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VIEWPOINTS
The Potential Role for Protein-Conjugate Pneumococcal
Vaccine in Adults: What Is the Supporting Evidence?
Daniel M. Musher, Rahul Sampath, and Maria C. Rodriguez-Barradas
The Medical Care Line (Infectious Disease Section), Michael E. DeBakey Veterans Affairs Medical Center and the Departments of Medicine and Molecular Virology and
Microbiology, Baylor College of Medicine, Houston, Texas
Covalent linking of a polysaccharide antigen
to a protein yielding a protein-conjugate
polysaccharide vaccine represented an extraordinary advancement in vaccinology,
although .50 years transpired from the
first description of this concept in the 1920s
to its first application in the late 1970s [1–
3]. The failure of infants and toddlers to
respond consistently to polysaccharide antigens greatly limited efforts to vaccinate
against infections caused by bacteria
that have polysaccharide capsules, including
Streptococcus
pneumoniae
[4] and
Received 9 September 2010; accepted 3 December 2010.
Presented in part: Annual Meeting of the Infectious
Diseases Society of America, Philadelphia, 29 October–1
November 2009; and the 7th International Symposium on
Pneumococci and Pneumococcal Diseases, Tel Aviv, Israel,
14–18 March 2010.
Correspondence: Daniel M. Musher, MD, Infectious
Disease Section, Michael E. DeBakey VAMC, Houston, TX
77030 ([email protected]).
Clinical Infectious Diseases 2011;52(5):633–640
Published by Oxford University Press on behalf of the
Infectious Diseases Society of America 2011.
1058-4838/2011/525-0001$37.00
DOI: 10.1093/cid/ciq207
Haemophilus influenzae type b [5]. In 1985,
a vaccine consisting of polyribosylribitol
phosphate, the capsular polysaccharide
(CPS) of H. influenzae type b, conjugated to
diphtheria toxoid was licensed in the
United States, followed soon thereafter by
a conjugate vaccine using CRM197, a nontoxic protein that differs from diphtheria
toxin in 1 amino acid at the 197 position
[6]. Widespread use of this vaccine in developed countries has nearly eliminated H.
influenzae type b meningitis [7].
In the 1990’s, these same concepts
were applied to pneumococcal CPS. In
a landmark study [8], 38,000 infants
were randomized to receive either 7valent pneumococcal conjugate protein
vaccine (PCV7), a preparation of CPS
from 7 serotypes that most frequently
infected children, conjugated to CRM197,
or a protein-conjugate meningococcal
vaccine. In PCV7-vaccinated children,
the incidence of invasive pneumococcal
disease was reduced by .90%. Not only
was the effect in vaccinated children
dramatic; with widespread use of this
vaccine, invasive pneumococcal disease
in children who had not been vaccinated
and in adults of all ages also decreased
substantially [9]. This phenomenon
is called the herd effect [10]: vaccinating
a critical number of members of a population, especially with an agent that reduces colonization and infection [11],
protects those who are unvaccinated.
Responses to Polysaccharide
Vaccines in Adults
Adults respond better than infants and
toddlers to polysaccharide antigens. With
the exception of a small proportion of
genetically determined nonresponders,
healthy adults predictably generate IgG
antibodies to most CPS after vaccination
with pneumococcal polysaccharide vaccine (PPV) [12]. Controversy persists
[13–15], but most investigators agree
that vaccination with the currently available 23-valent polysaccharide vaccine
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Vaccination with protein-conjugate pneumococcal vaccine (PCV) provides children with extraordinary protection
against pneumococcal disease, although the protective effect may be blunted by the emergence of replacement strains.
Studies in adults have compared PCV with pneumococcal polysaccharide vaccine (PPV) using surrogate markers of
protection, namely, serum anticapsular IgG antibody and opsonic activity. Results suggest that PCV is at least as effective as
PPV for the strains covered, but a definitive and consistent advantage has not been demonstrated. Unfortunately, persons
who are most in need of vaccine do not respond as well as otherwise healthy adults to either vaccine. Newer formulations of
PCV will protect against the most prevalent of the current replacement strains, but replacement strains will create a moving
target for PCVs. Unless an ongoing trial comparing 13-valent PCV with placebo (not to PPV) demonstrates a clearly better
effect than that seen in the past with PPV, cost-effectiveness considerations are likely to prevent widespread use of PCV in
adults.
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review, we examine the available data as
of 2010.
MATERIAL AND METHODS
We searched medical literature databases
for studies of pneumococcal conjugate
vaccine in adults from 1996 to the present,
focusing on studies that (1) were prospective and randomized; (2) contained
.2 study groups, including one that received a currently US Food and Drug
Administration–approved PCV (7-valent
or 13-valent) and a PPV comparator
group; (3) focused on adults, including
HIV-infected persons and other immunosuppressed populations; (4) measured pre- and postvaccination IgG
antibody levels to CPS and/or in vitro
opsonic activity (OPA) against S. pneumoniae (surrogates for protection, no
studies of protection having been reported); and (5) were published in refereed journals (Table 1).
