Available online at www.sciencedirect.com
Yellow fever vaccine — how does it work and why do rare cases
of serious adverse events take place?
Alan DT Barrett1 and Dirk E Teuwen2
Yellow fever 17D vaccine is one of the most successful
vaccines ever developed and over 540 million doses have been
used. Nevertheless there has been very little known about the
mechanism of protection induced by the vaccine. The last
couple of years have seen important advances made in
understanding how the vaccine works involving studies of the
innate and adaptive immune responses plus a systems biology
approach. Like all vaccines, the 17D vaccine causes rare
serious adverse events (SAEs) following immunization. At
present, the mechanism(s) of SAEs is(are) poorly understood
but our advances in understanding the immune response
induced by the vaccine have promise to help elucidate the
mechanism of SAEs.
Addresses
1
Sealy Center for Vaccine Development and Department of Pathology,
University of Texas Medical Branch, 301 University Blvd, Galveston, TX
77555-0436, United States
2
UCB Group, Brussels, Belgium
Corresponding author: Barrett, Alan DT ([email protected]) and
Teuwen, Dirk E ([email protected])
Current Opinion in Immunology 2009, 21:308–313
This review comes from a themed issue on
Vaccines
Edited by Greg Poland and Alan Barrett
Available online 10th June 2009
0952-7915/$ – see front matter
# 2009 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.coi.2009.05.018
Introduction
The yellow fever (YF) disease is caused by yellow fever
virus (YFV) and is found in sub-Saharan Africa and tropical
regions of South America. Wild-type YFV causes a pansystemic viral disease with viremia (up to 109 plaqueforming units (pfu)/ml), fever, hepatic, renal and myocardial injury, hemorrhage, shock, and up to 50% mortality
(Figure 1). The liver is the target organ in vertebrate hosts
and liver dysfunction results in patient’s skin turning
yellow in color. Hence the name of the disease is ‘yellow
fever’. There is no antiviral therapy to treat the disease and
the disease is prevented by the use of a live attenuated
vaccine, strain 17D. The 17D vaccine was developed in
1937 and has proved highly efficacious and one dose
appears to give immunity for life. Despite its success, it
is only in recent years that an understanding of how the
vaccine works has been documented. Here, we review
Current Opinion in Immunology 2009, 21:308–313
what is known about the mechanism of immunity and rare
adverse events following immunization, and where we
have gaps in our knowledge.
17D vaccine
The current status of 17D vaccine as of 2005 has been
reviewed recently [1]. YFV is the prototype member of
the genus Flavivirus, family Flaviviridae. It is a small
icosahedral virus, approximately 50 nM in diameter. The
virus has three structural proteins: core (C), membrane
(M), and envelope (E), and seven nonstructural proteins
(NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). The
genome is a single strand of positive-sense RNA, approximately 10 800 nucleotides in length, including 50 and 30
untranslated (UTR) regions. The virus particle consists of
the C protein that surrounds the genome and the M and E
proteins on the outside of the virion. The E protein is the
major immunogen. The nonstructural proteins are the
replicating machinery of the virus and are found only in
virus-infected cells.
The original 17D strain was developed following 176
passages of wild-type strain Asibi in mouse and chicken
tissue. Two substrains are used as the vaccine today,
substrains 17D-204 and 17DD, which are at passages
235-240 and 287-289, respectively, from wild-type Asibi
virus. Over 500 million doses have been administered since
the vaccine was derived in 1937. The genomes of Asibi,
17D-204 and 17DD viruses have been determined and the
wild-type Asibi differs from the vaccine viruses by 48
nucleotides encoding 20 amino acid substitutions. There
are no nucleotide differences in the 50 UTR and no amino
acid substitutions in the C protein while the 30 UTR has
four nucleotide changes and the other nine proteins each
have amino acid substitutions. The molecular basis of
attenuation of 17D has not been determined.
