings were held
to communicate vaccine messages including catchy phrases such
as: Don’t wait. Vaccinate! The vaccine companies sponsored EPIbranded marketing materials for learners and the community,
including school bags, lunch boxes, squeeze bottles, stationery, sun
hats, T-shirts and warm hats.
The dirt road was levelled, improving access to the village, and
the MoH accompanied by officials joined other stakeholders including traditional healers and local leaders in the launch programme.
This included child dancers and praise singers. As a sign of solidarity
the MoH participated in vaccinating the children (Fig. 3). Mothers
and caregivers could weigh their babies and receive other services
at the launch.
11. Vaccine product change
The intended simultaneous roll-out of RV together with PCV7
nationally never materialised due to unforeseen challenges. PCV7
and lyophilised RV were rolled out in the Eastern Cape Province
by March 2009 with PCV7 being introduced countrywide by April
2009. The manufacturer of the RV vaccine decided to switch production to the fully liquid vaccine, which needed to be registered
by the national drug regulatory authority, the Medicines Control
Council, and this effectively delayed the national implementation
of RV to 1 August 2009. One province rolled out both vaccines only
in October 2009, due to severe financial constraints.
C70
A.F. Baleta et al. / Vaccine 30S (2012) C66–C71
14. Anti-vaccination lobby
Although the anti-vaccination lobby is continually active, there
were no serious threats to the roll-out from this group. Before the
introduction, HCWs in some provinces raised concern that three
injections administered at one visit would be met with opposition
from parents. These fears were largely allayed with appropriate
inter-personal communication between HCWs and the caregivers.
15. Training and personnel capacity building
Fig. 4. A child with her Road to Health Card waits for vaccination at a health facility.
©SA Department of Health.
Training and capacity building of personnel and adapting data
collection systems was challenging across the 52 districts and the
more than 3500 facilities. The new Road to Health Card (RTHC)
used by HCWs to keep a record of the child’s vaccination status
only came into circulation in March 2011. Until then, vaccinators
were instructed to record the pentavalent vaccine in the DTP space
on the old RTHC, write “Pentaxim” (the DTaP-IPV/Hib vaccine) in
the DTP space, and record PCV7 in the Hib space on the old card
(Fig. 4).
In addition to data capturing challenges, the health facilities
were overstretched with the competing priorities of rendering a
comprehensive service. The global financial crisis had by that stage
hit South Africa and the moratorium on posts at national and
provincial level meant that existing staff had to carry the additional
burden. Pharmaceutical services were particularly under pressure
with pharmacists leaving the public service and others emigrating, resulting in a scarcity of skills in this area. Personnel shortages
affected supportive supervision, monitoring and evaluation of the
introduction of new vaccines.
16. Conclusion
12. Communication restores confidence
The deferred introduction of RV vaccine gave HCWs a welcome
gap to deal with teething problems around the PCV7 vaccine roll
out, and also helped ease budget constraints in the first year. However, the delay had a negative impact on community expectations.
Extensive and sustained social mobilisation and communication
created interest and demand for the vaccine so when caregivers
arrived at the facilities expecting the vaccine, they became angry
and upset that it was not available. Reassurance had to be given to
the public and confidence and trust in the government and EPI-SA
had to be restored.
13. Stock out challenges
Widespread stock outs of all three vaccines at various stages in
various provinces also affected public confidence in the SA-DoH’s
promise to deliver. The vaccine shortages were negatively presented in the media in Limpopo Province, for example, where it
was reported that there were no RVs in the public sector although
the private sector was well stocked. The headline of the article read:
Rotavirus Outcry: No vaccine in Limpopo Public Hospitals.
Poor communication led to delays. So, while the facilities were
expecting stocks to arrive, the depots were waiting for the facilities to place their orders. In addition, some provincial and district
depots had to handle large stocks and because some provinces had
not strengthened their cold chain capacity before implementation,
there was limited capacity to order and store vaccines from the
manufacturers. This resulted in the need for more frequent ordering to be able to meet the demand for the now eagerly awaited
vaccines at the facilities.
The introduction of new vaccines affects many aspects of the
healthcare system, including service delivery policies and vaccine procurement and logistics. Changes in any of these areas
can impact communication strategies and messages [16]. This is
why it is essential to plan communication about new vaccines
far in advance of their introduction. The MoH’s decision to introduce three new vaccines (PCV7 , RV and pentavalent) in 1 year put
enormous strain on finances and the overall healthcare system.
Communications and social mobilisation were put to the test. The
assistance of the vaccine companies in devising, printing and distributing appropriately targeted and translated material, helped to
relieve the under-funded and over-burdened health promotions
staff at national and provincial level.
Sustained advocacy efforts by the EPI-SA and the NAGI successfully influenced policy makers and politicians at the highest level.
In addition, the MoH had great foresight in making the important
decision to introduce the vaccines, which was ultimately reflected
positively in the media. The launch at Upper Telle proved successful, with the event receiving the local and international attention
that was planned for.
The hallmark of good communication planning is to be prepared
and plan for misinformation, confusion and negative reactions
when introducing something new into the healthcare system. People are often resistant to change and it takes time to win over “late
acceptors” and to respond to the questions and concerns of all relevant staff [16]. The delay in rolling out RV due to a change in the
product and the need to have it registered and the stock-outs left
caregivers disappointed, HCWs frustrated and caused some negative publicity. However with communication and clear consistent
messages, public confidence was restored.
Parents report that their most reliable source of information is
the HCW [17] which puts the onus on the SA-DoH to ensure HCWs
A.F. Baleta et al. / Vaccine 30S (2012) C66–C71
are up to speed with information about the new vaccines, that they
are well versed in risk benefit communication, that they are able
to answer all caregiver’s questions in a clear and consistent manner and that their interpersonal communication skills are such that
they do not alienate the caregiver. The SA-DoH prioritised training
of HCWs in all districts to equip them with these skills, but without
the financial backing and assistance of the vaccine companies they
may not have reached as many HCWs in the time required. The
moratorium on posts and the lack of skills in specific areas such as
pharmacy services, was not ideal at a time of great pressure and
added to the challenges faced by HCWs.
In spite of the challenges, the SA-DoH needs to be congratulated,
as the three vaccines were successfully advocated for, accepted by
the target audience, who through successful social mobilisation,
communication and information were willing to take up the vaccine in a relatively short period of time across the entire country.
This is evidenced by the fact that in 2009, eight of the nine provinces
had at least 80% coverage of fully vaccinated 1-year-olds [18].
Lessons learned include: ensuring that there is secure, sustainable financing and that human resources are strengthened; that
project management principles are crucial for introducing new
vaccines; planning takes time; introducing new vaccines must
strengthen the immunisation programme, not weaken it; and that
one new vaccine be added at a time, unless adequate time and
capacity is allocated for the introduction of more than one.
Conflict of interest statement
None declared.
References
[1] World Health Organization, UNICEF, World Bank. State of the world’s
vaccines and immunization, 3rd ed. Geneva: World Health Organisation. http://whqlibdoc.who.int/publications/2009/9789241563864 eng.pdf;
2009 [accessed October 2011].
[2] Rajaratnam KJ, Marcus JR, Flaxman AD, Wang H, Levin-Rector A, Dwyer L,
et al. Neonatal, postnatal, childhood, and under-5 mortality for 187 countries,
1970–2010: a systematic analysis of progress towards Millennium Development Goal 4. Lancet 2010;375(9730):1988–2008.
C71
[3] The United Nations Children’s Fund. South Africa Annual Report 2011.
http://www.unicef.org/southafrica/SAF resources annualreport2011.pdf;
March 2012 [accessed May 2012].
[4] World Health Organization. Global Immunization Vision and Strategy.
http://www.who.int/immunization/givs/en/; 2011 [accessed October 2011].
[5] The South African Department of Health. More protection for children from
disease. http://www.doh.gov.za/show.php?id=108; 1999 [accessed October
2011].
[6] Francois G, Dochez C, Mphahlele MJ, Burnett RJ, Van Hal G, Meheus A. Hepatitis B vaccination in Africa: mission accomplished? S Afr J Epidemiol Infect
2008;23(1):24–8.
[7] World Health Organization. WHO-UNICEF guidelines for developing a
comprehensive multi-year plan (cMYP). Expanded Programme on Immunization of the Department of Immunization, Vaccines and Biologicals. www.who.int/vaccines-documents/DocsPDF06/832.pdf; March 2006
[accessed October 2011].
[8] World Health Organization. Vaccine Introduction Guidelines. Adding
a vaccine to national immunization programme: decisions and implementation. Expanded Programme on Immunization of the Department
of Vaccines and Biologicals. http://www.who.int/vaccines-documents/
DocsPDF05/777 screen.pdf; 2005 [accessed October 2011].
[9] Ngcobo NJ, Cameron N. Introducing new vaccines into the childhood immunisation programme in South Africa. S Afr J Epidemiol Infect 2010;25(4):3–4.
[10] World Health Organization. Pneumococcal conjugate vaccines for
childhood immunization – WHO position paper. Wkly Epidemiol Rec
2007;12(82):93–104. http://www.who.int/wer/2007/wer8212.pdf [accessed
October 2011].
[11] World Health Organization. Rotavirus vaccines. WHO position paper. Wkly Epidemiol Rec 2007;32(82):285–96. http://www.who.int/wer/2007/wer8232.pdf
[accessed October 2011].
[12] Thom A. 140 baby deaths due to poor health services. http://www.healthe.org.za/news/article.php?uid=20032095 [accessed October 2011].
[13] Cohen C. National Institute for Communicable Diseases. Commun Dis
Surv Bull 2008;6(3). www.nicd.ac.za/assets/files/CommDisBullAug08 Vol0603
[accessed October 2011].
[14] World Health Organization. Mid-Level Management course for EPI managers.
Module 3: communication for immunization programmes; 2004.
[15] South
African
Department
of
Health.
Primary
healthcare
in
South Africa to receive a major boost. http://www.info.gov.za/
speeches/2008/08091013451003.htm; 2008 [accessed October 2011].
[16] Wittet S. Hepatitis B vaccine introduction: lessons learned in advocacy, communication, and training. Bill and Melinda Gates Children’s Vaccine Programme
at PATH. www.who.int/entity/immunization training/resources/en/hepb.pdf;
2001 [accessed October 2011].
[17] Grob P, Hallauer J, Kane M, Meheus A, Roure C, Van Damme P. Behavioural
issues in hepatitis B vaccination. Vaccine 2000;19:675–9.
[18] Health Systems Trust. The District Health Barometer 2008/09. Part A: indicator comparison by districts. Chapter 3. Output indicators: immunisation.
www.hst.org.za/uploads/files/DRAFTdhb0708 31.pdf; 2010 [accessed October
2011].
Vaccine 30S (2012) C72–C78
Contents lists available at SciVerse ScienceDirect
Vaccine
journal homepage: www.elsevier.com/locate/vaccine
Review
Addressing public questioning and concerns about vaccination in South Africa:
A guide for healthcare workers
Rosemary J. Burnett a,∗ , Heidi J. Larson b , Molelekeng H. Moloi a , E. Avhashoni Tshatsinde c ,
André Meheus d , Pauline Paterson b , Guido François d
a
Department of Public Health, University of Limpopo, Medunsa Campus, Pretoria, South Africa
Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom
c
Department of Pharmacology, University of Limpopo, Medunsa Campus, Pretoria, South Africa
d
Department of Epidemiology and Social Medicine, University of Antwerpen, Belgium
b
a r t i c l e
i n f o
Article history:
Received 27 October 2011
Received in revised form 21 February 2012
Accepted 16 March 2012
Keywords:
Anti-vaccination
Vaccination
South Africa
a b s t r a c t
Vaccination is one of the most cost-effective and successful public health interventions in the history of
mankind. Anecdotal evidence, the media, and South African-based anti-vaccination websites and blogs
point to the existence of anti-vaccination lobbies in South Africa, although the part played by these lobbies
in sub-optimal vaccination coverage is unknown at present. This article discusses some of the claims made
by South African anti-vaccination groups, including some drawn from anti-vaccination lobbyists based
in highly resourced countries. While research is underway to better understand the scope and influence
of anti-vaccine groups, it is important to build capacity among healthcare workers within the Expanded
Programme on Immunisation of South Africa to enable them to deal empathically and effectively with
parents and caregivers who have been exposed to anti-vaccination messages and who question the need
to vaccinate their children. Claims that vaccines cause adverse effects need to be supported by valid
and reliable scientific evidence. However, evidence alone that vaccines are safe and effective does not
always result in parents being convinced to vaccinate their children. In addition to providing important
evidence of vaccine safety, this paper discusses the important role of communication – especially dialogue
– in building public trust in vaccination with the ultimate goal of increasing vaccination coverage and
preventing future outbreaks of vaccine-preventable diseases.
© 2012 Elsevier Ltd. All rights reserved.
