Systematic Review of the Effect of Pneumococcal Conjugate Vaccine Dosing Schedules on Prevention of Pneumonia

Article (PDF Available)inThe Pediatric Infectious Disease Journal 33 Suppl 2(Suppl 2 Optimum Dosing of Pneumococcal Conjugate Vaccine For Infants 0 A Landscape Analysis of Evidence Supportin g Different Schedules):S140-51 · January 2014with40 Reads
DOI: 10.1097/INF.0000000000000082 · Source: PubMed
Abstract
Pneumonia is the leading cause of morbidity and mortality among children <5 years of age globally. Pneumococcal conjugate vaccines (PCVs) are known to provide protection against vaccine serotype pneumococcal pneumonia; uncertainty exists regarding the optimum PCV dosing schedule. We conducted a systematic review of studies published from 1994 to 2010 (supplemented post hoc with studies from 2011) documenting the effect of PCV dosing schedules on clinical and radiologically confirmed pneumonia, pneumococcal pneumonia and empyema among children of ages targeted to receive vaccine. Data on 2- and 3-dose schedules were included. Percent change of pneumonia incidence rates from baseline to most recent year post-PCV introduction was calculated. We identified 42 primary citations that evaluated PCV schedules and pneumonia. Thirty-seven (88%) were from North America, Europe or Australia; 37 (88%) evaluated PCV7 and 1 (2%) PCV10. Two studies (both observational) compared multiple schedules within the study. We found evidence of reduced clinical and radiologically confirmed pneumonia incidence for all schedules, including 2+1 (1 nonrandomized trial, 5 observational studies), 3+0 (5 randomized trials, 2 observational studies) and 3+1 (5 clinical trials, 24 observational studies) schedules. The magnitude of disease impact did not differ among schedules. Evidence for impact on pneumococcal pneumonia and empyema varied. All schedules (2+1, 3+0 and 3+1) reduced clinical and radiologically confirmed pneumonia. Quantifying differences in pneumonia disease impact between schedules was difficult due to heterogeneity among studies in design, case definition and population. These findings support World Health Organization recommendations for 3-dose schedules administered as either 3+0 or 2+1 regimens. Pneumonia impact data are still needed on expanded serotype PCV products, developing country settings and the role for a booster dose.
S140 | www.pidj.com The Pediatric Infectious Disease Journal •  Volume 33, Number 1, Supplement 2, January 2014
SUPPLEMENT
Background: Pneumonia is the leading cause of morbidity and mortality
among children <5 years of age globally. Pneumococcal conjugate vaccines
(PCVs) are known to provide protection against vaccine serotype pneumococ-
cal pneumonia; uncertainty exists regarding the optimum PCV dosing schedule.
Methods: We conducted a systematic review of studies published from
1994 to 2010 (supplemented post hoc with studies from 2011) documenting
the effect of PCV dosing schedules on clinical and radiologically confirmed
pneumonia, pneumococcal pneumonia and empyema among children of
ages targeted to receive vaccine. Data on 2- and 3-dose schedules were
included. Percent change of pneumonia incidence rates from baseline to
most recent year post-PCV introduction was calculated.
Results: We identified 42 primary citations that evaluated PCV schedules
and pneumonia. Thirty-seven (88%) were from North America, Europe
or Australia; 37 (88%) evaluated PCV7 and 1 (2%) PCV10. Two studies
(both observational) compared multiple schedules within the study. We
found evidence of reduced clinical and radiologically confirmed pneumonia
incidence for all schedules, including 2+1 (1 nonrandomized trial, 5 obser-
vational studies), 3+0 (5 randomized trials, 2 observational studies) and
3+1 (5 clinical trials, 24 observational studies) schedules. The magnitude
of disease impact did not differ among schedules. Evidence for impact on
pneumococcal pneumonia and empyema varied.