There are currently six manufacturers of 17D vaccine
producing a combination of approximately 30–60 million
doses per year and all 17D vaccine is produced in embryonated chicken eggs using technology that has changed
little since 1945. One dose of vaccine contains between
104 and 106 pfu of virus. Although limited studies indicate
that immunity lasts for at least 45 years, the World Health
Organization requires booster immunizations every 10
years to maintain protective immunity.
Host immune response following 17D
immunization
Until recently, the mechanism of protective immunity
induced by the vaccine was poorly understood. The last
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Yellow fever vaccine Barrett and Teuwen 309
Figure 1
Yellow fever virus infection.
couple of years have seen a number of publications that
have investigated innate and adaptive immune responses
to either 17D-204 or 17DD vaccine strains. Although a
low viremia (<200 pfu/ml) is detected in approximately
half of vaccinees following immunization, 17D-mediated
immunity occurs within 10 days in 95% of vaccinees and
induces protective immunity against all known wild-type
strains. Interestingly, the 17D vaccine is effective against
all 7 genotypes of wild-type YFV, which differ up to
25.1% at nucleotide level and 7.9% at amino acid
level. 17D vaccines induce rapid and specific humoral
immune response. IgM antibodies are detected between
three to seven days post-vaccination, reach a peak by two
weeks postvaccination, and then decline over several
months. The neutralizing antibody response is rapid,
detected by 7 days postvaccination, and may persist for
at least 45 years. All studies to date indicate that neutralizing antibody is the correlate of protection with over
98% of vaccinees being fully protected for at least 10 years
and it is considered the primary mechanism of protection
against re-exposure. A low neutralization titer of 1:10 has
been shown to be protective. Complement fixation (antiNS1) antibodies are detected by two weeks post wildtype YF infection and their levels increase rapidly but,
interestingly, they are not seen post-vaccination.
The 17D vaccine strain is a potent inducer of CD4+
and CD8+ cytotoxic T-cell responses against the nonstructural proteins NS1, NS2B, NS3, and the E structural protein. CD8+ T cells contribute to the protective
immune response by mediating viral clearance. The
CD8+ T-cell response to 17D YF reaches its peak 1–2
weeks post-vaccination [2], is detectable up to 19
months, and is thought to contribute to vaccine efficacy.
One recent study examining the activation events and
modulatory pathways in T cells after vaccination found
that CD4+ T cells were activated early (day 7), CD19+
T cells were activated by day 15, and CD8+ T cells
were activated late (day 30). This upregulation of
modulatory features on CD4+ and CD8+ T cells at
day 15 caused a lower level of CD38+ T cells by day 30
postvaccination [3].
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In addition, recent studies have shown that the innate
immune system also plays an important role in determining
the strength and quality of adaptive immune responses.
The 17D vaccine strain replicates minimally (maybe abortively?) in dendritic cells without causing substantial apoptotic cell death [4,5] and stimulates Toll-like receptors
(TLR)s 2, 7, 8, and 9 [6]. This results in the production of
proinflammatory cytokines IL-1b and TNF-a, and markers of the type I interferon (IFN-a/b) response are
expressed by peripheral blood cells, plus dendritic cell
activation, and maturation. These activated dendritic cells
most likely migrate to regional lymph nodes and stimulate
both cell-mediated and humoral adaptive immune
responses [4,5,7]. Viral interaction with alternate TLRs
modifies the Th1 and Th2 cytokine balance produced by
activated immune cells, and it is possible that nonviral
vaccine components could also influence this balance in
17D-204 immunization [6,7], while ELISpot has been used
to show that IFN-g and IL-4 were significantly increased
on day 15 post-17DD immunization [8]. The interferoninduced peripheral lymphocyte response by vaccinees may
be mediated in part through the action of 20 –50 oligoadenylate synthetase. Levels of this enzyme are increased in
lymphocytes by day 4 postvaccination and reach a maximum at day 7. Natural killer cells have also been shown to
play a role early in virus infection [9] plus upregulation of
FcgR and IL-10R following 17DD immunization.