RESULTS
PCV Versus PPV in Nonimmunosuppressed Adults
In the short term, antibody responses in
adults are generally better to PCV than to
PPV; IgG levels are as high or higher after
PCV than after PPV, and opsonic activity
is also greater. Jackson et al [32] studied
healthy persons aged 70–79 years, excluding those with immunocompromised conditions. All had received PPV
.5 years previously. The investigators
randomized persons to receive PPV23 or
PCV7 and included a dose-response
study of PCV7, using .1 mL, .5 mL (the
recommended pediatric dose), 1 mL, or
2 mL. In the dose-response study, 1 mL
was more immunogenic than the 2 lower
doses and was as effective as the 2-mL
dose. Four weeks after vaccination with
PPV23 or 1 mL of PCV7, IgG levels to 4
of 7 polysaccharides were significantly
greater in recipients of PCV7. One year
later, IgG levels had decreased
substantially but still exceeded baseline
for most CPS; for 2 CPS, levels after PCV
were significantly higher than those after
PPV. Opsonic activity, measured only at
4 weeks, was greater after PCV than after
PPV for all CPS, and differences were
significant for 5 of 7 CPS. The investigators concluded that ‘‘these results .
lend support to the concept that PCV
may offer some advantages over PPV in
older adults.’’
In similar studies, de Roux et al [33]
confirmed the findings of Jackson et al
[32], and Scott et al [34] showed similar
results in younger adults with a 13-valent
PCV. Most recently, Goldblatt et al [35]
found that results slightly favored PCV7
over PPV23 in successfully aging adults
50–80 years of age. Responses to either
vaccine decreased by 10% with each
decade of life.
Dransfield et al [36] undertook
a short-term study of persons aged .40
years who had chronic obstructive pulmonary disease. Fifty-two percent were
vaccine naive (the rest had received PPV
.5 years previously), and approximately
one-half had previously documented
pneumonia; relatively few had other
important comorbid conditions. The
results showed superiority of PCV7 over
PPV23, in IgG levels and opsonic activity
and in both for vaccine-naive and previously vaccinated persons. In multivariate analysis, younger age, vaccine
naivete´, and receipt of PCV were associated with higher antibody levels and
better fold responses.
It was not unexpected that vaccinenaive patients have higher post- to prevaccination fold increases in antibody
responses. Previously vaccinated patients
have higher baseline levels of IgG than do
those who are vaccine naive, consistent
with persistence of antibody in many
individuals for >5 years after vaccination
[24]. As was shown in classical studies by
Heidelberger et al [37], if the peak antibody level after revaccination is no
greater than the original peak and if the
baseline antibody level in previously
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(PPV23) reduces the risk of invasive
pneumococcal disease and probably
the rate of pneumococcal pneumonia
and/or all-cause community-acquired
pneumonia by 30%–60% [16–23].
Problems with PPV are essentially 2fold. First, much of the antibody response after vaccination is transitory.
Within 1–2 years after vaccination,
antibody levels decrease substantially,
although they remain, on average, 2fold higher than baseline for 5–10 years
[24, 25]. It is not known what level of
antibody is protective. Second, because
adults become more susceptible to
pneumococcal infection—with aging,
debilitation, or the development of
immunosuppressive conditions—their
antibody levels after vaccination and/or
the opsonic activity of their IgG, as
demonstrated in vitro or in vivo in
experimental animals, are lower than
those of healthy young adults [26, 27].
Perhaps the best placebo-controlled
study of PPV in older men with numerous comorbid conditions—the very
patients for whom such vaccination is
recommended—showed no benefit
[28], although this study was underpowered and its generalizability has
been questioned [29]. In contrast,
persons with successful aging maintain
good responses to PPV [30]. However,
in an important case-control study
[16], protection was demonstrated
for .5 years in adults aged ,50 years,
but it decreased in older persons, such
that no demonstrable benefit was observed in older persons .3 years after
vaccination.
On the basis of all these results, clinicians and researchers agree that there is
need for a better vaccine to protect older
and sicker adults against pneumococcal
infection. This agreement has led to
consideration of the routine use of PCV
in adults. A comprehensive review of
PCV in adults published in 2004 [31]
concluded that there was no obvious
superiority of conjugate vaccine over
polysaccharides vaccines in adults. In this
Table 1. Study Design for Randomized Vaccine Trials in Adults Comparing a Pneumococcal Protein Conjugate Vaccine (PCV) with the
23-Valent Pneumococcal Polysaccharide Vaccine (PPV) hat Met Inclusion Criteria for his Reviewa
Population,
study
Demographic
characteristic
Vaccination
status
Sample
size(no. of groups)
PCV type (dose);
schedule
Study end points
Young adults
Scott et al [34]
Age, 20–50
years
Naive
29 (2)
PCV-13 (.5 mL
subcutaneous);
PCV vs PPV
IgG and OPA
to the 13 PCV-CPS
at baseline and
4 weeks
after vaccination
Jackson
et al [32]
Age,70–79
years; healthy
All PPV .