Conclusions: All schedules (2+1, 3+0 and 3+1) reduced clinical and radio-
logically confirmed pneumonia. Quantifying differences in pneumonia dis-
ease impact between schedules was difficult due to heterogeneity among
studies in design, case definition and population. These findings support
World Health Organization recommendations for 3-dose schedules admin-
istered as either 3+0 or 2+1 regimens. Pneumonia impact data are still
needed on expanded serotype PCV products, developing country settings
and the role for a booster dose.
Key Words: pneumococcal conjugate vaccine, immunization schedule,
pneumonia, systematic review
(Pediatr Infect Dis J 2014;33:S140–S151)
G
lobally, pneumonia caused by the bacterium, Streptococcus
pneumoniae, is one of the leading causes of nonneonatal
death in children <5 years of age and is estimated to cause over
500,000 deaths and nearly 14 million episodes of disease annu-
ally.
1,2
Fortunately, pneumococcal conjugate vaccines (PCVs) hold
promise for preventing much of this burden and are one of the key
interventions recommended by the Global Action Plan for Preven-
tion and Control of Pneumonia as a means for rapidly reducing
pneumonia deaths.
3–5
Three PCV formulations, 7-valent (PCV7), 10-valent
(PCV10) and 13-valent (PCV13), have been licensed and made
commercially available. PCV7 was first licensed in 2000 using
a 4-dose schedule (3 primary doses plus 1 booster, 3+1) and was
shown to protect against the 7 vaccine serotypes that accounted
for a significant fraction of pneumococcal disease globally.
6
Since
2010, PCV10 and PCV13 have also been licensed using a 4-dose
schedule, although all formulations have been granted licensure in
the European Union and elsewhere for schedules using 2 primary
doses plus 1 booster (2+1) when used as part of a national immu-
nization program.
7–9
In addition, the World Health Organization
has recommended PCV for use on a schedule of 3 primary doses
without a booster, a typical Expanded Program on Immunization
schedule used in many developing countries.
4
The exact timing of
recommended doses varies by country because more policy mak-
ers have added PCV to existing immunization schedules.
Recently, GAVI Alliance support has led to a rapid increase
in the introduction of PCV into national immunization programs
among developing countries.
10
These introductions, coupled with
varying national schedules for administering PCV, have prompted
questions about which infant dosing schedule maximizes the impact
of PCV programs. To aid in policy development, we conducted a
comprehensive, systematic review of PCV dosing schedules and
their impact on pneumonia.
METHODS
Literature Search
This analysis is part of a larger project describing the
impact of PCV dosing schedules on invasive pneumococcal
disease (IPD), immunogenicity, nasopharyngeal carriage, pneu-
monia and indirect effects.
11–14
Details on the literature search
terms and methods used in this systematic review are described
elsewhere (see Methods Appendix
15
). In brief, a systematic
Systematic Review of the Effect of Pneumococcal Conjugate 
Vaccine Dosing Schedules on Prevention of Pneumonia
Jennifer D. Loo, MPH,* Laura Conklin, MD,* Katherine E. Fleming-Dutra, MD,*† Maria Deloria Knoll, PhD,‡
Daniel E. Park, MSPH,‡ Jennifer Kirk, MSc,§ David Goldblatt, MBChB, PhD,¶ Katherine L. O’Brien, MD, MPH,‡
and Cynthia G. Whitney, MD, MPH*
Copyright © 2013 by Lippincott Williams & Wilkins. This is an open-access
article distributed under the terms of the Creative Commons Attribution-Non
Commercial-No Derivatives 3.0 License, where it is permissible to download
and share the work provided it is properly cited. The work cannot be changed
in any way or used commercially.
ISSN: 0891-3668/14/3301-S140
DOI: 10.1097/INF.0000000000000082
Accepted for publication August 13, 2013.
From the *Respiratory Diseases Branch, Division of Bacterial Diseases, National
Center for Immunizations and Respiratory Diseases; †Epidemic Intelligence
Service, Centers for Disease Control and Prevention, Atlanta, GA; ‡Interna-
tional Vaccine Access Center, Johns Hopkins Bloomberg School of Public
Health, Baltimore, MD; §Westat Inc., Rockville, MD; and ¶Institute of Child
Health, University College London, London, United Kingdom.