Systems biology is now being applied to the study of the
17D immune response and is providing an opportunity to
understand how the various arms of the immune response
are integrated to give a protective immune response. It is
clear that 17D-204 vaccine-mediated immunity involves
both the innate and adaptive immune responses, which are
orchestrated by major transcription factors, including
STAT1, IRF7, and ETS2 [10,11]. Importantly, Querec
et al. [11] have identified C1qB and ETIF2ak4 as a 90%
predictor of CD8+ T-cell responses and TNFRSF17
(which encodes a receptor for growth factor BLyS-BAFF)
as a 100% predictor of the neutralizing antibody response
induced by the vaccine. These studies have great potential
to help elucidate the mechanism of protective immunity.
Current Opinion in Immunology 2009, 21:308–313
310 Vaccines
Table 1
Precautions and contraindications for the administration of YF 17D vaccine.
Age
Risk for adverse reactions appears to be age related
Infants younger than six months of age should not be vaccinated because they are more susceptible to neurological adverse event
Analysis of passively reported adverse events indicate that persons older than 60 years of age may be at increased risk for systemic adverse events
following vaccination compared with younger persons
Risk of any serious adverse event following vaccination has been estimated at about 4 per 100 000 doses for people aged 60–69 years old and 7.5
per 100 000 doses for people 70 years and older
Thymus disease (history of)
Thymus disease, including thymectomy, has been identified as a contraindication to YF vaccine as compromised thymic function is an
independent risk factor for YEL-AVD
Pregnancy
Safety of YF vaccination during pregnancy has not been well established
Pregnant women should be immunized only if travel to an area with risk of YF is unavoidable or when during an outbreak immunization campaign
Immunosuppression
Infection with YF vaccine virus poses a theoretical risk for travelers with, first, leukemia, lymphoma or generalized malignancy; second, history of
thymus disease or thymectomy; or third, treatment with corticosteroids, alkylating drugs, antimetabolites, or radiation
Immunosuppressed patients who are unable to effectively resist viral infections should not be vaccinated
Immunosuppression in association with HIV
Infection with YF vaccine virus also poses a theoretical risk for travelers with immunosuppression in association with HIV infection
Persons who are HIV-infected, but do not have AIDS or other symptomatic manifestations of HIV infection, and have established laboratory
verification of immune system function (e.g., CD4 >200/mm3), and who cannot avoid potential exposure to YF disease should be offered the
vaccination and monitored closely for possible adverse effects
Seroconversion rates after YF vaccination among asymptomatic HIV-infected persons are limited, but indicate that the seroconversion rate among
such persons may be reduced. Because vaccination of asymptomatic HIV-infected persons might be less effective than that of persons not
infected with HIV, measurement of the neutralizing antibody response to vaccination should be considered post-vaccination
Hypersensitivity
YF vaccine is produced in embryonated chicken eggs and should not be given to persons hypersensitive to eggs
Vaccine-associated adverse events
The 17D vaccine has an excellent safety record with only
rare cases of serious adverse events (SAEs) following
immunization. It is well tolerated with recipients reporting injection site pain, inflammation, mild headaches,
myalgia, low-grade fever, backache, or other minor symptoms that occur 2–11 days post-vaccination. There are a
number of precautions and contraindications (Table 1).
Two types of SAEs have been reported: first, vaccineassociated neurotropic disease (YEL-AND) caused by
Figure 2
Clinical summary of YEL-AND and YEL-AVD.
Current Opinion in Immunology 2009, 21:308–313
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Yellow fever vaccine Barrett and Teuwen 311
neuroinvasion of the 17D virus and second, vaccineassociated viscerotropic disease (YEL-AVD), a pansystemic infection starting often with hepatic involvement, a
condition very similar to wild-type YF infection
(Figure 1).