5 years prior
PCV-7 .1, .5, 1 and
2 ml Initial PCV at
4 different doses or
PPV followed by PPV
challenge (.1 ml) at 1
year for all groups
IgG to the 7 PCV-CPS at
1m and 1y post-vaccine,
and 1m post-PPV
challenge.OPA to same
CPS at 1m after initial
vaccination
de Roux
et al [33]
Age, .70
years; healthy
Naive
159(2)
PCV-7 (.5 mL);
initial PCV, at 1 year,
PCV vs PPV,initial PPV,
at 1year, PCV
IgG and OPS to the
7 PCV CPS at baseline
and 1 month after each
vaccination
Goldblatt
et al [35]
Age, 50–80
years; healthy
No prior PPV or
PCV 5 years prior
599(4)
PCV-7 (.5 mL);
single vaccine with
initial PCV or PPV
or PCV followed at
6 months by PCV
or PPV
IgG to the 7 PCV CPS
types at baseline,
1 month, and 6 months
after each vaccination
Myernick
et al [38]
Age, 55–70
years;Alaskan
natives
Naive
86(3)
PCV-7 (.5 mL);PPV or
PCV followed by PPV
at 2 months or at
6 months
IgG to 4 of the PCV CPS
and 1 non-PCV CPS and
OPA to same CPS on a
subset of 10/group at
2 months after initial and
final doses
Ridda et al [40]
Age, 60–100
years; frail
Naive
241(2)
PCV-7 (.5 mL);PCV
or PPV
IgG to 4 PCV CPS at
baseline and 6 months
after vaccination
Dransfield
et al [36]
Age, .40
years; moderate
to severe COPD
Vaccine naive or
vaccination
.5 years prior
120(2)
PCV-7 (1 mL);PCV
or PPV
IgG and OPA to the
7 PCV CPS at 1 month
after vaccination
PCV-7 (.5 mL);
sequential vaccination
8 weeks apart: PCV-PCV,
PCV-PPV, placebo-PPV,
or placebo-placebo
IgG and OPA to 5 of the
7 PCV CPS at baseline
and 8 weeks after each
vaccination (or placebo)
PCV-7 (.5 mL);
PCV followed by
PPV at 4 weeks
or no initial PCV and
PPV at 4 weeks
IgG to the 7 PCV CPS
and 2 non-PCV CPS at
baseline, 4, 8, and
24 weeks after enrollment
Middle-age and
older adults
220(5;
4 PCV, 1 PPV)
Feikin et al [41]
No PPV prior 5 years
Age, >17
years; CD4 cell
3
count, >200 cells/mm
Lesprit et al [42] CD4 cell count,
200–500 cells/mm3,
viral load,
,50,000 copies/mL
Naive or vaccination
.5 years prior
67(4)
212(2)
Survivors of
pneumonia
Musher
et al [43]
Recent admission
for pneumococcal
pneumonia
Vaccine naive or
prior vaccination
at any time
81(2)
PCV-7;PCV or PPV
followed 6 months
later by alternate vaccine
IgG to the 7 PCV CPS
and OPA to 4 of the
PCV CPS at baseline,
1 months, and 6 months
after each vaccination
.3 months to
3 years after
renal transplantation
Vaccine naive or
vaccination
.5 years prior
60(2)
PCV-7 (.5 mL);
PCV or PPV
IgG and OPA to the
7 PCV CPS at baseline
and 8 weeks after
vaccination
Transplant
recipients
Kumar et al [47]
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HIV-infected
adults
Table 1. (Continued)
Population,
study
Demographic
characteristic
Vaccination
status
Sample
size(no. of groups)
113(2)
PCV type (dose);
schedule
Kumar et al [49]
.3 months
after liver
transplantation
Vaccine naive or
vaccination
.5 years prior
PCV-7 (.5 mL);
PCV or placebo
followed at
8 weeks by PPV
Kumar et al [50]
6 months after
allogeneic stem
cell transplantation
Respective donors
vaccinated prior
to stem cell
collection; vaccine
status unknown
44 pairs of
PCV-7 (.5 mL);
donor-recipients(2) PCV or PPV to
recipient
(same vaccine as donor)
sten cell collection
vaccine status
unknown
recipient
(same vaccine
as donor)
Study end points
IgG to the 7 PCV CPS
at baseline, 8 weeks, and
16 weeks after enrollment
IgG to the 7 PCV CPS
at baseline
(day of transplantation),
before and 6 months
after vaccination
before and 6 months
after vaccination
Abbreviations: CPS, pneumococcal capsular polysaccharide; PCV-7, 7-valent PCV containing CPS 4, 6B, 9V, 14, 18C, 19F and 23F; PCV-13, 13-valent
PCV containing the 7 PCV-CPS and CPS 1, 3, 5, 6A, 7F, and 19A; PPV, 23-valent PPV containing CPS 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C,
19F, 19A, 20, 22F, 23F, and 33 at a dose of .5 mL unless otherwise specified; OPA, opsonophagocytic assay; non-PCV-CPS, CPS contained in PPV but not in PCV-7.
a
Results of each study are discussed in text.
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revaccination with PCV7. In another
study involving frail older persons, Ridda
et al [40] reported similar IgG antibody
levels 6 months after PPV23 or PCV7
that were inversely proportional to age
and frailty, as assessed by a standardized
measurement.
PCV Versus PPV in HIV-Infected Adults
Only 2 studies comparing PPV and PCV
in HIV-infected persons met our inclusion criteria. In a complex 4-arm
study involving HIV-infected persons
that included 2 vaccinations 8 weeks
apart (PCV7-placebo, PCV7-PCV7,
PCV7-PPV23, and placebo-placebo
groups) [41], IgG levels and opsonic activity were similar 8 weeks after participants received an initial dose of PCV7 or
PPV23. A second dose of either PCV7 or
PPV23 8 weeks after PCV7 vaccination
caused no further response. Persistence
of antibody .2 months after the second
dose was not reported. Another study
involving HIV-infected adults found no
difference between PCV7 and PPV23,
but suggested that an initial dose of
PCV7 followed by PPV23 caused a distinct booster effect [42].
PPV and PCV in Survivors of Pneumococcal Pneumonia
We [43] studied hospitalized patients
who survived pneumococcal pneumonia,
randomizing them at discharge to receive
either PPV23 or PCV7. Six months later,
in a cross-over design, they received the
alternative vaccine. IgG and opsonic activity to the 7 PCV CPS were measured
before and 1–2 and 6 months after each
vaccination.