1. Introduction
Vaccination for the prevention and control of infectious diseases is one of the most cost-effective and successful public health
interventions in the history of mankind [1–3]. In 1974 the World
Health Organization (WHO) launched the Expanded Programme
on Immunisation (EPI), with the aim of making safe and effective vaccines against six major infectious diseases (tuberculosis,
Abbreviations: AEFI, adverse event following immunisation; DTaP, diphtheria,
tetanus, acellular pertussis vaccine; EPI-SA, Expanded Programme on Immunisation of South Africa; HCW, healthcare worker; Hib, Haemophilus influenzae type
b vaccine; IPV, inactivated polio vaccine; MMR, measles, mumps, rubella vaccine;
MSVs, multiple simultaneous vaccines; NAGI, National Advisory Group on Immunisation; NITAG, National Immunization Technical Advisory Group; OPV, oral polio
vaccine; PCV, pneumococcal conjugate vaccine; RCT, randomised clinical trial; VPD,
vaccine-preventable disease; WHO, World Health Organization.
∗ Corresponding author at: Department of Public Health, PO Box 215, University
of Limpopo, Medunsa Campus, 0204, Pretoria, South Africa. Tel.: +27 12 521 3328;
fax: +27 86 612 2943.
E-mail addresses: rosemary [email protected], [email protected]
(R.J. Burnett).
0264-410X/$ – see front matter © 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.vaccine.2012.03.037
polio, measles, diphtheria, pertussis, and tetanus) accessible to
all children of the world. At that time the WHO was well on
the way to the global eradication of smallpox, with the world
being certified smallpox-free on the 8 May 1980. After this success, in 1988 the WHO set the year 2000 as the target for the
global eradication of polio [4]. Unfortunately, while most countries in the world are now polio-free, this aim has not yet been
fully achieved, with seven countries (Angola, Afghanistan, Chad,
Democratic Republic of the Congo, India, Nigeria, and Pakistan)
still being either polio-endemic or having re-established infections [5]. In 2005, through its Global Immunization Vision and
Strategy framework, the WHO set the year 2010 as the target
to reduce measles-related deaths globally by 90%, when compared to the year 2000 [6]. In the WHO Region of the Americas,
measles elimination has already been achieved [6], while in contrast measles outbreaks during 2009–2010 in 61% (28/46) of
African countries including South Africa [7] have set the WHO
African Region back in attaining measles elimination in the near
future. Measles outbreaks also continue to occur in countries with
strong health systems, such as some in the WHO European Region
[8].
R.J. Burnett et al. / Vaccine 30S (2012) C72–C78
2. Vaccination coverage and anti-vaccination opinion in
South Africa
The EPI of South Africa (EPI-SA) has made considerable progress
in the past 16 years, and currently eight of the nine provinces have
at least 80% coverage of fully vaccinated one year-olds [9]. This
includes a birth dose of both oral polio vaccine (OPV) and Bacille
Calmette Guérin (BCG); a further dose of OPV at 6 weeks; rotavirus
vaccine (RV) at 6 and 14 weeks; both hepatitis B (Hep B) and a pentavalent (diphtheria, tetanus, acellular pertussis, inactivated polio
virus, and Haemophilus influenzae type b) vaccine (DTaP-IPV/Hib)
at weeks 6, 10 and 14; pneumococcal conjugate vaccine (PCV13 )
at weeks 6 and 14; and both PCV13 and the first dose of measles
vaccine at 9 months [10]. However, when these aggregate data are
unpacked, it is clear that vaccination coverage remains sub-optimal
in several districts and sub-districts, with 12 of the 52 districts
having less than 80% coverage, three of which having coverage of
less than 70%. Of particular concern is that six sub-districts did not
achieve 80% first dose measles coverage, with two sub-districts in
the Eastern Cape achieving only 49.2% and 56.2% coverage. Even
more concerning is the second dose measles vaccination (administered at 18 months) drop-out rate, with the provincial drop-out
rate ranging from 12% to 21.4%, and six districts having drop-out
rates in excess of 20%, with one district in Gauteng Province having a drop-out rate of 28.4%. The worst performing sub-district
was in the Eastern Cape, with a drop-out rate of 61.6% [9]. Suboptimal measles vaccination coverage in South Africa led to a recent
measles outbreak, which started in the highly urbanised Gauteng
Province, the economic hub of the country, and then spread to all
nine provinces, with 5860 confirmed cases in 2009, and 12 499 in
2010 [11]. While many factors may contribute to pockets of low
coverage in the country (e.g., missed vaccination opportunities;
incorrect information given by clinic staff; unavailability of vaccines; and lack of access to clinics [12]), the part played by the
anti-vaccination lobbies in South Africa is as yet unexplored.
Anecdotal evidence, the media, and South African-based antivaccination websites and blogs point to the existence of such
lobbies in South Africa, which seem to be of two broad types: (1)
affluent, relatively educated, mainly white individuals, including
homeopaths, dentists, paediatricians, nurses, and their clients, who
use mass media including radio, TV, newspapers, popular magazines, websites and Internet blogs to communicate misinformation
about vaccines; and (2) poor, relatively uneducated, mainly black,
religious/cultural/traditional groups who do not use mass media.
However, very little is known about the extent, characteristics,
and influence of these anti-vaccination lobbies in South Africa.
Thus research is currently underway to gain a better understanding of what the anti-vaccination concerns are and what is driving
them, with the ultimate aim of developing interventions to increase
public confidence in vaccines and as a result to increase vaccination coverage in the country [3]. In the interim, it is important to
build capacity among healthcare workers (HCWs) to enable them
to deal empathically and effectively with parents/caregivers who
have been exposed to anti-vaccination messages and question the
need to vaccinate their children.
3. Study designs to prove causation
Claims that vaccines cause adverse effects need to be supported by valid and reliable scientific evidence. Immunisation
programmes in most countries address vaccine safety, including
surveillance of adverse events following immunisation (AEFIs) as a
major component of their programmes [1,2].
Characterisation of AEFIs, referred to as safety assessments,
should follow standard case definitions drawn up by the Brighton
C73
Table 1
Data needed to establish association between an AEFI and vaccination.
Experienced AEFI
Experienced no AEFI
Vaccinated
Exposed with the
outcome
Exposed without the
outcome
Not vaccinated
Unexposed with the
outcome
Unexposed without the
outcome
Collaboration, the world’s largest network of vaccine safety experts
[13]. This allows for the collection of valid comparable data across
many multinational sites both during pre-licensure randomised
clinical trials (RCTs) and post-licensure studies [14]. Recently the
size of Phase III RCTs (the final phase RCT before licensing, which
tests both vaccine safety and efficacy on a large statistically powerful number of volunteers) has been increased even further to allow
for the detection of very rare AEFIs. For example, the second generation rotavirus vaccines were tested on 60 000 infants in order to
detect if there was an association with intussusception, which had
previously been shown to have an attributable risk of 1 in 10 000
vaccinees in the post-licensure evaluation of RotaShield® [14].
Since very rare AEFIs may not have been detected during prelicensure Phase III RCTs, post-licensure evaluations are conducted
on an on-going basis. These evaluations cannot be conducted using
an experimental design, thus observational study designs must be
utilised instead. See Table 1 for the data needed from observational
studies to establish a link between an AEFI and a particular vaccine
or vaccine combination.
4. Anti-vaccination claims in South Africa and evidence to
refute them
A recent unpublished study on South African-based websites
and Internet blogs found that South African Internet-based antivaccination lobbyists are very much influenced by mass media
reports from around the world. Most either have links to antivaccination websites from highly resourced countries [15–17] such
as the United States of America (USA) which has been documented to have the most anti-vaccination sites on the world-wide
web [18,19], or cite anti-vaccination claims from these countries
[15,20,21]. Previous global studies have identified the claims on
the world-wide web discussed below [18,19,22–25]. Interestingly,
none of these previous studies identified South African-based antivaccination websites, thus clearly South Africa is still in the process
of catching up with global trends regarding Internet-based antivaccination lobbying. The claims that are irrelevant to the South
African context and are thus easy for South African HCWs to refute
are not discussed here, including mandatory vaccination and the
cost of vaccination. In South Africa, vaccination is not mandatory,
and healthcare, which includes vaccination, is offered free of charge
to pregnant women and under six year-olds at all clinics throughout
the country [26].
• “Vaccines are not safe and cause disease”
Some of the South African anti-vaccination messages on the
Internet give the overall impression that vaccines in general cause
disease [15,16], with some messages targeting specific vaccines
or constituents of vaccines as discussed below.
“The measles, mumps, rubella vaccine (MMR) causes autism”
While there have been claims that vaccines cause disease from
the time when vaccines were first introduced to the world in
the late 18th century, a more recent anti-vaccination movement
arose after a 1998 publication in The Lancet by Wakefield et al. that
linked MMR to autism [27]. Mass media reports that followed in
the United Kingdom (UK) led to MMR coverage dropping in the
C74
R.J. Burnett et al. / Vaccine 30S (2012) C72–C78
UK from 91% in 1997, to 82% in 2004 [28], with one study from
Bromley reporting only 60% coverage in 2003 [29].
The Wakefield study was extremely small (twelve children,
eight of whom it was claimed had developed autism shortly after
being vaccinated with MMR), there was no comparison group,
temporal sequence could not be established in most cases, and
the causal mechanism was not biologically plausible [30]. Many
very large (populations ranging from hundreds to more than
one million) ethically conducted epidemiological studies found
no association between MMR and autism [31–44] (see Table 2).
Unfortunately while the mass media were quick to spread the
news of the original Wakefield paper and his additional claims
in a press conference [3], they have been relatively silent on the
ensuing studies refuting his findings.
Despite this claim being fully refuted [14,30], with 10 of Wakefield’s 12 co-authors retracting the interpretation of the findings
[45], and the withdrawal of the article by The Lancet in 2010 [46]
with the author being erased from the medical register by the UK
General Medical Council [47], the repercussions are still being
experienced today – including in South Africa. These include
anecdotal reports of parents refusing to sign informed consent for
their children to be vaccinated in the mass immunisation campaigns held during the recent measles outbreak, and anecdotal
evidence from HCWs deployed in these campaigns points to fear
of the measles vaccine causing autism (although the MMR is not
used in the EPI-SA, it seems many people associate the measles
vaccine, and sometimes vaccines in general, with autism) being
one of the reasons behind this refusal. The claim that vaccines in
general cause autism can also be found on some South African
websites and Internet blogs [16,21], with links to websites based
in highly resourced countries [16].
“Thimerosal (thiomersal) causes autism”
Another common anti-vaccination claim that has been fully
refuted [14,30], is that thimerosal, a mercury-based preservative
(ethyl mercury) that is used in some multi-dose vaccines, causes
autism [1–3,14,28,30]. Thimerosal (sometimes referred to simply as mercury on these websites) is among a long list of “toxins”
cited on South African anti-vaccination websites [16,20,21] that
are “poisoning” vaccinated children and causing a myriad of diseases, as reported elsewhere [22,24,25]. As with the MMR claim,
there is some confusion about what it is in vaccines that supposedly causes autism, with one author erroneously stating that the
MMR vaccine contained “a mercury-based preservative” believed
by some parents to have caused autism in their children [17]. In
fact no preservatives are used in MMR since it is a live vaccine
– thimerosal would inactivate the vaccine and render it useless
[30].
Vaccines that contain thimerosal do not contain the element
mercury as such, just as table salt does not contain the very toxic
elements sodium and chlorine as such. However, in 1999, it was
recommended by the American Academy of Pediatrics and Public Health Service that, as a precaution, thimerosal should be
removed from infant vaccines. This was because there was scientific uncertainty about the effects of ethyl mercury, and most
of the infant vaccines contained thimerosal at that time. The concern was that 6-month-old infants could already have received as
much as 187.5 ␮g of ethyl mercury through vaccinations, which
exceeded the USA government limit allowed for methyl mercury [14]. Ethyl and methyl mercury are very different types
of mercury compounds, with ethyl mercury being processed
and excreted by the body more rapidly than methyl mercury
[48]. Methyl mercury occurs naturally in the environment, in
water, breast milk, infant formula, etc. [14]. Before thimerosal
was removed from most infant vaccines in the USA, more than
twice the amount of mercury contained in these vaccines as ethyl
mercury, was ingested in the form of methyl mercury by an exclusively breast-fed baby in the first 6 months of life [14].
Instead of welcoming this precaution to limit the exposure
of babies to mercury, the anti-vaccination lobby took advantage of the situation and reacted by linking thimerosal to autism
[1,30]. There is however no evidence to support any link between
thimerosal and autism, and mercury as a cause of autism is
biologically implausible, since the signs and symptoms of mercury poisoning are clinically very different from those of autism
[14,30]. In fact, many very large (up to 467 450 children) studies
have shown no link whatsoever [44,49–54] (see Table 3). Also,
the USA has not seen a concomitant drop in autism cases since
thimerosal was removed from infant vaccines in 1999 [3].