Vaccine-associated neurotropic disease
(YEL-AND)
Cases of YEL-AND (previously named postvaccine encephalitis) have similar profiles, irrespective of the manufacturing source of the 17D YF vaccine. Typically they
occur in first-time vaccinees only, with an onset of illness
2–30 days post-vaccination. The case fatality rate (CFR)
is <5% [12] (Figure 2).
Vaccine-associated viscerotropic disease
(YEL-AVD)
Cases of YEL-AVD (previously named febrile multiple
organ system failure or post-vaccination multiple organ
system failure) have been described among recipients of
vaccines produced by all 17D-204 and 17DD vaccine
manufacturers and, as with YEL-AND (Figure 2). All
cases have occurred in first-time vaccinees. The vaccine
virus has been cultured from blood, serum, heart, liver,
spleen, skin, brain, spinal cord, kidney, lungs and skeletal
muscle. Liver biopsy of a fatal case before death showed
minimal periportal inflammation, mild microvesicular
fatty change, and focal degeneration of parenchymal
tissue without hepatocellular necrosis. Significantly, no
nucleotide mutations have been identified in the vaccine
viruses isolated from vaccinees of YEL-AVD. YF antigen
can be detected in the liver and spleen and YF viral
particles have been identified by electron microscopy in
spleen and lung. Microscopic examination of liver tissue
showed midzonal necrosis, steatosis, eosinophilic
degeneration of hepatocytes, apoptosis with Councilman
bodies, microvesicular fatty changes, and minimal inflammation. Myocarditis and tubular necrosis have also been
observed and the neutralizing antibody titers against the
virus were higher than expected in some patients
(reviewed by [13]).
YEL-AVD was first reported in the literature in 2001 and
was initially considered to be a recent phenomenon until
Engel et al. [14] reported that a case had occurred in a
Brazilian woman, vaccinated in 1975. Following the initial
12 reports in 2001, an additional 39 cases have been
identified worldwide as of May 2009, yielding a total of
51 cases thus far [13,15]. The most recent cases are a
cluster of 4 fatal cases in the Ica Department of Peru out
of 42 000 persons given the same lot of 17D vaccine. At
the time of writing this review, the cause of this cluster is
currently under investigation and no cause has been
identified [16].
Three potential risk factors for the development of SAEs,
and of YEL-AND have been identified: first, advanced
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age (60 years or older); second, males [15]; and third,
history of thymus disease with a thymectomy.
The estimated frequency of YEL-AVD in USA is calculated between 0.3 and 0.5 cases per 100 000 doses distributed, while rates are higher among people 60–69
years old (1.1 case per 100 000 doses), and higher again
among those who are over 70 years (3.2 per 100 000
doses). The estimated incidence in the UK and in France
is similar at 0.25 case per 100 000 doses. An Australian
review of adverse events following YF immunization
revealed a similar increasing frequency of SAEs with
increasing age, and a Brazilian study revealed a similar
estimated risk of YEL-AVD ranging from 0.06 to 1.32
case per 100 000 doses [17]. The CFR of YEL-AVD is
around 60% with a higher CFR in women when compared to men. Although there is increasing incidence of
YEL-AVD with age, there is no evidence that the neutralizing antibody response is reduced in senior citizens
compared to younger adults [18].