IgG levels increased significantly in
response to either vaccine, and both
groups achieved similar levels. Six
months after PPV23, IgG antibody levels
returned to baseline, whereas 6 months
after PCV7, they remained significantly
elevated for all 7 CPS (Figure 1), suggesting an advantage of PCV7 over
PPV23.
Revaccination at 6 months, however,
showed more complex results. Patients
who received PPV23 followed by PCV7
had an increase in IgG level at 1–2
months that approached but did not
surpass the initial peak. In contrast, those
who received PCV7 followed by PPV23
appeared to exhibit a booster response,
with a further increase in IgG level above
the original peak [44]. However, 6
months after revaccination, mean IgG
levels in both groups had returned to the
original baseline. Opsonic activity closely
followed IgG levels at each time point
and for all CPS studied. The observed
effect of revaccination was consistent
with initial antigenic stimulation followed by induction of suppression because of activity of long-lived regulatory
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vaccinated persons is higher, then, of
necessity, the fold increase will be lower
in previously vaccinated persons. This
lower fold increase has been used to
suggest that revaccinated persons are less
responsive to vaccine than are vaccinenaive persons, a concept that might be
misleading if, after revaccination, they
were to achieve antibody levels similar to
those in first-time vaccinees.
Studies cited thus far suggest that, up
to 6 months after vaccination, antibody
responses to PCV are at least as good as
or better than those to PPV. Two other
studies, however, found no differences
between PCV7 and PPV23 [36, 38]. In
Alaskan natives [38], a population at
high risk for invasive pneumococcal
disease [39], persons aged 55–70 years
had virtually identical antibody levels
and opsonic activity 2 months after
vaccination with PPV23 or PCV7. A
PCV7 booster dose 6 months (but not 2
months) after initial vaccination stimulated a further antibody increase. Two
months after final vaccination, however,
levels were equivalent in those who had
received and those who had not received
a booster. This study suggested that revaccination at close intervals is followed
by diminished antibody responses,
whereas responses are better when a longer interval has elapsed. There appeared
to be no lasting benefit from 6-month
Figure 1. A, IgG to 2 representative pneumococcal capsular polysaccharides (types 6B and 19F) after patients received 23-valent pneumococcal
polysaccharide vaccine (PPV23), followed 6 months later by 7-valent protein-conjugate pneumococcal vaccine (PCV7; dashed line), or PCV7, followed 6
months later by PPV23 (solid line). B, Opsonophagocytosis of Streptococcus pneumoniae type 6B after patients received PPV23, followed 6 months later
by PCV7 (dashed line), or PCV7, followed 6 months later by PPV23 (solid line). Similar responses were observed with 6 other capsular polysaccharides
studied. Reprinted with permission from Musher DM, Rueda AM, Nahm MH, Graviss EA, Rodriguez-Barradas MC. Initial and subsequent response to
pneumococcal polysaccharide and protein-conjugate vaccines administered sequentially to adults who have recovered from pneumococcal pneumonia. J
Infect Dis 2008;198(7):1019-27 [43]. Ó 2008 by the Infectious Diseases Society of America. All rights reserved.
most of their study participants had been
vaccinated .5 years previously.
PCV Versus PPV in Transplant Recipients.
Kumar et al [47] compared PCV7 with
PPV23 in patients .3 years after renal
transplantation who had stable renal
function and were receiving immunosuppressive drugs. IgG responses to each
capsular polysaccharide, defined as a 2fold increase in titer and a post vaccine
level of >1 lg/mL, were poor for both
groups (13%–40% for PPV and 17%–
50% for PCV); similar numbers of persons had a response to any serotype
(80%–83%). The rate of response to
PCV7 exceeded that for PPV23 only for
CPS 23F. OPA results (fold increases or
response rates) were not different between the groups. Three years later, IgG
levels remained similar in the 2 groups of
patients [48]. Similarly, in liver transplant recipients [49], there were no differences in IgG levels or OPA between
recipients of PPV23 or PCV7, and there
was no additional benefit of administering PPV23 after PCV7. These 2 studies
suggest that recipients of solid organ
transplants respond similarly to PPV or
PCV and that there is no benefit to the
sequential use of PCV followed by PPV.
In a single study [50] involving allogeneic stem cell transplant recipients, antibody responses 6 months after
vaccination with PPV23 or PCV7 were
low, but they tended to be somewhat better
among patients vaccinated with PCV7; in
Figure 2. IgG after patients received 23-valent pneumococcal polysaccharide vaccine (PPV23), followed 6 months later by 7-valent protein-conjugate
pneumococcal vaccine (PCV7; A), or PCV7, followed 6 months later by PPV23 (B), with patients stratified according to prior vaccination status. The dotted
line represents those who had received PPV23 within the previous year; the dashed line represents those vaccinated with PPV23 1–5 years previously;
and the solid line represents those vaccinated with PPV23 .5 years previously or never vaccinated. Representative data are shown for capsular
polysaccharide 6B; similar responses were observed with 6 other capsular polysaccharides studied. Reprinted with permission from Musher DM, Rueda
AM, Nahm MH, Graviss EA, Rodriguez-Barradas MC. Initial and subsequent response to pneumococcal polysaccharide and protein-conjugate vaccines
administered sequentially to adults who have recovered from pneumococcal pneumonia. J Infect Dis 2008;198(7):1019–27 [43]. Ó 2008 by the Infectious
Diseases Society of America. All rights reserved.