“Multiple simultaneous vaccines (MSVs) cause chronic disease”
It has also been hypothesised that receiving too many vaccines overwhelms the immature immune system and causes
chronic diseases, including autism, all of which have been fully
refuted [14,30]. Similar claims are seen on South African websites,
including an electronic newspaper interview of a homeopath who
believes that vaccines are immunosuppressive [55], and an antivaccination website authored by a medical doctor who believes
that vaccines cause immune overload, destroying the immune
system and causing many diseases and death [16]. This claim
seems to be based on a belief that natural disease builds immunity
while vaccines destroy immunity [19,22–25]. In fact, a vaccine
acts very much like a natural infection – without causing infection
– since it contains the same (or similar) antigens as the causative
organism that elicits the immune response from the host.
There is no evidence supporting any link between MSVs and
autism, or that MSVs weaken the immune system leading to
the development of other chronic diseases, or that MSVs cause
more severe AEFIs [30,56]. While the number of vaccines that
infants receive has increased over the last 30 years, due to
improved technology the immunologic load has decreased and
not increased. For example, in the USA in 2009, fourteen vaccines
delivered <200 antigens, compared to 1980, when seven vaccines
delivered >3000 antigens [30]. The whole-cell pertussis vaccine
that was introduced in 1926 contained about 3000 antigens and
was thus responsible for most of the antigenic load, whereas the
acellular pertussis vaccine introduced in 1991 contains only 2–5
antigens [14]. In addition, children are exposed to many foreign
antigens every day through ingesting bacteria along with the
food they eat and interacting with their environment, and they
also get a number of bacterial and viral infections every year
[30,56]. Also, unvaccinated and vaccinated children respond
to non-vaccine preventable infections in the same way, which
illustrates that vaccination does not weaken the immune system
[30]. Finally, autism is not an immune-mediated disease, thus
it is not biologically plausible that an inappropriate immune
response from a weakened or over-stimulated immune system
could cause autism [30].
• “Vaccines are ineffective”
The notion that vaccines are ineffective is often based on the
perception that the majority of people who get the disease have
been vaccinated. In countries where vaccine coverage is high, this
may well be the case, because no vaccine is 100% effective, with
most being 85–95% effective [56]. The WHO provides an excellent
hypothetical example of a high school with 1000 pupils who have
never been exposed to measles to illustrate this phenomenon. Of
the 1000 children, 995 are fully vaccinated against measles, and
all 1000 are exposed to measles. Of the 5 unvaccinated children,
R.J. Burnett et al. / Vaccine 30S (2012) C72–C78
C75
Table 2
Studies showing no link between MMR and autism.
References
Number of subjectsa
Study design
Country
Peltola et al. [31]
Taylor et al. [32]
Patja et al. [33]
Farrington et al. [34]
Kaye et al. [35]
Dales et al. [36]
DeWilde et al. [37]
Fombonne and Chakrabarti [38]
Taylor et al. [39]
Mäkelä et al. [40]
Madsen et al. [41]
DeStefano et al. [42]
Smeeth et al. [43]
Fombonne et al. [44]
∼1 500 000 (0)b
498 (498)
1 800 000 (0)
357 (357)
305 (305)
Not availablec
355 (71)
272 (272)
473 (473)
535 544 (352)
537 303 (738)
2448 (624)
5763 (1294)
27 749 (61)
Prospective cohort
Case series
Prospective cohort
Case series
Ecological
Ecological
Case control
Ecological
Case series
Retrospective cohort
Retrospective cohort
Case control
Case control
Ecological
Finland
UK
Finland
UK
UK
USA
UK
UK
UK
Finland
Denmark
USA
UK
Canada
Source: Based on Amanna and Slifka [28] and Gerber and Offit [30].
a
Number of autism cases in parentheses.
b
3 million doses.
c
Birth cohorts in California from 1980 to 1994 enrolled in kindergarten (sample ∼600–1900 per year).
all 5 (100%) get measles, while of the 995 vaccinated children,
7 (0.7%) get measles. This can be reported to make it seem that
vaccines are ineffective, while still telling the truth: 58.3% (7/12)
of those with measles were vaccinated. Alternatively, it can and
should be reported more transparently: 100% (5/5) of those who
were unvaccinated got measles, while only 0.7% (7/995) of those
who were vaccinated got measles. In fact the vaccine was 99.3%
effective, and if none of the children were vaccinated, perhaps
all 1000 would have got measles [56]. Further evidence of the
effectiveness of vaccines is discussed in Section 4.
On the South African websites studied, the claim that vaccines
are ineffective appears frequently [17,21,57] and is sometimes
linked to profit motives [16,17] which brings us to the next
anti-vaccination claim.
• “Vaccination policies are driven by profit”
One common perception is that the vaccine industry profits
greatly from selling vaccines, and that the scientists who develop
and test vaccines, as well as the physicians who promote them
have a vested interest in claiming that vaccines work because
they are being paid by the vaccine industry. This conflict of interest theory is probably one of the oldest anti-vaccination claims
circulating on the world-wide web [18,19,22,24,25] that has been
adopted by South African anti-vaccination Internet bloggers and
website owners [17,20]. Others simply claim that vaccinations
do not work, they just make money for drug companies [16],
the public are “cash cows” [57], or the vaccines themselves are
“cash cows” [17]. An unusual perception that has arisen in the
USA and has been cited on a South African website, concerns the
motive behind why the vaccine industry sells vaccines as loss
leaders (i.e. at very low prices to attract buyers for sales of more
profitable goods). This view, which has not been reported in any
other website survey, suggests that the pharmaceutical industry
aims to vaccinate millions of children with cheap vaccines that
have serious AEFIs (which include infections needing expensive
antibiotics and other more expensive vaccines to prevent these
infections), in order to make much more profit out of the drugs
needed to treat these AEFIs [58].
Testing a vaccine for efficacy is a very expensive business, and
this is only one part of a very long process in taking a vaccine from
concept to the market. Also, the cost of developing and producing a vaccine is more than US$500 million, and only one in four or
five candidate vaccines make it to the marketplace [59]. Finally,
the extremely low incidence of severe AEFIs highlighted in Section 4 shows that it is illogical to suggest that the pharmaceutical
industry makes a great deal of profit from AEFIs.
Paediatricians and family physicians who advocate vaccination
and provide vaccination services in their practices, largely do not
profit from vaccinating children. Studies conducted in the USA
have found that most primary care physicians working in the
private sector do not profit from vaccinating privately insured
children, and actually make a loss when vaccinating those from
the public sector, which results in a net loss made from providing
vaccinations [60]. Thus some physicians in the private sector have
seriously considered stopping the provision of all childhood vaccinations [61]. In South Africa, EPI vaccinations are provided free
to privately insured children through the public sector. For those
preferring to use private sector clinics for EPI vaccinations, the
vaccines themselves are often provided free through the Department of Health, although the private sector clinics are allowed
to charge an administration fee (Amayeza Info Centre, personal
communication). Clearly then, vaccinations do not generate huge
profits for South African physicians either.
Contrary to anti-vaccination lobby claims, it is not only those
paid by the pharmaceutical industry who recommend vaccines.
Independent scientists who have no links whatsoever to the pharmaceutical industry have validated findings of vaccine safety and
Table 3
Studies showing no link between thimerosal and autism.
References
Number of subjectsa
Study design
Country
Stehr-Green et al. [49]
Madsen et al. [50]
Hviid et al. [51]
Verstraeten et al. [52]
Heron and Golding [53]
Andrews et al. [54]
Fombonne et al. [44]
Not available
956 (956)
467 450 (440)
140 887 (223)
12 956
103 043 (106)
27 749 (61)
Ecological
Ecological
Retrospective cohort
Retrospective cohort
Prospective cohort
Retrospective cohort
Ecological
Sweden and Denmark
Denmark
Denmark
USA
UK
UK
Canada
Source: Based on Gerber and Offit [30].
a
Number of autism cases in parentheses.
C76
R.J. Burnett et al. / Vaccine 30S (2012) C72–C78
Table 4
The reduction of VPDs globally from 1980 to 2009.
VPD
1980 reported global incidence
and vaccination coverage
Diphtheria
Tetanus
Pertussis
Polio
Measles
97 511
114 251
1 982 355
52 795
4 211 431
2009 reported global incidence
and vaccination coverage
857
9836
106 207
1779
222 408
DTP3: 26%
Polio3: 25%
MCV1: 13%
DTP3: 89%
Polio3: 89%
MCV1: 92%
Source: WHO [64].
DTP3: third dose of diphtheria–tetanus–pertussis vaccine; MCV1: first dose of measles-containing vaccine.
efficacy in numerous studies discussed in Section 4. In addition,
most industrialised and a number of low and middle income
countries, including South Africa, have independent national
technical advisory bodies which use scientific evidence to guide
national policymakers and programme managers on immunisation policies and programmes, called National Immunization
Technical Advisory Groups (NITAGs) [62]. The South African
NITAG is referred to as the National Advisory Group on Immunisation (NAGI), and is made up of eight leading academic experts
in disciplines related to immunisation from universities throughout the country, a representative from the Medicines Regulatory
Authority, as well as three ex-officio members from the EPI-SA,
and one each from the United Nations Children’s Fund and the
WHO [63]. The scientific evidence on which the NITAGs have
based their guidance and recommendations, has convinced governments and public health practitioners all over the world to
recommend vaccination as the most cost-effective tool for the
prevention and control of VPDs.
The public also needs to understand that many in the antivaccination lobby make a profit out of advocating alternatives to
vaccination, or sell books promoting anti-vaccination, or attract
parents with fears about vaccination to their websites in order
to sell unrelated products. This is evidenced by many websites
with anti-vaccination messages having links to online shopping, or promoting homeopathy or other alternative services
[18,19,21,22,24,25].
• “Diseases have declined because of improved sanitation and
nutrition, not because of vaccination”
It is true that improved housing, less crowded living conditions, improved education, reduced birth rates, better nutrition,
water-borne sewerage, clean piped water, antibiotics and other
medical treatments, have all greatly contributed to reduce the
burden of infectious diseases. However, some anti-vaccination
lobbies claim that vaccination has played no part in the declining
incidence [19,22,24], a claim that some South African antivaccination website owners have also adopted [21].
Contrary to these claims, ecological studies have shown that
since the introduction of vaccines, the specific diseases they target have decreased dramatically in each country where they have
been introduced. For example, in the USA, when the measles vaccine was introduced in 1963, there was an average of 503 282
cases per year; this was reduced to 44 cases in 2002. Also in the
USA, when the rubella vaccine was introduced in 1969, rubella
cases dropped from 57 686 (including 29 deaths), to only 18 cases
in 2002 [28]. Again in the USA, when Hib vaccination was introduced in 1990, there were 20 000 Hib cases in that year, with only
1419 cases in 1993 [56]. Even long after the introduction of the
older vaccines, as vaccination coverage has increased in different
parts of the world, there has been a concomitant global reduction
in these VPDs [64] (see Table 4).
Conversely, following vaccine scares when a government has
withdrawn a vaccine from their EPI or vaccine coverage drops
dramatically because of public fears, this has been followed by
an outbreak of the disease [28,56]. For example, in response
to vaccine scares when pertussis vaccination levels dropped,
incidence increased dramatically, as was seen in the UK during
1974–1978, with 100 000 pertussis cases and 36 deaths, and in
Japan from 1974 to 1979, with 13 000 pertussis cases and 41
deaths. In the 1990s low diphtheria immunisation rates in the
former Soviet Union resulted in an increase from 839 cases in
1989 to 50 000 cases and 1700 deaths in 1994 [56].
• “The risk of AEFIs is higher than the risk of the disease”
Vaccines have often been called “victims of their own success”
[1,2,24,65]. Because they have been so successful at reducing
the incidence of the diseases they target, the uncommon and
rare AEFIs that they induce have become, in the view of the
anti-vaccination lobby, more common and more feared than the
diseases themselves [1,2,24,28,66]. Yet the diseases that vaccines
prevent often have very serious complications that were very
common in the pre-vaccination era, thus the risk of the disease far
outweighs the risk of vaccination as can be seen in Table 5. Parents and HCWs seldom see the diseases that vaccines prevent,
and thus many question the need for vaccines for what they perceive as rare and mild diseases. Most AEFIs are in fact very mild
(tenderness, redness, and mild fever) and short-lived [56]. Very
rarely is there a serious AEFI (1 per several thousands or millions,
or so rare that one cannot calculate the risk [56,67]; see Table 5),
but clearly for the families involved, serious AEFIs can be devastating events that cause them to seriously doubt the benefits of
vaccination.
AEFIs are similarly viewed by some South African antivaccination Internet bloggers and website owners as more
common and more dangerous than the diseases they are meant to
Table 5
Risk of disease versus risk of vaccination.
Disease
Risk of disease
Risk of vaccination
Measles
Encephalitis or severe allergic
reaction: 1 in 1 million
Diphtheria
Pneumonia: 1 in 20
Encephalitis: 1 in 2000
Death:
1 in 5 in developing
countries
1 in 3000 in
industrialised countries
Death: 1 in 20
Tetanus
Death:
25–70 in 100 generally
Pertussis
10–20 in 100 with good
intensive care
Pneumonia: 1 in 8
Encephalitis: 1 in 20
Death: 1 in 200
Source: WHO [56] and CDC [67].