Mechanism of YEL-AVD
A major obstacle of studying YEL-AVD is the limited
number of cases and availability of limited samples at
early times following immunization. The latter is not
surprising as the initial clinical symptoms of YEL-AVD
are not recognized because prodromal signs and symptoms are aspecific and not suggestive of a potential wildtype YF like disease. In addition, other than the Ica
cluster, there has never been more than one case associated with a particular lot of 17D vaccine. Overall, those
limited samples have greatly hindered research on YELAVD and the mechanism of YEL-AVD remains to be
elucidated. Nevertheless there have been some important studies during the last few years. Significantly, in
several YEL-AVD cases, there are large and prolonged
viremias and elevation of liver enzymes, characteristic of
that seen in wild-type YF infection [19,20]. Antigenspecific B-cell and T-cell responses indicating no apparent impairment to the host immune response have been
documented [19]. On the other hand, YEL-AVD cases
have shown reduced platelet counts and the role of the
complement needs to be further studied. Anomalies in
the innate immune response, including increased IL-6,
IL-8, MCP-1, monokine induced by IFN-g, and GRO
have also been identified. A comprehensive study of a
fatal YEL-AVD in a young female patient in the United
States identified heterozygous genetic polymorphisms in
chemokine receptor CCR5 and its ligand RANTES, but
OAS1, OAS2, TLR3, and DC-SIGN were wild-type
[21,22]. A potential hypothesis centers around a disconnection between the signaling of innate immune
response and the timely activation of the adaptive
immune response. In contrast to the above studies, two
recent studies have found few affects in immunization
related to immune suppression. A study of 102 HIVinfected patients who received 17D vaccine revealed that
Current Opinion in Immunology 2009, 21:308–313
312 Vaccines
HIV-infected patients responded to 17D vaccine less
than non-HIV-infected individuals in terms of numbers
of individuals who had generated neutralizing antibodies
and the neutralizing antibody titer was generally lower.
Nonetheless, there was no evidence (of increased incidence) of either YEL-AVD or YEL-AND [20]. A study of
70 rheumatological patients using immunosuppressors
and vaccinated with 17DD vaccine, revealed that 16
patients (22.5%) reported some minor adverse effect,
only one presented a mild adverse effect, and adverse
events were no more frequent than those exist among
immunocompetent individuals [23].
Conclusions
Recent years have seen great strides in our understanding
of the immune response induced by 17D vaccine. These
advances have important implications as a proof-of-principle to understand how one dose of vaccine can give
apparent life-long protective immunity.
Despite intensive multidisciplinary efforts to understand
the potential mechanisms of YEL-AVD and YEL-AND
our understanding is still poor. There is an urgent need for
further research on the interaction of the virus, host
genetics, and the host immune response following immunization to understand why YEL-AND and YEL-AVD
develop in certain cases. To this end an International
Laboratory Network has been established for YF vaccineassociated adverse events ([24]). An important part of the
investigation process is the collection of appropriate
samples to study YF adverse events and dos Santos
et al. [25] have developed a protocol to analyze blood
samples from cases of severe adverse events.
Overall, 17D vaccine is the only approach to the prevention of the YF disease. Despite the occurrence of rare
YEL-AND and YEL-AVD cases, the benefit–risk ratio of
YF immunization is very positive for travelers and for
persons during YF outbreak control campaigns. As with
all vaccines, it is necessary to carefully consider whether
or not the individual should receive the vaccine. 17D
immunization should be given only to individuals who are
going to a location at a time when there is a risk of YF.
Furthermore, contraindications to administration of the
vaccine should be carefully evaluated (see Table 1).
Clearly, only those who have a demonstrable risk of
acquiring YF should be immunized.
References and recommended reading
Papers of particular interest, published within the period of the review,
have been highlighted as:
of special interest
of outstanding interest
1.
Barrett AD, Monath TP, Barban V, Niedrig M, Teuwen DE: 17D
yellow fever vaccines: new insights. A report of a workshop
held during the World Congress on medicine and health in the
Current Opinion in Immunology 2009, 21:308–313
tropics, Marseille, France, Monday 12 September 2005.
Vaccine 2007, 25(15):2758-2765.
2.
Miller JD, van der Most RG, Akondy RS, Glidewell JT, Albott S,
Masopust D, Murali-Krishna K, Mahar PL, Edupuganti S, Lalor S
et al.: Human effector and memory CD8+ T cell responses to
smallpox and yellow fever vaccines. Immunity 2008, 28(5):710722.