Support for this project was provided by Program for Appropriate Technology
in Health (PATH) through funding from The GAVI Alliance. The views
expressed by the authors do not necessarily reflect the views of CDC, GAVI,
PATH or IVAC. M.D.K. has received support from Novartis for participation
on a Data and Safety Monitoring Board, meeting travel reimbursement from
Pfizer and grant support from Merck. D.G.s laboratory performs contract and
or collaborative research for/with Pfizer, GlaxoSmithKline, Merck, Novar-
tis and Sanofi Pasteur. D.G. has received travel or honorarium support for
participation in external expert committees for Merck, Sanofi Pasteur, Pfizer
and GlaxoSmithKline. K.O.B. received grant support from Pfizer, GlaxoS-
mithKline and has received travel or honorarium support for participation in
external expert committees for Merck, Aventis-pasteur and GlaxoSmithKline.
The authors have no other funding or conflicts of interest to disclose.
Address for correspondence: Jennifer D. Loo, MPH, Respiratory Diseases Branch,
Division of Bacterial Diseases, National Center for Immunizations and Respi-
ratory Diseases, Centers for Disease Control and Prevention, 1600 Clifton
Road, NE, Mailstop C-25, Atlanta, GA 30333. E-mail: JLoo@cdc.gov.
The Pediatric Infectious Disease Journal Volume 33, Number 1, Supplement 2, January 2014 PCV Dosing and Pneumonia
© 2013 Lippincott Williams & Wilkins
www.pidj.com | S141
literature review was performed to collect all available English
language data published from January 1994 to September 2010
(supplemented post hoc with studies from 2011) on the effect of
various PCV vaccination schedules among immunized children
on immunogenicity, nasopharyngeal colonization, IPD, pneu-
monia and on indirect effects among unvaccinated populations.
Articles published in 14 databases, from ad hoc unpublished
sources and abstracts from meetings of the International Sympo-
sium on Pneumococci and Pneumococcal Disease (1998–2010)
and the Interscience Conference on Antimicrobial Agents and
Chemotherapeutics (1994–2010), were searched. We included all
randomized controlled clinical trials (RCTs), nonrandomized tri-
als, surveillance database analyses and observational studies of
any PCV schedule on one or more outcomes of interest. Studies
were included for abstraction if pneumococcal polysaccharide
vaccine (PPV23) was used as a booster dose, but not as a primary
dose. Titles and abstracts were reviewed twice and those with rel-
evant content on 1 of the 5 outcomes (immunogenicity, carriage,
invasive disease, pneumonia and indirect effects) underwent full
review using a standardized data collection instrument. We did
not search non-English language literature because of the low
likelihood they would have relevant data for this project. Details
on the search methods are provided in the Methods Appendix.
15
Data Abstraction
Citations recovered through the literature search went
through several stages of independent review to determine their
eligibility, as described (see Methods Appendix
15
). Citations
meeting inclusion criteria were categorized on an outcome-
specific basis into “study families,” where each family included
abstracts or publications generated from a single protocol, popu-
lation, surveillance system or other data collection system rel-
evant to that outcome. Investigators identified primary data from
the individual studies making up each study family for inclusion
in the analysis. The primary data were selected as the most current
and complete data available for that study family. In some cases,
these data were drawn from >1 publication within a family. We
also defined “study arms” as a group of children distinguished by
immunization schedule or PCV product.
We abstracted core information on the following: num-
ber of children in a “study arm;” PCV manufacturer, valency
and conjugate protein; co-administered vaccines; country; age
at each dose and date of study and publication. Additional data
abstracted for pneumonia included specific endpoints, case defi-
nitions, study design, study population and incidence rates or
percent change.