With DTaP:
Continuous crying followed by
complete recovery: 1 in 1000
Acute encephalopathy: 0–10.5
in 1 million
Convulsions or shock, then full
recovery: 1 in 14 000
R.J. Burnett et al. / Vaccine 30S (2012) C72–C78
prevent [16,20,21], as previously reported [24,28,66]. The notion
that childhood infectious diseases are mild or trivial has been
found on the world-wide web for many years [22–24], and the
practice of throwing parties for unvaccinated children when one
of them has a VPD so that all can “naturally” be infected [2], is now
being advocated by a homeopath interviewed by a South African
newspaper published on the Internet [55].
There are also many (the vast majority) reported AEFIs that
are totally unrelated to vaccination, which are recorded in registries and databases throughout the world as part of the routine
procedure required for pre- and post-licensure evaluation. These
AEFIs are purely coincidental, as they occur following vaccination, but are not caused by the vaccination (i.e. they are not
adverse events caused by vaccination). However, it is not up to
the individual HCW to assess if an AEFI is related or unrelated
to vaccination, so all AEFIs are recorded and then reviewed by
panels of experts who investigate whether a reported AEFI is
actually caused by a vaccine. For example, if a child is vaccinated for measles while incubating an influenza infection and
then presents with influenza symptoms shortly thereafter, this
may be recorded as an AEFI despite it being merely coincidental
and not caused by the measles vaccine. There are less clear-cut
coincidental cases, as can be seen in the autism cases exploited
by Wakefield and colleagues, and the anti-vaccination lobby.
The first signs and symptoms of autism coincidentally appear
at around the same age when children in the UK receive their
MMR vaccines, thus it is not surprising that children who develop
signs and symptoms of autism have coincidentally recently been
vaccinated with MMR [14,28,30]. The parents of these children
sometimes believe and vehemently support the misinformation
propagated by the anti-vaccination lobby that the MMR was
directly responsible for their child developing autism, as documented in their personal testimonies on the Internet [19,22,24].
C77
helpful and interesting. Finally, the key is to ensure that the information is well understood, using terms that are not confusing or
too technical [69].
6. Conclusion
Increasing numbers of South Africans are accessing misinformation about vaccinations on the Internet, which may have a negative
impact on vaccination coverage in pockets of the country where
Internet usage is widespread. Outbreaks that arise in these pockets
because of vaccine refusal may spill over to other provinces where
vaccination coverage is low for reasons other than vaccine refusal.
The recent measles outbreak which started in Gauteng Province, the
economic hub of the country with a high level of migrant labour,
and then spread to all nine provinces, is a case in point. Thus
it is crucial to monitor public questioning and concerns regarding vaccination in order to understand the concerns and respond
appropriately in good time [3]. Research is needed to (a) characterise the South African anti-vaccination lobby; (b) investigate the
psychological, socio-cultural, and political determinants that have
led to loss of trust in vaccination by some South African parents;
and (c) measure the impact of the anti-vaccination lobby on vaccination coverage. At the same time, steps need to be taken to ensure
that HCWs involved in the EPI-SA fully understand this misinformation and are prepared to address some of the difficult questions
and perceptions which they may be confronted with. HCWs should
be allowed the time for dialogue with questioning parents, and be
supported with information and skills to listen to, and engage with
parents with empathy in a way that builds trust and allows for true
understanding.
Conflict of interest statement
None declared.
5. Talking to parents who question vaccines
Addressing some of the difficult questions about the risks of
vaccines that South African parents who have been exposed to
anti-vaccination messages may ask of HCWs, has been covered in
this paper. However, providing scientific evidence to questioning
parents does not always result in parents being convinced to vaccinate their children [3]. Good communication and dialogue skills
are needed [14,68]. Earning trust, creating awareness, deepening
understanding, gaining agreement on solutions, and motivating
action [69], are goals that HCWs need to strive for when communicating the risks and benefits of vaccination to parents.
Determinants of trust include the parents’ perception of the
expertise of the HCW, as well as how open, honest, caring and
concerned the HCW appears to be [3]. HCWs must first earn the
parents’ trust before they can address their fears and suspicions
[1,3,69]. First, the HCW should acknowledge the parents’ concerns
[69], and then explain that there are safety measures in place to prevent AEFIs as far as possible, and that if they do occur, that they are
extremely rare when compared to the risk of contracting the diseases that the vaccine(s) can prevent. Second, endorse fundamental
values [69]. For example, the health of South African children is EPISA’s most important priority, which is a fundamental value shared
by all parents. Third, cast a positive identity [69]. For example, build
self-confidence in parents by not ridiculing the source of misinformation that has led them to question vaccination, because they
will feel defensive. Instead, empathise with parents who are genuinely worried about causing harm to their children, and give them
a list of reputable books, journals and websites (such as SAVIC’s:
www.savic.ac.za) that do publish credible articles on vaccination
for lay people, and admit to using these sources and finding them
References
[1] François G, Duclos P, Margolis H, Lavanchy D, Siegrist CA, Meheus A, et al. Vaccine safety controversies and the future of vaccination programs. Pediatr Infect
Dis J 2005;24(November (11)):953–61.
[2] François G, Kramvis A, Van Hal G, Lambkin A, Dochez C, Meheus A. Vaccination
in the line of fire. S Afr J Epidemiol Infect 2008;23(1):53–7.
[3] Larson HJ, Cooper LZ, Eskola J, Katz SL, Ratzan S. Addressing the vaccine confidence gap. Lancet 2011;378(August 6 (9790)):526–35.
[4] World Health Organization. Polio vaccines and polio immunization in
the pre-eradication era: WHO position paper. Wkly Epidemiol Rec
2010;85(23):213–28.
Available
from
<http://www.who.int/wer/2010/
wer8523.pdf> [accessed February 2012].
[5] Independent Monitoring Board of the Global Polio Eradication Initiative. Available from <http://www.polioeradication.org/Portals/0/Document/Aboutus/
Governance/IMB/3rdIMBMeeting/IMB.Report.July.pdf>; July 2011 [accessed
February 2012].
[6] World
Health
Organization.
Measles
vaccines:
WHO
position
paper. Wkly Epidemiol Rec 2009;84(35):349–60. Available from
<http://www.who.int/wer/2009/wer8435.pdf> [accessed February 2012].
[7] World Health Organization. Measles outbreaks and progress towards meeting measles pre-elimination goals: WHO African Region, 2009–2010. Wkly
Epidemiol Rec 2011;86(April 1 (14)):129–36.
[8] World Health Organization. Increased transmission and outbreaks of
measles, European Region, 2011. Wkly Epidemiol Rec 2011;86(December 2
(49)):559–64.
[9] Health Systems Trust. The District Health Barometer 2008/09. Part A: indicator comparison by districts. Output indicators: immunisation. Available from
<http://www.hst.org.za/sites/default/files/dhb0809 31.pdf>; 2010 [accessed
February 2012].
[10] South African Department of Health. Expanded Programme on Immunisation
– EPI (SA) Revised Childhood Immunisation Schedule from April 2009. Available from <http://www.kznhealth.gov.za/vaccinations.pdf>; 2009 [accessed
February 2012].
[11] National Institute for Communicable Diseases. Communicable Diseases
Surveillance Bulletin. Available from <http://www.nicd.ac.za/assets/files/
Communicable%20Diseases%20Surveillance%20Bulletin%20March%202011.
pdf>; 2011 March [accessed February 2012].
C78
R.J. Burnett et al. / Vaccine 30S (2012) C72–C78
[12] Corrigall J, Coetzee D, Cameron N. Is the Western Cape at risk of an outbreak of
preventable childhood diseases? Lessons from an evaluation of routine immunisation coverage. S Afr Med J 2008;98(January (1)):41–5.
[13] Brighton Collaboration. Immunize safely. Available from <http://
brightoncollaboration.org/public>; 2010 [accessed February 2012].
[14] Offit PA, Davis RL, Gust D. Vaccine safety. In: Plotkin S, Orenstein W, editors.
Vaccines. 4th edition Saunders; 2003. p. 1629–44 [chapter 74].
[15] Henry. Nwo polisiestaat is hier! Vaccine awakening. Available from
<http://www.boerevryheid.co.za/forums/showthread.php?10512-NwoPolisiestaat-Is-Hier>!; November 20, 2007 [accessed February 2012].
[16] Katme AM. Harms of Vaccine – time to start talking!!. Available from <http://
samuslims.co.za/index.php?option=com content&view=article&id=67:harmsof-vaccine-time-to-start-talking&catid=53:vaccine-dangers&Itemid=72>;
originally posted October 29, 2009 and updated April 16, 2010 [accessed
February 2012].
[17] Cape Town Smile Studios. Thimerosal and autism goes to court. Available
from
<http://www.ctss.co.za/our-services-mainmenu-75/mercury-toxcitymainmenu-76/thimerosal-and-autism.html>; 2011 [accessed February
2012].
[18] Nasir L. Reconnoitering the antivaccination web sites: news from the front. J
Fam Pract 2000;49(August (8)):731–3.
[19] Wolfe RM, Sharp LK, Lipsky MS. Content and design attributes of antivaccination web sites. JAMA 2002;287(June 26 (24)):3245–8.
[20] Schlafly P (citing Mercola J). Who decides what drugs are forced on children?
Available from <http://www.healthycells.co.za/articles.asp?id=35>; March 26,
2009 [accessed February 2012].
[21] Hayes T. Why we don’t vaccinate. Available from <http://www.
hayesfamily.co.za/blog/?page id=1190>; last updated November 23, 2010
[accessed February 2012].
[22] Davies P, Chapman S, Leask J. Antivaccination activists on the world wide web.
Arch Dis Child 2002;87(July (1)):22–5.
[23] Zimmerman RK, Wolfe RM, Fox DE, Fox JR, Nowalk MP, Troy JA, et al. Vaccine
criticism on the World Wide Web. J Med Internet Res 2005;7(June 29 (2)):e17.
[24] Kata A. A postmodern Pandora‘s box: anti-vaccination misinformation on the
Internet. Vaccine 2010;28(February 17 (7)):1709–16 [Epub 2009 December
30].
[25] Bean SJ. Emerging and continuing trends in vaccine opposition website content.
Vaccine 2011;29(Febuary 24 (10)):1874–80 [Epub 2011 Jan 14].
[26] Nkonki LL, Chopra M, Doherty TM, Jackson D, Robberstad B. Explaining household socio-economic related child health inequalities using multiple methods
in three diverse settings in South Africa. Int J Equity Health 2011 April 4;10:13.
[27] Wakefield AJ, Murch SH, Anthony A, Linnell J, Casson DM, Malik M, et al.
Ileal–lymphoid–nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet 1998;351(Febraury 28 (9103)):637–41.
[28] Amanna I, Slifka MK. Public fear of vaccination: separating fact from fiction.
Viral Immunol 2005;18(2):307–15.
[29] Wroe AL, Bhan A, Salkovskis P, Bedford H. Feeling bad about immunising our
children. Vaccine 2005;23(Febraury 10 (12)):1428–33.
[30] Gerber JS, Offit PA. Vaccines and autism: a tale of shifting hypotheses. Clin Infect
Dis 2009;48(Febraury 15 (4)):456–61.
[31] Peltola H, Patja A, Leinikki P, Valle M, Davidkin I, Paunio M. No evidence
for measles, mumps, and rubella vaccine-associated inflammatory bowel
disease or autism in a 14-year prospective study. Lancet 1998;351(May 2
(9112)):1327–8.
[32] Taylor B, Miller E, Farrington CP, Petropoulos MC, Favot-Mayaud I, Li J, et al.
Autism and measles, mumps, and rubella vaccine: no epidemiological evidence
for a causal association. Lancet 1999;353(June 12 (9169)):2026–9.
[33] Patja A, Davidkin I, Kurki T, Kallio MJ, Valle M, Peltola H. Serious adverse events
after measles–mumps–rubella vaccination during a fourteen-year prospective
follow-up. Pediatr Infect Dis J 2000;19(December (12)):1127–34.
[34] Farrington CP, Miller E, Taylor B. MMR and autism: further evidence against a
causal association. Vaccine 2001;19(June 14 (27)):3632–5.
[35] Kaye JA, del Mar Melero-Montes M, Jick H. Mumps measles, and rubella vaccine
and the incidence of autism recorded by general practitioners: a time trend
analysis. BMJ 2001;322(Febraury 24 (7284)):460–3.
[36] Dales L, Hammer SJ, Smith NJ. Time trends in autism and in MMR immunization
coverage in California. JAMA 2001;285(March 7 (9)):1183–5.
[37] DeWilde S, Carey IM, Richards N, Hilton SR, Cook DG. Do children who
become autistic consult more often after MMR vaccination? Br J Gen Pract
2001;51(March (464)):226–7.
[38] Fombonne E, Chakrabarti S. No evidence for a new variant of measles–
mumps–rubella-induced autism. Pediatrics 2001;108(October (4)):E58.
[39] Taylor B, Miller E, Lingam R, Andrews N, Simmons A, Stowe J. Measles,
mumps, and rubella vaccination and bowel problems or developmental regression in children with autism: population study. BMJ 2002;324(Febraury 16
(7334)):393–6.