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cells. This study failed to include a group
that simply received PCV7 without subsequent vaccination, which might have
been the best approach [32].
Our study also stratified IgG responses
based on prior vaccine status (Figure 2).
Persons who had received PPV23 within
the previous year had almost no response
to vaccination. Those who had received
PPV23 within 1–5 years responded less
well than those with histories of more
remote or no vaccination. Dagan et al
[45] found that recent exposure to
a pneumococcal serotype by simple colonization was associated with serotypespecific vaccine hyporesponsiveness. Although some investigators [32, 46] found
that prior vaccination with PPV23 did
not inhibit short-term responses to PCV,
the context of the present report, this study
is difficult to interpret because stem cell
donors had also been previously vaccinated with PPV23 or PCV7.
Effectiveness of PCV Versus PPV
Safety and Tolerability
Both PPV23 and PCV7 appear to be safe
in adults [19, 24, 53]. Although there is
a moderately high rate of local discomfort at the injection site (redness, pain,
and swelling), the discomfort is tolerable,
rarely discouraging individuals from
continuing to participate in ongoing
studies. Younger age, healthier status,
and revaccination at ,1 year are associated with increased rate of local reactions.
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All these data, based on measurements of
IgG levels and/or opsonic activity, suggest that PCV7 is at least as good as and
very likely to be somewhat better than
PPV23 in inducing immunity to pneumococcal infection. Limited data on
PCV13 suggest that similar results might
be expected [34, 54, 55]. For either
PPV23 or PCV7, persons at greatest risk
of infection exhibit the poorest responses. Favoring the use of PCV is the
potentially better persistence of antibody, especially because it appears that
hyporesponsiveness will limit the effectiveness of a strategy based on repeated
pneumococcal vaccination at close intervals. We have shown that persons
who, on a genetic basis, do not respond
to PPV may develop IgG to CPS in PCV
[56]. A large study of PCV13 is underway
in the Netherlands [57], and in the absence of any results, the manufacturer is
already positioning this vaccine to replace PPV23 [58]. However, this study
will not answer the essential question of
which vaccine is better in adults because,
it compares PCV13 with placebo.
On the basis of these observations,
should PCV replace PPV in adults? The
principal disadvantages of PCVs are their
lesser breadth of coverage and the appearance of replacement strains, nonvaccine serotypes that, with widespread use
of a vaccine, emerge as common causes of
pneumococcal disease [59, 60]. Although
newer formulations of PCV contain up to
15 serotypes and include some that have
emerged as replacement strains after PCV7
(for example type 19A), they do not include others (such as 6C). Furthermore,
the widespread use of a new PCV is likely
to lead to newer replacement strains, rendering the formulation of conjugate
pneumococcal vaccine a moving target
[61, 62]. The idea of PCV13 vaccination
followed closely by vaccination with
PPV23 raises all the aforementioned issues
of hyporesponsiveness.
What is the cost-effectiveness of
pneumococcal vaccination of adults?
Studies relying on data obtained in the
United States and published before 2002
estimated
the
incremental
costeffectiveness of PPV23 vaccination at
about $3500 per quality-adjusted life
year (QALY) [63]. The cost-effectiveness
of PPV23 was lower in western Europe
[64]. As a result of widespread vaccination of children, the incidence of pneumococcal disease in adults in the United
States and Europe has decreased. A more
recent study [65] using data from 2003–
2004 calculated the incremental costeffectiveness ratio of a single dose of PPV
at age 65 years at $26,000 per QALY, and
at age 75–80 years at .$71,000 per QALY. Vaccination at age 65 years and again
at age 75 years would cost $88,000 per
QALY. Since 2003, the price of PPV23
has more than doubled. At present, the
price of PPV23 (Pneumovax) is $43 per
dose, the price of PCV7 (Prevnar) is $84
per dose, and that of PCV13 (Prevnar13)
is $103 per dose [66]. The cost of using
PCV13 would double if the recommended dose for adults is twice the pediatric dose [32, 43] and would be 5
times that of the PPV23. On balance, it is
likely that the cost-effectiveness of
pneumococcal vaccination in general will
decrease in developed countries and that
the cost of routine PCV13 in adults
would be prohibitive, whereas a potential
benefit over PPV23 will not have been
demonstrated.
CONCLUSION
With the decreased rates of pneumococcal
disease in adults in developed countries,
the potential for emergence of new replacement strains with conjugate vaccines;
the higher cost for PCV13, compared with
PPV23; and a possible preference for administering double the pediatric dose of
PCV13 in adults, it is doubtful that widespread use of PCV13 in adults would be
cost-effective. Although an ongoing field
trial of PCV13 in adults [57] does not
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No studies have compared the effectiveness of PCV with that of PPV in adults.
However, 2 studies in HIV-infected patients, one comparing PPV23 with placebo and the other comparing PCV7
with placebo, have had similar clinical
end points [51, 52]. An initial study involving Ugandan adults [51] showed no
benefit and, perhaps, a deleterious effect
of PPV23. In contrast, a subsequent
clinical trial in Malawi documented significant protection from PCV7. In this
study, survivors of pneumococcal pneumonia (mean age, 32 years) were randomized to receive PCV7 or placebo [52]
and were followed up thereafter for
a mean of 1.2 years. Nearly 90% of the
participants were HIV infected. The rates
of protection were 74% in HIV-infected
persons and 73% in the entire group.