This article presents the data on the direct effects of PCV
on pneumonia in children of an age targeted for vaccination. As
studies included a variety of case definitions for endpoints, findings
were grouped by endpoint according to the following categories:
clinical pneumonia (including lower respiratory tract infections and
acute respiratory tract infections), radiologically confirmed pneu-
monia, pneumococcal pneumonia (including bacteremic pneumo-
nia) and empyema.
Inclusion and Exclusion Criteria
We included data published during or after 1994 from clin-
ical trials, surveillance database analyses and observational stud-
ies of PCV schedules on immunogenicity, IPD, nasopharyngeal
carriage, pneumonia and indirect effects. We included all
licensed and unlicensed PCV products (denoted as PCV with a
number indicating the valency, eg, PCV7). We excluded studies
with vaccination series beginning after 12 months of life, as well
as observational studies that only reported data before or after
PCV introduction but not for both periods. Unless 50% vacci-
nation coverage was documented, observational studies were also
excluded if vaccination was only available through the private
sector or to high-risk groups. Studies that only provided inci-
dence rates during the year of vaccine introduction, or did not
specify a period, were excluded.
Pneumococcal Vaccine Dosing Schedules
We defined a primary series as either 2 or 3 doses received
before 7 months of age. A booster dose was defined as a dose of
PCV or PPV23 received after 9 months of age and after the com-
pletion of a primary series. A complete series was defined as the
primary series plus any booster doses implemented in a population;
examples of this include a 2-dose primary series with or without
a booster (2+1, 2+0) or a 3-dose primary series with or without a
booster (3+1, 3+0).
Data Analysis
Studies evaluating impact on pneumonia following PCV
introduction used a variety of methods; the variety prevented us
from performing a formal meta-analysis. Therefore, we conducted
descriptive analyses of the amount and variability of the data and of
the magnitude of the change in the pneumonia outcomes observed
for each dosing schedule type. We also performed subanalyses to
evaluate various endpoints related to pneumonia. Studies report-
ing only qualitative data with no ability to determine magnitude of
impact were excluded from analysis.
For observational studies reporting pneumonia incidence
over time, we calculated percent change as: (baseline incidence
—post-PCV introduction incidence)/baseline incidence. Baseline
incidence was defined as the mean of all data points reported before
PCV introduction. When annual data on postintroduction incidence
were available, we calculated percent change using the data point
given for each year reported. When only the average postintroduc-
tion incidence rate over a period of years was provided, we calcu-
lated percent change from baseline to the reported rate and assigned
it to the median year of the date range provided. When possible,
incidence rates during the year of introduction were excluded from
these calculations. We conducted all analyses using SAS 9.3 (SAS
Institute Inc., Cary, NC).
RESULTS
Descriptive Characteristics of Included Studies
Of 12,980 citations reviewed, we identified 106 pneumo-
nia outcome citations that met initial criteria for further evalua-
tion (Fig. 1). After further review, 81 citations met inclusion cri-
teria for full data abstraction; of these, 39 studies were excluded
from analysis because they contained duplicate data of included
studies or reported changes in pneumonia risk only qualitatively
so magnitude of impact could not be assessed. Of the 42 included
citations, 20 evaluated clinical pneumonia, 13 radiologically
confirmed pneumonia, 16 pneumococcal pneumonia and 9 all-
cause empyema; however, case definitions varied widely for each
endpoint.
16–57
Almost all (n = 39, 93%) citations of pneumonia were pub-
lished during or after 2004. Most citations were from North Amer-
ica (n = 23, 55%), Europe (n = 9, 22%) or Oceania (n = 5, 12%),
with the remaining 5 from Africa (n = 3, 7%), Asia (n = 1, 2%)
and Latin America (n = 1, 2%). Although many studies focused on
the general population of children, 6 citations focused on high-risk
groups (ie, children with HIV or indigenous populations). Thirty-
seven citations evaluated PCV7 and only one study evaluated
PCV10
57
(Table 1).