[40] Mäkelä
A,
Nuorti
JP,
Peltola
H.
Neurologic
disorders
after
measles–mumps–rubella
vaccination.
Pediatrics
2002;110(November
(5)):957–63.
[41] Madsen KM, Hviid A, Vestergaard M, Schendel D, Wohlfahrt J, Thorsen P, et al.
A population-based study of measles, mumps, and rubella vaccination and
autism. N Engl J Med 2002;347(November 7 (19)):1477–82.
[42] DeStefano F, Bhasin TK, Thompson WW, Yeargin-Allsopp M, Boyle C. Age at
first measles–mumps–rubella vaccination in children with autism and schoolmatched control subjects: a population-based study in metropolitan Atlanta.
Pediatrics 2004;113(Febraury (2)):259–66.
[43] Smeeth L, Cook C, Fombonne E, Heavey L, Rodrigues LC, Smith PG, et al. MMR
vaccination and pervasive developmental disorders: a case–control study.
Lancet 2004;364(September 11–17 (9438)):963–9.
[44] Fombonne E, Zakarian R, Bennett A, Meng L, McLean-Heywood D. Pervasive
developmental disorders in Montreal, Quebec, Canada: prevalence and links
with immunizations. Pediatrics 2006;118(July (1)):e139–50.
[45] Murch SH, Anthony A, Casson DH, Malik M, Berelowitz M, Dhillon AP, et al.
Retraction of an interpretation. Lancet 2004;363:750.
[46] The Lancet. Retraction – ileal–lymphoid–nodular hyperplasia, nonspecific colitis, and pervasive developmental disorder in children. Lancet
2010;375(February 6 (9713)):445.
[47] General Medical Council. Dr Andrew Jeremy Wakefield. Determination on Serious Professional Misconduct (SPM) and sanction.
Available from <http://www.gmc-uk.org/Wakefield SPM and SANCTION.
pdf 32595267.pdf>; May 24, 2010 [accessed February 2012].
[48] Centers for Disease Control and Prevention. Vaccine safety. Frequently
asked questions about thimerosal (ethylmercury). <http://www.cdc.gov/
vaccinesafety/Concerns/thimerosal/thimerosal faqs.html>; 2011 [accessed
February 2012].
[49] Stehr-Green P, Tull P, Stellfeld M, Mortenson PB, Simpson D. Autism and
thimerosal-containing vaccines: lack of consistent evidence for an association.
Am J Prev Med 2003;25(August (2)):101–6.
[50] Madsen KM, Lauritsen MB, Pedersen CB, Thorsen P, Plesner AM, Andersen
PH, et al. Thimerosal and the occurrence of autism: negative ecological evidence from Danish population-based data. Pediatrics 2003;112(September (3
Pt 1)):604–6.
[51] Hviid A, Stellfeld M, Wohlfahrt J, Melbye M. Association between
thimerosal-containing vaccine and autism. JAMA 2003;290(October 1 (13)):
1763–6.
[52] Verstraeten T, Davis RL, DeStefano F, Lieu TA, Rhodes PH, Black SB, et al.
Safety of thimerosal-containing vaccines: a two-phased study of computerized
health maintenance organization databases. Pediatrics 2003;112(November
(5)):1039–48.
[53] Heron J, Golding J, ALSPAC Study Team. Thimerosal exposure in infants and
developmental disorders: a prospective cohort study in the United Kingdom does not support a causal association. Pediatrics 2004;114(September
(3)):577–83.
[54] Andrews N, Miller E, Grant A, Stowe J, Osborne V, Taylor B. Thimerosal exposure in infants and developmental disorders: a retrospective cohort study
in the United Kingdom does not support a causal association. Pediatrics
2004;114(September (3)):584–91.
[55] Brodie N. To vaccinate or. . .. Available from <http://mg.co.za/article/2008-0805-to-vaccinate-or>; August 5, 2008 [accessed February 2012].
[56] World Health Organization. Six common misperceptions about immunization. Available from <http://www.who.int/immunization safety/aefi/
immunization misconceptions/en/index.html>; 2010 [accessed February
2012].
[57] Ginger. Much ado about measles. Available from <http://www.news24.com/
MyNews24/Letters/Much-ado-about-measles-20091016>; October 16, 2009
[accessed February 2012].
[58] Tenpenny S. Reasons to just say no to vaccines. Available from
<http://www.newswithviews.com/Tenpenny/sherri19.htm>; 9 July, 2008
[accessed February 2012].
[59] World Health Organization. State of the world’s vaccines and immunization. Available from <http://whqlibdoc.who.int/publications/2009/
9789241563864 eng.pdf>; 2009 [accessed February 2012].
[60] Coleman MS, Lindley MC, Ekong J, Rodewald L. Net financial gain or loss
from vaccination in pediatric medical practices. Pediatrics 2009;124(December
(5)):S472–91.
[61] Freed GL, Cowan AE, Clark SJ. Primary care physician perspectives on
reimbursement for childhood immunizations. Pediatrics 2009;124(December
(5)):S466–71.
[62] Duclos P. National Immunization Technical Advisory Groups (NITAGs): guidance for their establishment and strengthening. Vaccine 2010;28(April 19
(1)):A18–25.
[63] Schoub BD, Ngcobo NJ, Madhi S. The National Advisory Group on Immunization
(NAGI) of the Republic of South Africa. Vaccine 2010;28(April 19 (1)):A31–4.
[64] World
Health
Organization.
WHO
vaccine-preventable
diseases: monitoring system 2010 global summary. WHO/IVB/2010.
<http://whqlibdoc.who.int/hq/2010/WHO IVB 2010 eng.pdf>; 2010 [accessed
February 2012].
[65] Heininger U. The success of immunization-shovelling its own grave? Vaccine
2004;22(May 7 (15–16)):2071–2.
[66] André FE. Vaccinology: past achievements, present roadblocks and future
promises. Vaccine 2003;21(January 30 (7–8)):593–5.
[67] Centers for Disease Control and Prevention. Vaccines and immunizations. Some common misperceptions. <http://www.cdc.gov/vaccines/vacgen/6mishome.htm#Givingachildmultiple>; 2011 [accessed February 2012].
[68] Waisbord S, Larson HJ. Why invest in communication for immunisation? Evidence and lessons learned. A joint publication of the Health Communication
Partnership based at Johns Hopkins Bloomberg School of Public Health/Center
for Communication Programs (Baltimore) and the United Nations Children’s
Fund (New York); 2005.
[69] Rowan KE. Explaining illness through the mass media: a problem-solving
perspective. In: Whaley BB, editor. Explaining illness: research, theory, and
strategies. Lawrence Erlbaum Associates; 2000.
Vaccine 30S (2012) C79–C86
Contents lists available at SciVerse ScienceDirect
Vaccine
journal homepage: www.elsevier.com/locate/vaccine
Review
Financing vaccinations – The South African experience
Mark S. Blecher a,∗ , Filip Meheus b , Aparna Kollipara a , Robert Hecht c ,
Neil A. Cameron d , Yogan Pillay e , Luisa Hanna a
a
National Treasury, Private Bag X115, Pretoria, South Africa
Institute of Tropical Medicine, Nationalestraat 155, 2000 Antwerp, Belgium
Results for Development, 1100 15th Street, NW, Suite 400, Washington, DC 20005, United States
d
University of Stellenbosch, Private Bag X1, Matieland 7602, South Africa
e
Department of Health, Private Bag X828, Pretoria 0001, South Africa
b
c
a r t i c l e
i n f o
Article history:
Received 8 November 2011
Received in revised form 14 March 2012
Accepted 10 April 2012
Keywords:
Financing
Pneumococcal
Rotavirus
Vaccinations
South Africa
a b s t r a c t
South Africa provides a useful country case study for financing vaccinations. It has been an early adopter
of new vaccinations and has financed these almost exclusively from domestic resources, largely through
general taxation. National vaccination policy is determined by the Department of Health, based on advice
from a national advisory group on immunisation. Standard health economic criteria of effectiveness, costeffectiveness, affordability and burden of disease are used to assess whether new vaccinations should
be introduced. Global guidelines and the advice of local and international experts are also helpful in
making the determination to introduce new vaccines. In terms of recent decisions to introduce new
vaccines against pneumococcal disease and rotavirus diarrhoea in children, the evidence has proved
unequivocal. Universal rollout has been implemented even though this has led to a fivefold increase in
national spending on vaccines. The total cost to government remains below 1–1.5% of public expenditures
for health, which is viewed by the South African authorities as affordable and necessary given the number
of lives saved and morbidity averted. To manage the rapid increase in domestic spending, efforts have
been made to scale up coverage over several years, give greater attention to negotiating price reductions
and, in some cases, obtain initial donations or frontloaded deliveries to facilitate earlier universal rollout.
There has been strong support from a wide range of stakeholders for the early introduction of new
generation vaccines.
© 2012 Elsevier Ltd. All rights reserved.
1. Introduction
Vaccination provides a powerful technological tool to improve
the health of the world’s population. However because of the nature
of infectious disease transmission, no country can be entirely secure
as long as reservoirs of infectious cases exist in any country; with
increasing levels of travel and migration in many parts of the
world including Southern Africa, continuous spread of vaccine
preventable and other infectious diseases is likely. A significant
number of low income countries do not have the health resources to
fully finance their vaccination programmes and thus rely on various
forms of international financial support.
This article provides a practical country case study of financing vaccinations. South Africa is a middle income country with
∗ Corresponding author. Tel.: +27 21 464 6119.
E-mail addresses: [email protected] (M.S. Blecher),
[email protected] (F. Meheus), [email protected] (A. Kollipara),
[email protected] (R. Hecht), [email protected] (N. Cameron),
[email protected] (Y. Pillay), [email protected] (L. Hanna).
0264-410X/$ – see front matter © 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.vaccine.2012.04.042
relatively high child mortality (under 5 mortality rate in 2010
was 57/1000) [1], substantially driven by the HIV epidemic. South
Africa’s public health care system is funded through general taxes
and health services are provided free at the point of use at the
primary health care level. Funding new interventions requires,
through economic evaluation of cost-effectiveness, the Department
of Health to demonstrate the case that additional resources should
be allocated during annual budget negotiations. The context for the
introduction of new vaccinations in South Africa has been assisted
by the overall fiscal stability of government, the presence of fiscal space (i.e. budgetary room that allows a government to provide
resources for a desired purpose without any prejudice to the sustainability of government’s financial position) [2] and the political
priority given to improving maternal and child health, noting the
large burden of disease and relatively poor child survival indicators in South Africa. Pneumonia and diarrhoea accounted for 17%
of deaths of children under five years of age [3].
There is a high degree of acceptance of vaccination as a basic
public good in South Africa and as an essential element of primary
health care delivery. In addition to the usual childhood vaccines, South Africa has introduced four new generation vaccines:
C80
M.S. Blecher et al. / Vaccine 30S (2012) C79–C86
Hepatitis B (1996), Haemophilus influenzae type b (1998) and
Pneumococcal and Rotavirus vaccines (2008). In 2002 the Minister of Finance co-chaired a global conference of Ministers of Health
and Finance on vaccination in Cape Town and was a patron of Global
Alliance for Vaccines and Immunisation (GAVI). South Africa also
contributes to the International Finance Facility for Immunisation
and is an important global site for vaccine research on tuberculosis
(TB) and HIV, illustrating the political will given to vaccines.
such as the annual Budget Review [9] and the two yearly Intergovernmental Fiscal review series [10]. Comparisons of global
spending by government on health services were derived from the
World Health Organisation [11]. Fiscal space was assessed through
national indicators including trends in domestic revenue, government expenditure, fiscal deficit, and debt as proportion of gross
domestic product (GDP), and interest expenditure as a proportion
of total expenditure.
1.1. Financing vaccinations
3. Results
Financing vaccines needs to be seen within the broader architecture of financing health care within specific countries. Health
financing is often considered within a conceptual framework of
raising revenue (sources of funds, financing mechanism, collecting
agency), pooling (risk pools, resource allocation) and purchasing
(benefit package, payment mechanisms). GAVI considers a good
financing mechanism should be equitable, efficient (administratively not too expensive), effective (generates adequate, timely and
reliable resources) and should promote accountability and selfsustainability [4].
Vaccines are generally considered a global public good. Given
the nature of infectious diseases it is essential to ensure high
enough levels of immunization coverage in order to achieve herd
immunity, and reduce and possibly eliminate transmission. For
this reason out of pocket payments that may prevent in particular the poor from seeking immunization services are generally a
poor method of financing vaccines [5]. Where countries have multiple funding pools, a national regulatory framework for at least
a set of minimum benefits (including access to immunization) is
needed. There are many useful international publications on the
pros and cons of different financing methods [4,6,7]. Besides the
more usual methods of financing health services by governments
and donors, various innovative methods have been put in place to
assist in financing vaccinations on a global level especially to support low income countries or coordinate purchasing across regions.