Protection decreased dramatically with
time, from 85% in the first year after
vaccination to 25% thereafter. The reason(s) for discrepant results in these 2
studies remain(s) unknown, and it is
further uncertain whether such results
could be extrapolated to populations in
developed countries where combination
antiretroviral therapy is more readily
available and the rate of pneumococcal pneumonia in the population is
lower.
DISCUSSION
include a PPV23 arm, a stunning result
might provide indirect evidence to favor
use of conjugate vaccine. The distinctly
better outcome with PCV7 [67], compared
with PPV23 [51], in separate studies and
different
populations
of
HIVinfected adults in Africa leave open to
question an option favoring PCV in that
population.
10.
11.
12.
Acknowledgments
Financial support. This work was supported
by the Department of Veterans Affairs through
Merit Review Funding (to DMM and MCR-B).
Potential conflicts of interest. DMM’s laboratory has received funding from Merck. All
other authors: no conflicts.
1. Avery OT, Goebel WF. Chemo-immunological
studies on conjugated carboydrate-proteins.
II. Immunological specificity of synthetic
sugar-protein antigen. J Exp Med 1929; 50:
533–50.
2. Schneerson R, Barrera O, Sutton A, Robbins
JB. Preparation, characterization, and immunogenicity of Haemophilus influenzae
type b polysaccharide-protein conjugates.
J Exp Med 1980; 152:361–76.
3. Eskola J, Black S, Shinefield H. Pneumococcal conjugate vaccines. In: Plotkin SA,
Orenstein WA, eds. Vaccines. 4th ed. Philadelphia: Saunders, 2004:589–624.
4. Douglas RM, Paton JC, Duncan SJ,
Hansman DJ. Antibody response to pneumococcal vaccination in children younger
than five years of age. J Infect Dis 1983;
148:131–7.
5. Smith DH, Peter G, Ingram DL, Harding AL,
Anderson P. Responses of children immunized with the capsular polysaccharide of
Hemophilus influenzae, type b. Pediatrics
1973; 52:637–44.
6. Robbins JB, Schneerson R. Polysaccharideprotein conjugates: a new generation of
vaccines. J Infect Dis 1990; 161:821–32.
7. Peltola H, Kilpi T, Anttila M. Rapid disappearance of Haemophilus influenzae type
b meningitis after routine childhood immunisation with conjugate vaccines. Lancet
1992; 340:592–4.
8. Black S, Shinefield H, Fireman B, 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.
9. Lexau CA, Lynfield R, Danila R, et al.
Changing epidemiology of invasive pneumococcal disease among older adults in the
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
against pneumonia in middle-aged and
older adults: a matched case-control study.
Vaccine 2009; 27:1504–10.
Musher DM, Manoff SB, Liss C, et al. Safety
and antibody response, including antibody
persistence for 5 years, after primary
vaccination or revaccination with pneumococcal polysaccharide vaccine in middleaged and older adults. J Infect Dis 2010;
201:515–24.
Musher DM, Manoff SB, McFetridge RD,
et al. Pneumococcal polysaccharide vaccine,
and immunogenicity and safety of 2nd and
3d doses in older adults. Vaccine 2011;
Submitted for publication.
Romero-Steiner S, Musher DM, Cetron MS,
et al. Reduction in functional antibody activity against Streptococcus pneumoniae in
vaccinated elderly individuals highly correlates with decreased IgG antibody avidity.
Clin Infect Dis 1999; 29:281–8.
Musher DM, Phan HM, Watson DA,
Baughn RE. Antibody to capsular polysaccharide of Streptococcus pneumoniae at
the time of hospital admission for pneumococcal pneumonia. J Infect Dis 2000;
182:158–67.
Simberkoff MS, Cross AP, Al-Ibrahim M,
et al. Efficacy of pneumococcal vaccine in
high-risk patients. Results of a Veterans
Administration Cooperative Study. N Engl J
Med 1986; 315:1318–27.
Fedson DS, Liss C. Precise answers to the
wrong question: prospective clinical trials
and the meta-analyses of pneumococcal
vaccine in elderly and high-risk adults.
Vaccine 2004; 22:927–46.
Carson PJ, Nichol KL, O’Brien J, Hilo P,
Janoff EN. Immune function and vaccine
responses in healthy advanced elderly patients. Arch Intern Med 2000; 160:2017–24.
Abraham-Van Parijs B. Review of pneumococcal conjugate vaccine in adults: implications on clinical development. Vaccine
2004; 22:1362–71.
Jackson LA, Neuzil KM, Nahm MH, et al.
Immunogenicity of varying dosages of 7-valent pneumococcal polysaccharide-protein
conjugate vaccine in seniors previously
vaccinated with 23-valent pneumococcal
polysaccharide vaccine. Vaccine 2007; 25:
4029–37.
de Roux A, Schmole-Thoma B, Siber GR,
et al. Comparison of pneumococcal conjugate polysaccharide and free polysaccharide
vaccines in elderly adults: conjugate vaccine
elicits improved antibacterial immune responses and immunological memory. Clin
Infect Dis 2008; 46:1015–23.
Scott DA, Komjathy SF, Hu BT, et al. Phase 1
trial of a 13-valent pneumococcal conjugate
vaccine in healthy adults. Vaccine 2007;
25:6164–6.
Goldblatt D, Southern J, Andrews N, et al.
The immunogenicity of 7-valent pneumococcal conjugate vaccine versus 23-valent
Conjugate Pneumococcal Vaccine in Adults
d
CID 2011:52 (1 March)
d
639
Downloaded from http://cid.oxfordjournals.org/ by guest on September 30, 2014
References
13.
era of pediatric pneumococcal conjugate
vaccine. JAMA 2005; 294:2043–51.