Demonstration of early CD8+ T-cell response following immunization is
much larger than previously recognized.
Martins MA, Silva ML, Marciano AP, Peruhype-Magalha˜es V, EloiSantos SM, Ribeiro GL, Correa-Oliveira R, Homma A, Kroon EG,
Teixeira-Carvalho A et al.: Activation/modulation of adaptive
immunity emerges simultaneously after 17DD yellow fever
first-time vaccination: is this the key to prevent severe adverse
reactions following immunization? Clin Exp Immunol 2007,
148(1):90-100.
A study of upregulation and downregulation of various T-cell markers and
hypothesis that a ‘controlled microenvironment’ may be key for preventing YEL-AVD.
3.
4.
Barba-Spaeth G, Longman RS, Albert ML, Rice CM: Live
attenuated yellow fever 17D infects human DCs and allows for
presentation of endogenous and recombinant T cell epitopes.
J Exp Med 2005, 202(9):1179-1184.
5.
Palmer DR, Fernandez S, Bisbing J, Peachman KK, Rao M,
Barvir D, Gunther V, Burgess T, Kohno Y, Padmanabhan R et al.:
Restricted replication and lysosomal trafficking of yellow
fever 17D vaccine virus in human dendritic cells. J Gen Virol
2007, 88(Pt 1):148-156.
6.
Querec T, Bennouna S, Alkan S, Laouar Y, Gorden K, Flavell R,
Akira S, Ahmed R, Pulendran B: Yellow fever vaccine YF-17D
activates multiple dendritic cell subsets via TLR2, 7, 8, and 9 to
stimulate polyvalent immunity. J Exp Med 2006, 203(2):413-424.
7.
Querec TD, Pulendran B: Understanding the role of innate
immunity in the mechanism of action of the live attenuated
Yellow Fever Vaccine 17D. Adv Exp Med Biol 2007, 590:43-53
(Review).
8.
Santos AP, Matos DC, Bertho AL, Mendonc¸a SC, Marcovistz R:
Detection of Th1/Th2 cytokine signatures in yellow fever 17DD
first-time vaccines through ELISpot assay. Cytokine 2008,
42(2):152-155.
9.
Martins MA, Silva ML, Elo´i-Santos SM, Ribeiro JG, PeruhypeMagalha˜es V, Marciano AP, Homma A, Kroon EG, TeixeiraCarvalho A, Martins-Filho OA: Innate immunity phenotypic
features point toward simultaneous raise of activation and
modulation events following 17DD live attenuated yellow fever
first-time vaccination. Vaccine 2008, 26(9):1173-1184.
10. Gaucher D, Therrien R, Kettaf N, Angermann BR, Boucher G, Filali Mouhim A, Moser JM, Mehta RS, Drake DR 3rd, Castro E et al.:
Yellow fever vaccine induces integrated multilineage and
polyfunctional immune responses. J Exp Med 2008,
205(13):3119-3131.
Immune response to vaccination is preceded by coordinated induction of
transcription factors.
11. Querec TD, Akondy RS, Lee EK, Cao W, Nakaya HI, Teuwen D,
Pirani A, Gernert K, Deng J, Marzolf B et al.: Systems biology
approach predicts immunogenicity of the yellow fever vaccine
in humans. Nat Immunol 2009, 10(1):116-125.
Use of systems biology to investigate the immune response following 17D
vaccination and identification of molecules that predict the CD8+ an
antibody response of vaccinees.
12. McMahon AW, Eidex RB, Marfin AA, Russell M, Sejvar JJ,
Markoff L, Hayes EB, Chen RT, Ball R, Braun MM et al.:
Neurologic disease associated with 17D-204 yellow fever
vaccination: a report of 15 cases. Yellow Fever Working
Group. Vaccine 2007, 25(10):1727-1734.
13. Hayes EB: Acute viscerotropic disease following vaccination
against yellow fever. Trans R Soc Trop Med Hyg 2007,
101(10):967-971.