These include advance market commitments (AMC), volume guarantees, long-term purchase contracts, pooled procurement such as
Pan American Health Organisation’s (PAHO) Revolving Fund, the
International Finance Facility for Immunisation (IFFIm) and sector
wide donor support (SWAp) [4,8].
3.1. Financing vaccination in South Africa
2. Methodology
South African government budget documentation from 2008 to
2011 pertaining to new generation vaccines was reviewed, with
a particular focus on criteria used to assess new generation vaccines for funding. Funding of vaccinations is presented in the
context of recent health financing indicators from South Africa.
Prices were determined initially in South African Rand and are presented in $US for purposes of international comparison based on
an average exchange rate of R8.25 in 2008:$1. Trends in health
expenditure were analysed from publications and databases of
the National Treasury (Department of Finance) in South Africa,
South Africa is a middle income country and so does not qualify for GAVI support. Despite relatively slow economic growth, its
fiscal position has generally been stable with low levels of public
debt (33.8% of GDP in 2011/12) and relatively small budget deficits
(although these have increased during the recent global recession). Its total level of government revenue, mainly from taxation,
amounted to 28.4% of GDP in 2011/12 (as compared for example to
40% in a developed country such as the UK) [9]. These factors have
contributed to some fiscal space to increase spending on vaccination, in the context of a high burden of disease, increasing prioritization of health by government and a relatively average level of
health financing compared to other middle income countries [11].
In South Africa, approximately 83% of the population of 50.5
million is uninsured and relies primarily on public services; 17% of
the population is insured by mainly private health insurance called
medical schemes [12]. South Africa is in the process of developing a
National Health Insurance (NHI) system, however this is still in the
process of policy and legislative development [13]. Total expenditure on health services amounts to 8.5% of GDP in 2011/12, of which
4.2% is from public sources, 4.1% from private sources and 0.2%
from donors [10]. Public sector health services (and thus vaccines)
in South Africa are financed predominantly in the public sector
through general tax revenue. The sources of funds for general tax
revenue are mainly personal income tax (36.7%), corporate income
tax (19.8%) and value added tax (24.8%). Spending on public sector
health services has increased from 3.4% of GDP in 1995/96 to 4.2%
in 2011/12 or from 3% to 3.9% using a narrower definition (Department of Health only, excluding other government departments and
entities, spending on healthcare).
The vaccination programme is financed virtually entirely
through domestic resources. All vaccines provided through the
public sector are free at the point of use (i.e. no user charges). The
budget for vaccines (medicines component only) is approximately
$131 million (R1.08 billion) in 2011/12. Costs of personnel and
other components of visit costs are estimated at approximately $57
million per annum (R469m). The introduction of new generation
vaccines led to a fivefold increase in expenditure on vaccines (fourfold in real terms) (Table 1). Despite constituting approximately
13% of public sector medicine expenditure, total spending on vaccines amounts to just under 1% of expenditure on public health
services in South Africa. This, makes even new generation vaccines
Table 1
Budget for vaccines and as a proportion of total spending on public sector health services (nominal Rand million).
Health spending
Spending on
Medicines, total
Vaccines
Vaccines spending as a % of
Medicine spending, total
Health spending, total
2004/05
2005/06
2006/07
2007/08
2008/09
2009/10
2010/11
2011/12
43,040
49,808
56,719
65,930
79,015
93,020
102,890
115,099
3,129
188
3,705
197
4,538
208
4,905
219
5,494
320
6,403
646
8,042
862
8,267
1,080
6.0%
0.4%
5.3%
0.4%
4.6%
0.4%
4.5%
0.3%
5.8%
0.4%
10.1%
0.7%
10.7%
0.8%
13.1%
0.9%
Sources: National Treasury databases and publications [9] Department of Health unpublished data.
M.S. Blecher et al. / Vaccine 30S (2012) C79–C86
C81
Table 2
Health spending in context of overall fiscus.a
Rand billion
2004/05
2005/06
2006/07
2007/08
2008/09
2009/10
2010/11
2011/12
GDP
Revenue: GDP ratio
Total government revenue
Total government expenditure
Health spending as a
proportion of total
government expenditure in
main budget
Health spending in public
sector (narrowb )
Health spending in public
sector (narrow) as % of GDP
1,431
24.3%
348
369
11.7%
1,580
26.1%
412
417
12.0%
1,807
26.6%
481
470
12.1%
2,082
26.9%
560
541
12.2%
2,320
26.2%
609
636
12.4%
2,443
23.9%
585
743
12.5%
2,667
24.8%
660
810
12.7%
2,915
25.0%
730
885
13.0%
43
50
57
66
79
93
103
115
3.0%
3.2%
3.1%
3.2%
3.4%
3.8%
3.9%
3.9%
Source: National Treasury databases and publication series [9,10].
a
Numbers are expressed in nominal terms (i.e. not adjusted for inflation) in SA Rand.
b
Narrow refers to national and provincial Departments of Health only and excludes health related spending by other departments and entities.
relatively affordable. Latin American countries that have been rapid
adopters of new vaccines generally spend around 1% of their health
budgets for vaccine purchases. A recent analysis of the 15 countries
expected to graduate from GAVI support by 2015 and become financially self-sufficient thereafter also suggests that most of them will
be able to pay for all vaccines using less than 1% of estimated future
public spending for health [14].
In the private sector, although medical schemes have regulatory
imposed prescribed minimum benefits, these are not always perfectly aligned with the public sector vaccination programme. This
means that users in the private sector sometimes pay out-of-pocket
for vaccines administered by private providers, even though they
have the option of receiving them free of charge at public facilities.
Table 2 shows health spending in the context of total government expenditure on the main budget in nominal terms (i.e. not
adjusted for inflation). Each year as the GDP grows this leads to
revenue increases and additional funds become available for allocation. These amounts increase further if tax policy makes provision
for revenue as a proportion of GDP to rise, as it did from 2004/05
to 2008/09. As it happened the rollout of some of the new generation vaccines in the 2009/10 year was followed shortly by the
onset of the global economic recession (see reduced revenue: GDP
ratio in 2009/10), but government maintained spending levels on
social services through the recession by temporarily increasing the
deficit (see difference between expenditure and revenue). Health
expenditure has increased by on average R10 billion ($1.2 billion)
per annum in nominal or current terms (R5 billion or $606 million in real terms) over the period from 2004/05 to 2011/12 and in
this context the introduction of new generation vaccines has been
relatively affordable.
Comparing the level of government spending for health services
across middle income countries (Table 3), South Africa’s level of
spending (despite the WHO numbers varying slightly from what
was presented above) is fairly comparable with that of other middle income countries with similar levels of economic development
as measured by percentage of GDP (3.9% for South Africa in Table 2
vs. 3.5% upper middle income average in Table 3). However South
Africa’s health outcome indicators are considerably poorer, mainly
driven by HIV. It has been estimated that the cost of HIV for public
health services alone is approximately 0.7% of GDP in 2011/12 and
this cost continues to rise [15,16]. Given the higher burden of disease in South Africa it has been suggested that spending should be
above the average for middle income countries.
3.2. Economic evaluation of new vaccines
As the financial implications of introducing new vaccinations are
fairly substantial they usually require additional resources. In the
South African context, given that the vaccination schedule is set
through national policy and thus raises similar financial implications for all levels of government, the introduction of new vaccines
is typically addressed in the annual round of budget negotiations.
The tabling and consideration of new budget bids by government in South Africa requires inclusion of a range of sufficient
evidence to enable the evaluation of the bid. Criteria that have
proved useful repeatedly in the South African context include:
• Burden of disease: data reported by the National Department of
Health.
• Effectiveness of the vaccine: published studies in reputable international journals, if possible meta-analysis or Cochrane reviews.
• Cost-effectiveness of the vaccine: while international studies provide useful information, local studies are usually required, given
very different cost structures across countries.
• Total cost and affordability: depends on fiscal space, prioritization, success in price negotiations and contracting.
• Feasibility of implementation and availability of a credible implementation plan. If there are doubts about feasibility, pilot studies
may be useful.
• International guidelines and advice of the South African National
Advisory Group on Immunisation (NAGI) and other local and
international experts.
• Political process: Besides the technical aspects, the budget process also involves communication between the Ministers of
Health and Finance and approval by a wider committee of Ministers, the national Cabinet and Parliament.
3.3. Protecting funding at a sub-national level
South Africa consists of nine provinces which are responsible
for operational aspects of health service delivery. Provinces have
substantial powers over financial allocations [17,18] and although
they have historically had relatively limited discretion in introducing new vaccines there is risk that each province may fund
national programmes in a different manner. To address, this several mechanisms were put in place to ensure greater consistency in
the approach to adoption and uptake of new vaccines. Changes to
the vaccination schedule were thoroughly discussed at a number
of inter-governmental forums which coordinate activities across
the various levels of government. New vaccination schedules were
released as national policy with appropriate guidelines and extensive training was initiated. The new policy was identified as a
budget priority and provinces were required to report back to the
national level on their proposed budgets for priority areas prior to
finalization of the budget process. Conditional grants are a potential mechanism to earmark and protect funding allocated at the
C82
M.S. Blecher et al. / Vaccine 30S (2012) C79–C86
Table 3
Comparing government spending on health across selected middle income countries.
Country
Chile
Mexico
Russia
Turkey
Venezuela
Uruguay
Brazil
Malaysia
Argentina
Botswana
South Africa
Costa Rica
Namibia
Peru
Thailand
China
Morocco
India
Vietnam
Low income
Lower middle income
Upper middle income
High income
Gov health
expenditure as % of
GDP
2000
2007
3.4
2.4
3.2
3.1
2.4
6.1
2.9
1.7
5.0
2.7
3.4
5.0
4.2
2.8
1.9
1.8
2.0
1.1
1.6
1.8
1.6
3.2
6.1
3.6
2.7
3.5
3.5
2.7
5.9
3.5
2.0
5.1
4.3
3.6
5.9
3.2
2.5
2.7
1.9
2.3
1.1
2.8
2.2
1.8
3.5
6.9
GDP per capita
(current US$)
Per capita gov
health expenditure
(PPPa int $)
Total health
expenditure as a %
of GDP
Gov health
expenditure as % of
total health
expenditure
Life
expectancy
2007
2000
2007
2000
2007
2000
2007
2008
320
236
247
272
199
500
202
159
452
218
223
360
174
134
89
42
32
16
23
14
35
243
1631
507
372
512
467
324
678
348
268
671
568
340
656
196
191
209
104
68
29
72
28
76
419
2492
6.6
5.1
5.4
4.9
5.7
11.2
7.2
3.2
9
4.4
8.5
6.5
6.1
4.7
3.4
4.6
4.2
4.4
5.4
4.7
4.4
6.2
10.2
6.2
5.9
5.4
5
5.8
8
8.4
4.4
10
5.7
8.6
8.1
7.6
4.3
3.7
4.3
5
4.1
7.1
5.3
4.3
6.4
11.2
52.1
46.6
59.9
62.9
41.5
54.6
40
52.4
55.5
61
40.5
76.8
68.9
58.7
56.1
38.7
46.6
24.5
30.1
37.6
37
52
59.4
58.7
45.4
64.2
69
46.5
74
41.6
44.4
50.8
74.6
41.4
72.9
42.1
58.4
73.2
44.7
45.4
26.2
39.3
41.9
42.2
55.2
61.3
79
75
68
72
74
76
72
74
75
54
51
79
61
73
69
73
71
64
74
9877
9741
9146
8865
8252
7206
7185
7028
6604
6545
5933
5891
4216
3771
3689
2651
2373
1096
804
Source: World Health Statistics [11].
a
PPP: Purchasing Power Parity.
national level in South Africa for implementation by provinces, but
have not to date been used for the examples cited in this article.
3.4. Case study: pneumococcal vaccine
Pneumococcal conjugate vaccine (PCV) was first licensed for use
and introduced in the private sector in South Africa in 2005 with
the public sector introducing it from the latter half of 2008. Some
of the key criteria used in the evaluation were:
Burden of disease: Unlike diphtheria, whooping cough and
tetanus which have been virtually eliminated in South Africa, pneumonia is amongst the top four causes of mortality of South African
children under five years of age, pneumococcus being the most
common cause. Local data provided by the National Advisory Group
on Immunisation estimated there are 100,000 cases of pneumococcal pneumonia annually with high fatality rates among the severe
cases, which number 14,500–16,000 per annum. South Africa has
a high rate of child mortality (57/1000) which motivated strongly
for intervention.
Effectiveness: Strong evidence was available on effectiveness of
pneumococcal conjugate vaccine. South Africa has a Cochrane centre. The Cochrane review [19] meta-analysis and the results of
several trials were considered. As it happened one of the early
landmark trials was done in South Africa, showing the vaccine’s
effectiveness to be 65% in HIV-infected children and 83% in HIVuninfected children [20].
Cost-effectiveness: According to WHO-CHOICE guidelines for
low and middle income countries, interventions which cost less
than GDP per capita can be regarded as highly cost-effective and
between one to three times GDP per capita as cost-effective [21].
Local estimates of cost effectiveness calculated by the National
Treasury and National Advisory Group on Immunisation ranged
from R4,312 to R11,109 per DALY averted ($523–$1,347). This is
less than national GDP per capita (R51,500) and was considered
highly cost-effective.