Musher DM. Pneumococcal vaccine–direct
and indirect ("herd") effects. N Engl J Med
2006; 354:1522–4.
Kayhty H, Auranen K, Nohynek H, Dagan R,
Makela H. Nasopharyngeal colonization:
a target for pneumococcal vaccination. Expert Rev Vaccines 2006; 5:651–67.
Musher DM, Groover JE, Watson DA, et al.
Genetic regulation of the capacity to make
immunoglobulin G to pneumococcal capsular polysaccharides. J Investig Med 1997;
45:57–68.
Conaty S, Watson L, Dinnes J, Waugh N.
The effectiveness of pneumococcal polysaccharide vaccines in adults: a systematic
review of observational studies and
comparison with results from randomised controlled trials. Vaccine 2004;
22:3214–4.
Lipsky BA, Hirschmann JV. Pneumococcal
polysaccharide vaccines do not protect the
elderly from pneumococcal infections. Neth
J Med 2004; 62:33–5.
Moberley SA, Holden J, Tatham DP, Andrews RM. Vaccines for preventing pneumococcal infection in adults. Cochrane
Database Syst Rev 2008; CD000422.
Shapiro ED, Berg AT, Austrian R, et al. The
protective efficacy of polyvalent pneumococcal polysaccharide vaccine. N Engl J Med
1991; 325:1453–60.
Centers for Disease Control and Prevention.
Prevention of pneumococcal disease of the
Advisory Committee on Immunization
Practices (ACIP). MMWR Morb Mortal
Wkly Rep 1997; 46:1–18.
Dear K, Holden J, Andrews R, Tatham D.
Vaccines for preventing pneumococcal infection in adults. Cochrane Database Syst
Rev 2003; CD000422.
Fedson DS, Musher DM. Pneumococcal
vaccine. In: Plotkin SA, Orenstein WB, eds.
Vaccines. 4th ed. Philadelphia: W.B. Saunders, 2004:529–88.
Melegaro A, Edmunds WJ. The 23-valent
pneumococcal polysaccharide vaccine. Part
I. Efficacy of PPV in the elderly: a comparison of meta-analyses. Eur J Epidemiol 2004;
19:353–63.
Musher DM, Rueda-Jaimes AM, Graviss
EA, Rodriguez-Barradas MC. Effect of
pneumococcal vaccination: a comparison
of vaccination rates in patients with bacteremic and nonbacteremic pneumococcal
pneumonia. Clin Infect Dis 2006; 43:
1004–8.
Johnstone J, Marrie TJ, Eurich DT,
Majumdar SR. Effect of pneumococcal vaccination in hospitalized adults with community-acquired pneumonia. Arch Intern
Med 2007; 167:1938–43.
Vila-Corcoles A, Salsench E, RodriguezBlanco T, et al. Clinical effectiveness of 23valent pneumococcal polysaccharide vaccine
36.
37.
38.
39.
41.
42.
43.
44.
45.
640
d
CID 2011:52 (1 March)
d
Musher et al
46. Miiro G, Kayhty H, Watera C, et al. Conjugate pneumococcal vaccine in HIV-infected
Ugandans and the effect of past receipt of
polysaccharide vaccine. J Infect Dis 2005;
192:1801–5.
47. Kumar D, Rotstein C, Miyata G, Arlen D,
Humar A. Randomized, double-blind, controlled trial of pneumococcal vaccination in
renal transplant recipients. J Infect Dis 2003;
187:1639–45.
48. Kumar D, Welsh B, Siegal D, Chen MH,
Humar A. Immunogenicity of pneumococcal vaccine in renal transplant recipients–
three year follow-up of a randomized trial.
Am J Transplant 2007; 7:633–8.
49. Kumar D, Chen MH, Wong G, et al. A
randomized,
double-blind,
placebocontrolled trial to evaluate the prime-boost
strategy for pneumococcal vaccination in
adult liver transplant recipients. Clin Infect
Dis 2008; 47:885–92.
50. Kumar D, Chen MH, Welsh B, et al. A
randomized, double-blind trial of pneumococcal vaccination in adult allogeneic stem
cell transplant donors and recipients. Clin
Infect Dis 2007; 45:1576–82.
51. French N, Nakiyingi J, Carpenter LM, et al.
23-valent pneumococcal polysaccharide
vaccine in HIV-1-infected Ugandan adults:
double-blind, randomised and placebo
controlled trial. Lancet 2000; 355:2106–11.
52. French N, Gordon SB, Mwalukomo T, et al.
A trial of a 7-valent pneumococcal conjugate
vaccine in HIV-infected adults. N Engl J
Med 2010; 362:812–22.
53. Center KJ, Strauss A. Safety experience with
heptavalent
pneumococcal
CRM197conjugate vaccine (Prevenar) since vaccine
introduction. Vaccine 2009; 27:3281–4.
54. Dinleyici EC, Yargic ZA. Current knowledge
regarding the investigational 13-valent
pneumococcal conjugate vaccine. Expert
Rev Vaccines 2009; 8:977–86.
55. Metersky ML, Dransfield MT, Jackson LA.
Determining the optimal pneumococcal
vaccination strategy for adults: is there a role
for the pneumococcal conjugate vaccine?
Chest 2010; 138:486–90.