Overview of YEL-AVD cases.
14. Engel AR, Vasconcleos PFC, McArthur MA, Barrett ADT:
Characterization of a viscerotropic yellow fever vaccine
variant from a patient in Brazil. Vaccine 2006, 24(15):2803-2809.
www.sciencedirect.com
Yellow fever vaccine Barrett and Teuwen 313
15. Lindsey NP, Schroeder BA, Miller ER, Braun MM, Hinckley AF,
Marano N, Slade BA, Barnett ED, Brunette GW, Horan K et al.:
Adverse event reports following yellow fever vaccination.
Vaccine 2008, 26(48):6077-6082.
16. World Health Organization: Wkly Epidemiol Rec2008, 83:285
289.
Review of YEL-AVD cases that took place in Ica, Peru cluster and the
identification of gaps in our knowledge of the adverse events.
17. Fernandes GC, Camacho LA, Sa´ Carvalho M, Batista M, de
Almeida SM: Neurological adverse events temporally
associated to mass vaccination against yellow fever in Juiz de
Fora, Brazil, 1999–2005. Vaccine 2007, 25(16):3124-3128.
18. Monath TP, Cetron MS, McCarthy K, Nichols R, Archambault WT,
Weld L, Bedford P: Yellow fever 17D vaccine safety and
immunogenicity in the elderly. Hum Vaccine 2005, 1(5):207-214.
19. Bae HG, Domingo C, Tenorio A, de Ory F, Mun˜oz J, Weber P,
Teuwen DE, Niedrig M: Immune response during adverse
events after 17D-derived yellow fever vaccination in Europe. J
Infect Dis 2008, 197(11):1577-1584.
Elevation in cytokines and reduction in platelet counts may be surrogate
markers for and early warning of the development of YEL-AVD.
20. Veit O, Niedrig M, Chapuis-Taillard C, Cavassini M, Mossdorf E,
Schmid P, Bae HG, Litzba N, Staub T, Hatz C et al.:
Immunogenicity and safety of yellow fever vaccination for 102
HIV-infected patients. Clin Infect Dis 2009, 48(5):659-666.
www.sciencedirect.com
21. Belsher JL, Gay P, Brinton M, DellaValla J, Ridenour R, Lanciotti R,
Perelygin A, Zaki S, Paddock C, Querec T et al.: Fatal multiorgan
failure due to yellow fever vaccine-associated viscerotropic
disease. Vaccine 2007, 25(50):8480-8485.
The best description to date of a case of YEL-AVD, which also demonstrates the gaps in our knowledge.
22. Pulendran B, Miller J, Querec TD, Akondy R, Moseley N, Laur O,
Glidewell J, Monson N, Zhu T, Zhu H et al.: Case of yellow fever
vaccine-associated viscerotropic disease with prolonged
viremia, robust adaptive immune responses, and
polymorphisms in CCR5 and RANTES genes. J Infect Dis 2008,
198(4):500-507.
Follow-up to Belsher et al. [21] study that undertakes a detailed study of
the immune response in the case of YEL-AVD.
23. da Mota LM, Oliveira AC, Lima RA, dos Santos-Neto LL, Tauil PL:
Vaccination against yellow fever among patients on
immunosuppressors with diagnoses of rheumatic diseases.
Rev Soc Bras Med Trop 2009, 42(1):23-27.
24. Barrett AD, Niedrig M, Teuwen DE: International laboratory
network for yellow fever vaccine-associated adverse events.
Vaccine 2008, 26(43):5441-5442.
25. dos Santos AP, Bertho AL, Martins Rde M, Marcovistz R: The
sample processing time interval as an influential factor in flow
cytometry analysis of lymphocyte subsets. Mem Inst Oswaldo
Cruz 2007, 102(1):117-120.
Current Opinion in Immunology 2009, 21:308–313