Total cost and affordability: In South Africa approximately 1.066
million children are born annually [22]. For the purpose of assessing feasibility and affordability prior to procurement, the unit price
was estimated at R600 per course ($73, or $24.30 per dose) based
on early discussions with suppliers. The total cost estimated at 85%
coverage was R542 million per annum ($65.7 million). This was
considered too large to be addressed within a single budget, but
sufficient fiscal space existed for it to be reached by year two or
three, if the intervention could be progressively rolled out. With
the benefit of hindsight, these initial unit costs can be considered
relatively high, and subsequently turned out to be more expensive than PAHO and GAVI prices [23,24]. However early adoption
of the vaccine was deemed imperative, and it was thought likely
that cheaper prices would be obtained over time as global and
domestic volumes increased, generic and innovator competition
entered the market, and improved intelligence on global pricing
patterns was obtained. Costs were partially offset by a frontloaded
in-kind donation of additional doses and support for cold chain
capacity, training of health workers, disease monitoring and social
mobilisation and communication, which improved the short-term
affordability. While bundling was not a necessity, it was the outcome of negotiations with the single supplier, who made offers
of additional support which enabled the early rollout of the vaccine. Various complexities regarding pricing and affordability are
considered further in the discussion section below.
Feasibility: Pneumococcal vaccine could easily be incorporated
into the routine child immunization schedule, and could be given
simultaneously with a new pentavalent combined vaccine. A
seven-valent pneumococcal strain was introduced as a short-term
decision, as it was the only product licensed and registered at the
time (South Africa has since introduced the 13-valent vaccine in
2011). The National Health Laboratory Service has a pneumococcal surveillance programme that monitors incidence and mortality
rates. Additional provision will be made for cold chain requirements and extensive training will be implemented on the revised
M.S. Blecher et al. / Vaccine 30S (2012) C79–C86
schedules. Countries such as the UK and Australia had recently
introduced the vaccine successfully.
International guidelines: In 2007 the World Health Organisation
vaccination recommendations were widened to include pneumococcus, recommending prioritisation in countries with a high level
of infant mortality, a high number of annual deaths or in countries
with a high prevalence of HIV. In 2008 their use and funding support
for low income countries was recommended by GAVI.
Expert advice: The South African National Advisory Group on
Immunisation (NAGI) strongly recommended introduction. This
view was backed by several leading paediatricians, infectious disease specialists and the South African Medical Research Council.
Political process: Budget bids are tabled by the Minister of Health
to the Minister of Finance. The bid for vaccine introduction followed
extensive technical advice from NAGI and detailed discussions with
provinces. Budget recommendations were approved by national
Cabinet and Parliament noting the priority of maternal and child
health given poor child survival indicators.
Conclusion: The overall assessment process was systematic and
the findings were extremely positive. The only borderline concern was affordability, however the earliest possible adoption of
the vaccine was deemed imperative, and prices were expected to
fall reasonably quickly. On the basis of this positive evaluation,
$131 million (R1.08 billion) was allocated over three years for
new vaccines in Budget 2009, with annual allocations rising over
three years in line with affordability. The vaccine was introduced
mid-year in 2008 in a number of pilot sites and national rollout
commenced in 2009. Full national rollout could only be afforded
by the third year. Negotiated arrangements with pharmaceutical
companies to front-load higher volumes allowed for earlier rollout. In 2011, based on greater competition and transparency about
international prices, South Africa has been able to re-negotiate substantially lower prices (see Section 4).
C83
Feasibility: SA has a well-established, high coverage vaccination programme and the new vaccine could be added with limited
difficulty to the routine child immunisation schedule. Rotavirus is
an oral vaccine, and the need for training of health care workers,
upgrading of cold chain capacity and other administration issues
were considered feasible in the South African context, despite short
term health systems weaknesses. Countries in Latin America had
recently introduced the vaccine successfully.
International guidelines: In 2008, GAVI endorsed the use of the
rotavirus vaccine and was on the point of subsidising its use in
low income countries. WHO had prequalified products in 2007 and
UNICEF approved its use. From 2007 WHO recommended use of
the vaccine in countries where infrastructure and financing was
available and where efficacy data showed a significant public health
impact [39] and from 2009 for all countries [33].
Expert advice: NAGI and local paediatric and infectious disease
experts supported its introduction.
Political aspects: Support was provided from the National
Department of Health following a large outbreak of diarrhoea
deaths in the Ukuhlamba district of Eastern Cape in a context of
high child mortality rates in South Africa.
Conclusion: The decision to introduce the vaccination was driven
by the high burden of rotavirus disease, evidence that the vaccine
could substantially reduce incidence of severe cases and support
from local experts (NAGI) and global organisations (GAVI, WHO).
Immunisation for rotavirus appeared to have a positive cost-benefit
ratio given high incidence of childhood diarrhoea and related morbidity and mortality in South Africa. The vaccine was funded for
implementation from late 2008. South Africa was – the first country in Africa to introduce rotavirus vaccine. Since its adoption, the
WHO Strategic Advisory Group of Experts have reviewed the data
from efficacy studies conducted in Africa and has recommended the
universal inclusion of rotavirus vaccines in national immunization
programs.
3.5. Case study: rotavirus vaccine
Burden of disease: South Africa has a high child mortality rate
(57/1000). Diarrhoea is the third major cause of mortality in infants
(10,786 deaths in 2000) and is especially high among poor children. Rotavirus causes 25–50% of child diarrhoea, 3,591–5,383 child
deaths and 25–58% (30,000) of hospitalisations due to diarrhoea
(personal communication National Health Laboratory Service and
NAGI). The majority of rotavirus infections occur in children under
one [25,26].
Effectiveness: At the time the decision was taken, substantial evidence was available that rotavirus vaccines are effective
in preventing rotavirus infections, particularly serious infections
with a 2004 Cochrane review of 64 trials reported effectiveness
in preventing 43–90% of severe cases [27,28]. Rotavirus vaccine
immunogenicity and safety trials had demonstrated effectiveness
and safety in the countries where these trials were conducted,
including in Europe, and in North and South America [29,30].
Interim results of a landmark South African and Malawian study
[31] became available in 2008 and once published [32] helped to
pave the way for revisions in global guidelines for rotavirus [33].
Cost-effectiveness and cost–benefit: Several published studies
were available showing cost effectiveness in Asia, Vietnam, Mexico
and the USA [34–37]. A local cost–benefit analysis provided by the
National Advisory Group on Immunisations suggested benefits of
reduced hospitalization alone would cover much of the costs of
introducing the new vaccine. Unit costs were expected to decrease
over time noting international comparisons [24,38].
Total cost and affordability: Total cost for 1.06 million children
was estimated at $22 million per annum (85% coverage, $24 per
course). This was considered affordable in the South African context
(0.17% of total health expenditure).
4. Discussion
4.1. Decision making in South Africa
South Africa provides a useful country case study for financing
vaccinations because it has been a fairly early adopter of new
vaccines financed virtually exclusively from domestic resources.
The analysis shows that despite the higher costs of new generation
vaccines, they have been considered affordable given that they constitute a relatively small portion of the health budget (0.9%) while
contributing to important outcomes of decreasing child morbidity
and mortality. Standard health economic criteria of burden of disease, effectiveness, cost-effectiveness and affordability provided a
fairly straight forward and robust way for the country to evaluate
the new interventions. On this basis, considerable additional
allocations were made leading to a fivefold increase in the vaccines
budget.
The technical assessments required for effectiveness, costeffectiveness and affordability are not unduly complex and these
processes have been facilitated by the presence of a strong national
vaccine advisory committee and some strong domestic institutions
such as the National Institute of Communicable Diseases in the
National Health Laboratory Service and the Medical Research
Council. These decisions were enabled by the presence of fiscal
space, sound macro-economic policy, debt and fiscal management
and in the context of a well functioning national revenue service.
The decisions were supported by good data from international
trials including a meta-analysis (including support from the local
Cochrane collaborating centre), clear global recommendations
from WHO and GAVI along with expert local advice. The decision
was also supported by political prioritization of health and the
C84
M.S. Blecher et al. / Vaccine 30S (2012) C79–C86
need to address relatively poor child survival rates. When all of the
evidence and other factors were combined, the government came
to the conclusion that the new vaccines represented good value
for money and their adoption should be an important component
of the national strategies for improving child health.
Where affordability was borderline the intervention was rolledout over a period of two to three years, to take advantage of
progressively increasing availability of public funds and the fact
that it can take several years to scale up a new vaccine intervention
(even when the new technology can be relatively easily integrated
within existing health services).
4.2. Pricing and affordability
Pricing is integrally linked to questions of affordability and
universal roll-out of new generation vaccines. In South Africa,
purchasing of vaccines is undertaken through a central transversal tender, conducted by a public private partnership, specifically
established for the supply and local manufacturing of vaccines.
With the benefit of hindsight, lower prices could possibly have been
achieved in the initial tender. However given the urgency of introduction of the new vaccines it was considered imperative to embark
rapidly on the rollout. Various complexities need to be considered
in relation to pricing. It is now generally accepted that vaccine
prices should be tiered by country income group, acknowledging
the need for innovation and appropriate incentive arrangements
to encourage new vaccine development such as for malaria, TB
and HIV [40]. Costs for pneumococcal vaccine appear to vary from
$7 per dose in GAVI eligible countries (half of which is subsidised
[41]) $10–15 a dose for lower-middle income countries, and around
$20, (with an upper limit of $30 used in the sensitivity analysis) in
upper middle income countries [42]. PAHO appears to have secured
a price of $15 per dose [38].
When South Africa entered into initial purchasing arrangements
in mid-2008 this preceded the PAHO and GAVI pooled procurement processes. At the time, there was a single innovator supplier.
Prior to the tender, the prevailing price in the private sector in the
country was more than twice as expensive (personal communication National Health Laboratory Service and NAGI). The country had
experienced with the introduction of new antiretroviral medication
a pattern of initially high prices as a result of a single innovator company and low volumes, followed by a series of rapid price
decreases as greater competition and higher volumes entered the
market. At the time of writing it appears likely that pricing reductions of the order of 30–40% will be obtained in the second tender
for pneumococcal vaccine to be awarded in the 2011/12 financial
year.
Although South Africa has been able to afford the new generation vaccines, it initially paid more than other similar income
countries, for example in Latin America [24] and substantially more
than low income countries [23]. While the need for tiered pricing for vaccination is understood [4] (some of this may relate to
a willingness to pay a premium for innovation to encourage new
vaccine development) part of this relates to limited availability of
information on global pricing patterns and benchmarks. Efforts to
improve intelligence on global price benchmarks and prices being
offered to other countries could also help to speed up the pace of
price decline and enhance affordability. Substantial use of international price benchmarking and vastly improved availability of
information on medications for HIV and AIDS from Médecins sans
Frontières (MSF) and the Clinton Health Access Initiative (CHAI)
amongst others [43] played an important role in achieving lower
prices in a recent South African national tender for AIDS medicines.
Similar global benchmarking information on vaccine pricing might
allow more middle income countries to negotiate affordable prices
and thus speed up universal rollout of new generation vaccines.
The global community may be able to assist countries by facilitating the creation of more open and transparent systems for
tracking vaccine prices and for refining the basis for fair price tiering
[40].
Other strategies include pooled procurement, technology transfer arrangements, and improving the regulatory environment.
Regional or global purchasing arrangements such as through
PAHO or GAVI [40] have helped bring down prices and improve
access, and might be useful for a wider set of countries. Consideration should be given to introducing such arrangements for
the Southern African Development Community (SADC) region or
to building stronger cooperative agreements with GAVI, UNICEF
and PAHO. Even if South Africa does not formally purchase using
these mechanisms it might benefit through closer relationships to
receive greater intelligence on pricing with these structures. The
government did not explore technology transfer arrangements, as
those designed in Brazil BioMangiunos, an area that is currently
being explored in the new tenders. A recent practice note by
the South African Treasury makes publication of tender awards
mandatory [44]. More rapid and efficient regulatory registration
processes (e.g. for WHO pre-qualified products) to bring products
to market earlier and introduce competition are also likely to assist
in price reduction.
4.3. Programmatic issues and impact of the rollout
A 2011 WHO/UNICEF/NDOH study [45] evaluated the introduction of the new vaccines, noting that the training for the new
vaccines was properly organized, and well cascaded to facility level
in all provinces. However it cited some serious challenges including
poor data collection, vaccination stock shortages, and shortage of
cold chain capacity. There has also been poor collaboration between
the public sector support for new generation vaccines and the regulatory aspects of prescribed minimum benefits for private medical
schemes, with no accompanying revision of the latter. This led to
an inconsistency in the public and private financing environments
suggesting a need to coordinate basic benefits across different
financing streams and for the regulatory approach to be aligned
with policy changes.
These logistical and operational weaknesses suggest greater
attention should have been given to planning and to various additional costs of complementary inputs required for rollout. Some
form of earmarking of the funds allocated, such as through a new
conditional grant, might have made for smoother rollout.