56. Musher DM, Groover JE, Watson DA, Rodriguez-Barradas MC, Baughn RE. IgG
responses to protein-conjugated pneumococcal capsular polysaccharides in persons
who are genetically incapable of responding
to unconjugated polysaccharides. Clin Infect
Dis 1998; 27:1487–90.
57. Hak E, Grobbee DE, Sanders EA, et al. Rationale and design of CAPITA: a RCT of 13-
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
valent conjugated pneumococcal vaccine
efficacy among older adults. Neth J Med
2008; 66:378–83.
Weycker D, Sato R, Strutton D, Edelsberg
J, Jackson LA. Public health and economic
impact of 13-valent pneumococcal conjugate vaccine (PCV13) in US adults aged
.50 years [abstract 462]. FortyeighthAnnual Meeting, Infectious Diseases
Society of America. Vancouver, 2010.
Pelton SI, Dagan R, Gaines BM, et al.
Pneumococcal conjugate vaccines: proceedings from an interactive symposium at the
41st Interscience Conference on Antimicrobial Agents and Chemotherapy. Vaccine
2003; 21:1562–71.
Cohen R, Levy C, Bonnet E, et al. Dynamic
of pneumococcal nasopharyngeal carriage in
children with acute otitis media following
PCV7 introduction in France. Vaccine 2009;
28:6114–21.
Jacobs MR, Good CE, Bajaksouzian S,
Windau AR. Emergence of Streptococcus
pneumoniae serotypes 19A, 6C, and 22F and
serogroup 15 in Cleveland, Ohio, in relation
to introduction of the protein-conjugated
pneumococcal vaccine. Clin Infect Dis 2008;
47:1388–95.
Siira L, Rantala M, Jalava J, et al. Temporal
trends of antimicrobial resistance and clonality of invasive Streptococcus pneumoniae
isolates in Finland, 2002 to 2006. Antimicrob
Agents Chemother 2009; 53:2066–73.
Smith KJ, Zimmerman RK, Lin CJ, et al.
Alternative strategies for adult pneumococcal polysaccharide vaccination: a costeffectiveness analysis. Vaccine 2008; 26:
1420–31.
Evers SM, Ament AJ, Colombo GL, et al.
Cost-effectiveness of pneumococcal vaccination for prevention of invasive pneumococcal disease in the elderly: an update
for 10 Western European countries. Eur J
Clin Microbiol Infect Dis 2007; 26:531–40.
Smith KJ, Zimmerman RK, Nowalk MP,
Roberts MS. Age, revaccination, and
tolerance effects on pneumococcal vaccination strategies in the elderly: a costeffectiveness analysis. Vaccine 2009; 27:
3159–64.
http://www.cdc.gov/vaccines/programs/
VFC/cdc-vac-price-list.htm 2010.
French N, Gordon SB, Mwalukomo T, et al.
A trial of a 7-valent pneumococcal conjugate
vaccine in HIV-infected adults. N Engl J
Med 2010; 362:812–22.
Downloaded from http://cid.oxfordjournals.org/ by guest on September 30, 2014
40.
polysaccharide vaccine in adults aged 50–
80 years. Clin Infect Dis 2009; 49:1318–25.
Dransfield MT, Nahm MH, Han MK, et al.
Superior immune response to proteinconjugate vs. free pneumococcal polysaccharide vaccine in COPD. Am J Respir Crit
Care Med 2009; 15:495–505.
Heidelberger M, DiLapi MM, Siegel M,
Walter AW. Persistence of antibodies in human subjects injected with pneumococcal
polysaccharides. J Immunol 1950; 65:535–41.
Miernyk KM, Butler JC, Bulkow LR, et al.
Immunogenicity and reactogenicity of
pneumococcal polysaccharide and conjugate
vaccines in Alaska native adults 55–70 years
of age. Clin Infect Dis 2009; 49:241–8.
Davidson M, Parkinson AJ, Bulkow LR,
Fitzgerald MA, Peters HV, Parks DJ. The
epidemiology of invasive pneumococcal
disease in Alaska, 1986–1990—ethnic differences and opportunities for prevention. J
Infect Dis 1994; 170:368–76.
Ridda I, Macintyre CR, Lindley R, et al.
Immunological responses to pneumococcal
vaccine in frail older people. Vaccine 2009;
27:1628–36.
Feikin DR, Elie CM, Goetz MB, et al. Randomized trial of the quantitative and functional antibody responses to a 7-valent
pneumococcal conjugate vaccine and/or 23valent polysaccharide vaccine among HIVinfected adults. Vaccine 2001; 20:545–53.
Lesprit P, Pedrono G, Molina JM, et al.
Immunological efficacy of a prime-boost
pneumococcal vaccination in HIV-infected
adults. AIDS 2007; 21:2425–34.
Musher DM, Rueda AM, Nahm MH,
Graviss EA, Rodriguez-Barradas MC.
Initial and subsequent response to
pneumococcal polysaccharide and proteinconjugate vaccines administered sequentially
to adults who have recovered from pneumococcal pneumonia. J Infect Dis 2008;
198:1019–27.
O’Brien KL, Hochman M, Goldblatt D.
Combined schedules of pneumococcal conjugate and polysaccharide vaccines: is hyporesponsiveness an issue? Lancet Infect Dis
2007; 7:597–606.
Dagan R, Givon-Lavi N, Greenberg D, Fritzell B, Siegrist CA. Nasopharyngeal carriage
of Streptococcus pneumoniae shortly before
vaccination with a pneumococcal conjugate
vaccine causes serotype-specific hyporesponsiveness in early infancy. J Infect Dis
2010; 201:1570–9.