Despite these challenges, the implementation and rollout of
the two vaccines was achieved rapidly and has seen some
success. In just one financial year from 2009/10 to 2010/11,
coverage increased from 22.8% to 72.8% for pneumococcal vaccine, and 34.6% to 72.8% for rotavirus vaccine [46,47]. Initial
information on child health outcomes is also promising. Early
indications from the National Health Laboratory Service shows
the reduction of invasive pneumococcal disease in children under
two by 61% [48] and a local case control study on the effectiveness of PCV7 in South Africa, suggests a reduction of between
27.3% and 58.9% of all presumed bacterial pneumonia (PBP) [49].
Mortality data from Statistics South Africa suggest that that total
deaths for children under five reduced by 17.3% between 2008
and 2009 (StatsSA, mortality and causes of death: findings from
death notification 2011), while data from the South African Medical Research Council suggests a 16% reduction of child deaths
from 2008 to 2010 (personal communication Medical Research
Council). However these improvements in outcomes are not necessarily attributable to the new vaccines and coincide also with
improvements in HIV prevention of mother-to-child transmission
and treatment programmes.
M.S. Blecher et al. / Vaccine 30S (2012) C79–C86
C85
4.4. Financing vaccines
Acknowledgements
The country case studies suggest that it is relatively easy to
assess the potential of countries to domestically fund their own
vaccination programmes, using a simple set of indicators such as
national GDP, a minimum level of public funding for health as a
proportion of GDP (e.g. 2%), and affordability based on the share of
vaccine costs in total government health expenditures (e.g. 1–1.5%).
There is a set of low income countries that (even if they were to
increase health spending as a proportion of GDP) do not have a sufficient GDP base to generate sufficient revenue for public health
services. These countries are likely to remain partially dependent
on global financing support. Approximately 72 countries were candidates for GAVI support at a per capita income of <US$1 000. Given
the increase of global GDP/capita amongst low income countries,
the eligibility cut off increased to $US1 500 per capita in January
2011 and 16 countries are anticipated to graduate from GAVI assistance by 2015 [14]. The need for such bilateral, multilateral and
donor support has been reported by a number of global studies
which usefully cost basic packages of health services and highlight
the importance of health in economic development [50]. In contrast
a middle income country such as South Africa should be able to fully
fund its vaccination programmes, although donors may play a transitional role in introducing new initiatives since domestic budget
cycles and scaling up of funding levels can take time.
The introduction of Human Papilloma Virus (HPV) vaccine may
be the next vaccine candidate to be evaluated for introduction in
South Africa. Preliminary analysis suggests that although the vaccine is relatively expensive, this has not been the primary barrier
to its implementation, but rather the relatively poor state of school
health services and difficulty of reaching pre-adolescents most at
risk. Attention is being given to strengthening these services, while
cost and cost-effectiveness are further analyzed.
The authors wish to acknowledge inputs from Andre Meheus,
Nomkhosi Zulu and Candy Day.
5. Conclusion
South Africa provides a useful case study of a middle income
country that has been an early adopter of new generation vaccines.
In a context of relatively high child mortality, vaccines are considered a priority intervention and a public good. Introduction of
new vaccines is predominantly tax funded from the central level
(although some difficulties may arise in maintaining prioritization
of funds at provincial level). Evaluation of new vaccines for funding follows fairly standardized economic evaluation techniques of
effectiveness, cost-effectiveness and affordability. Although new
generation vaccines have led to a fivefold increase in spending on
vaccine products, spending is still less than 1% of the public health
budget and the introduction of new generation vaccines has been
considered cost-effective.
The successful introduction of new vaccines in middle income
countries is likely to be facilitated by:
• Improved understanding of effectiveness, cost-effectiveness and
cost–benefit ratios for new generation vaccines.
• Better access to information on global pricing and benchmarks.
• Further development of global and regional partnerships such as
for purchasing and information sharing.
• Improved regulatory processes to bring new products and competition earlier to the market.
• Appropriate incentive design to reward new vaccine development and innovation.
Role of the funding source
This study did not receive any financial support.
Conflict of interest statement
None declared.
References
[1] UNICEF/WHO [Internet]. UN Inter-agency group for child mortality estimates.
Available from: www.childmortality.org [cited 05.01.2012].
[2] Heller PS. Understanding fiscal space. Washington, DC: International Monetary
Fund; 2005. Report no.: PDP/05/4.
[3] Black RE, Cousens S, Johnson HL, Lawn JE, Rudan I, Bassani DG, et al. Global,
regional, and national causes of child mortality in 2008: a systematic analysis.
Lancet 2010;375:1969–87.
[4] Global Alliance for Vaccines and Immunisation (GAVI). Immunisation financing
options: a resource for policy makers. Geneva: GAVI; 2002.
[5] England S, Kaddar M, Nigam A, Pinto M. Practice and policies on user fees for
immunization in developing countries. Geneva: World Health Organization;
2001. Report no.: WHO/V&B/01.07.
[6] Kaddar M, Lydon P, Levine R. Financial challenges of immunization: a look at
GAVI. Bulletin of the World Health Organization 2004;82:697–702.
[7] The World Bank and the GAVI Alliance. Immunization financing toolkit: a
resource for policy-makers and program managers. 2010.
[8] Ngcobo NJ, Cameron NA. Introducing new vaccines into the childhood immunisation programme in South Africa. South African Journal of Epidemiology and
Infection 2010;25:3–4.
[9] Republic of South Africa. National treasury. Budget review 2011. Pretoria:
National Treasury; 2011.
[10] Republic of South Africa. National treasury. Intergovernmental fiscal review
2011. Pretoria: National Treasury; 2011.
[11] World Health Organization [Internet]. World Health Statistics. Available from:
http://www.who.int/gho/database/en/ [cited 15.01.12].
[12] Council for Medical Schemes. Annual report 2009–2010. Pretoria: Council for
Medical Schemes; 2009.
[13] Republic of South Africa, Department of Health. National health act (61/2003):
policy on national health insurance. Government Gazette 2011;554.
[14] Saxenian H, Cornejo S, Thorien K, Hecht R, Schwalbe N. An analysis of how the
GAVI alliance and low- and middle-income countries can share costs of new
vaccines. Health Affairs 2011;30:1122–33.
[15] aids2031 Cost and Financing Working Group. The long run costs and financing of HIV/AIDS in South Africa. Washington, DC: Results for Development
Institute; 2010.
[16] Haaker M. Fiscal dimensions of HIV/AIDS in South Africa. Washington, DC:
World Bank; 2011.
[17] Government of South Africa. Constitution of the Republic of South Africa 1993.
Pretoria: South African Government; 1994.
[18] Republic of South Africa. Department of Health. National Health Act. Pretoria:
Department of Health; 2004.
[19] Lucero MG, Dulalia VE, Nillas LT, Williams G, Parreno RN, Nohynek H, et al.
Pneumococcal conjugate vaccines for preventing vaccine-type invasive pneumococcal disease and pneumonia with consolidation on X-ray in children under
two years of age. Cochrane Database of Systematic Reviews 2004:CD004977.
[20] Klugman KP, Madhi SA, Huebner RE, Kohberger R, Mbelle N, Pierce N. A trial of
a 9-valent pneumococcal conjugate vaccine in children with and those without
HIV infection. New England Journal of Medicine 2003;349:1341–8.
[21] World Health Organization-Choosing Interventions that are cost-effective
(WHO-CHOICE) [Internet]. Cost-effectiveness thresholds. Available from:
http://www.who.int/choice/costs/CER thresholds/en/index.html
[cited
15.01.12].
[22] Statistics South Africa. Midyear population estimates. Pretoria: Statistics South
Africa; 2010.
[23] UNICEF [Internet]. Supplies & logistics. Available from: http://www.unicef.
org/supply/ [cited 06.10.11].
[24] PAHO Revolving Fund: vaccine and syringe prices for 2009. Immunization
Newsletter 2009;31:4–7.
[25] Steele AD, Peenze I, de Beer MC, Pager CT, Yeats J, Potgieter N, et al. Anticipating
rotavirus vaccines: epidemiology and surveillance of rotavirus in South Africa.
Vaccine 2003;21:354–60.
[26] Waggie Z, Hawkridge A, Hussey GD. Review of rotavirus studies in Africa:
1976–2006. Journal of Infectious Diseases 2010;202(Suppl.):S23–33.
[27] Soares-Weiser K, Goldberg E, Tamimi G, Pitan OC, Leibovici L. Rotavirus
vaccine for preventing diarrhoea. Cochrane Database of Systematic Reviews
2004:CD002848.
[28] Rotavirus vaccine for the prevention of rotavirus gastroenteritis among children. Recommendations of the Advisory Committee on Immunization Practices
(ACIP). MMWR Recommendations and Reports 1999;48:1–20.
[29] Vesikari T, Matson DO, Dennehy P, Van Damme P, Santosham M, Rodriguez
Z, et al. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant
rotavirus vaccine. New England Journal of Medicine 2006;354:23–33.
C86
M.S. Blecher et al. / Vaccine 30S (2012) C79–C86
[30] Ruiz-Palacios GM, Perez-Schael I, Velazquez FR, Abate H, Breuer T, Clemens
SC, et al. Safety and efficacy of an attenuated vaccine against severe rotavirus
gastroenteritis. New England Journal of Medicine 2006;354:11–22.
[31] Madhi S, Lerumo T, Louw C, Kirsten M, Neuzil K, Steele D, et al. Efficacy of human
rotavirus vaccine RIX4414 (RotarixTM ) in South African infants during the first
year of life – an interim analysis. In: 8th international rotavirus symposium.
2008.
[32] Madhi SA, Cunliffe NA, Steele D, Witte D, Kirsten M, Louw C, et al. Effect of
human rotavirus vaccine on severe diarrhea in African infants. New England
Journal of Medicine 2010;362:289–98.
[33] Meeting of the diarrhoeal and enteric vaccines advisory committee, October
2008 – executive summary. Weekly Epidemiological Record 2009;84:
30–6.
[34] Podewils LJ, Antil L, Hummelman E, Bresee J, Parashar UD, Rheingans R. Projected cost-effectiveness of rotavirus vaccination for children in Asia. Journal
of Infectious Diseases 2005;192(Suppl. 1):S133–45.
[35] Fischer TK, Anh DD, Antil L, Cat ND, Kilgore PE, Thiem VD, et al. Health
care costs of diarrheal disease and estimates of the cost-effectiveness of
rotavirus vaccination in Vietnam. Journal of Infectious Diseases 2005;192:
1720–6.
[36] Widdowson MA, Meltzer MI, Zhang X, Bresee JS, Parashar UD, Glass RI. Costeffectiveness and potential impact of rotavirus vaccination in the United States.
Pediatrics 2007;119:684–97.
[37] Valencia-Mendoza A, Bertozzi SM, Gutierrez JP, Itzler R. Cost-effectiveness of
introducing a rotavirus vaccine in developing countries: the case of Mexico.
BMC Infectious Diseases 2008;8:103.
[38] International AIDS Vaccine Initiative (IAVI). Procurement and pricing of new
vaccines for developing countries. Policy Brief #16. 2008.
[39] World Health Organization. Rotavirus vaccines. Weekly Epidemiological
Record 2007;82:285–95.
[40] Center for Global Development Advance Market Commitment Working Group.
Making markets for vaccines: ideas to action. Washington, DC: 2005.
[41] UNICEF [Internet]. Vaccine price data. Available from: http://www.unicef.
org/supply/index 57476.html [cited 12.03.12].
[42] Nakamura MM, Tasslimi A, Lieu TA, Levine O, Knoll MD, Russell LB, et al. Cost
effectiveness of child pneumococcal conjugate vaccination in middle-income
countries. International Health 2011;3:270–81.
[43] Médecins sans Frontières. Untangling the web of antiretroviral price reductions
2010;12.
[44] Republic of South Africa, National Treasury. Instruction note on enhancing compliance monitoring and improving transparency and accountability in supply
chain management. Pretoria: National Treasury; 2011.
[45] World Health Organization, UNICEF, National Department of Health. Report of
the post introduction evaluation of new vaccines in South Africa 2011.
[46] Republic of South Africa, Department of Health. Annual report 2009/10. South
Africa: Pretoria; 2010.
[47] Republic of South Africa, Department of Health. Annual report 2008/09. South
Africa: Pretoria; 2009.
[48] von Gottberg A, Cohen C, de Gouveia L, Quan V, Meiring S, Madhi SA, et al. Trends
in invasive pneumococcal disease after PCV7 introduction in South Africa. In:
12th international symposium on pneumococci and pneumococcal diseases.
2012.
[49] Madhi S, Groome M, Zar H, Kapongo C, Mulligan C, Moore D, et al. Effectiveness of penumococcal conjugate vaccine (PCV) against presumed bacerial
pneumonia in South African HIV uninfected children: a case–control study. In:
12th international symposium on pneumococci and pneumococcal diseases.
2012.
[50] The commission on macroeconomics and health. Macroeconomics and health:
investing in health for economic development. Geneva: World Health Organization; 2001.