Loo et al The Pediatric Infectious Disease Journal Volume 33, Number 1, Supplement 2, January 2014
S142 | www.pidj.com © 2013 Lippincott Williams & Wilkins
Studies Directly Comparing Dosing Schedules
(n=2 Studies)
We identified only 2 studies, both observational, that com-
pared the effectiveness of different PCV dosing schedules within
the study itself. One study directly evaluated the impact of 2 ver-
sus 3 primary PCV doses against clinical pneumonia incidence in
a general pediatric population.
28
This propensity-score-matched,
case-cohort study conducted in the United States evaluated the
rate of hospitalizations and ambulatory visits for lower respira-
tory tract infections and found that children who received 3 pri-
mary PCV doses had fewer ambulatory visits and hospitaliza-
tions up to the point of receipt of a booster dose (9.5 admissions
per 1000 children) than those who only received 2 primary doses
[17.3 admissions per 1000 children; rate difference = 7.8 cases
per 1000 children (95% confidence interval (CI): 0.8–14.8)]. This
difference disappeared after the booster dose was administered
[23.2 admissions per 1000 children vs. 20.9 admissions per 1000
children for 3+1 vs. 2+1, respectively; rate difference = −2.3
cases per 1000 children (95% CI: −14.8 to 9.3)]. This differ-
ence between 2 and 3 primary doses was seen for children born
in the 2002 birth cohort, but not for children born in 2003; the
authors hypothesized that by 2003, 3 years after introduction
of PCV7, herd effects had lessened the difference in risk between
the 2 groups. The other study directly comparing dosing sched-
ules, a retrospective cohort conducted among Australian Indig-
enous infants,
53
evaluated risk of clinical and radiologically con-
firmed pneumonia after each of 3 PCV7 primary doses plus 1
PPV23 booster (3+PPV23) but did not find evidence of reduced
risk for either endpoint by number of doses.
Studies of Single Schedules
Two-dose Primary Schedules, With a Booster, in the
General Population (n = 6 Studies)
Of studies assessing a single schedule, none evaluated the
impact of 2 primary doses on pneumonia in the first year of life
(ie, up to the point of receiving the booster dose) or in the second
year of life without a booster dose (2+0). We identified 6 studies
(6 citations) that evaluated the impact of a 2+1 schedule on
pneumonia: one prospective cohort trial
35
and 5 observational
studies.
16,30,34,50,54
The cohort study was a nonrandomized, single-
blinded Italian study that found an impact of PCV7 on radio-
logically confirmed pneumonia (vaccine efficacy: 65%, 95%
CI: 47–78%; Table 2). Parents participating in the study could
choose whether to have their children vaccinated, and providers and
106 Citations in original search
(88 original and 18 updates)
14 Reviews
7 No pneumonia
outcome
Other exclusions:
2 PPV23 only
1 post PCV data only
1 age ineligible group
81 Citations included for further
analysis
51 Families
2 Case- control
studies
2 Families
(Indirect effects
only; not analyzed)
19 Clinical trials
9 Families
11 with primary
data
9 Families
60 Observational
studies
40 Families
31 with primary,
analyzable data
31 Families
13 Duplicate
data
16 Qualitative
data
106 Citations in original search
(88 original and 18 updates)
14 Reviews
7 No pneumonia
outcome
Other exclusions:
2 PPV23 only
1 post PCV data only
1 age ineligible group
81 Citations included for further
analysis
51 Families
19 Clinical trials
9 Families
11 with primary
data
9 Families
60 Observational
studies
40 Families
31 with primary,
analyzable data
31 Families
13 Duplicate
data
16 Qualitative
data
FIGURE 1. Flowchart of included citations.
The Pediatric Infectious Disease Journal Volume 33, Number 1, Supplement 2, January 2014 PCV Dosing and Pneumonia
© 2013 Lippincott Williams & Wilkins
www.pidj.com | S143
parents were not blinded to the intervention; these design limita-
tions may explain why the point estimate is higher than that seen in
blinded RCTs of pneumonia.
Of the 5 observational studies, 3 reported data on clinical
pneumonia, 2 on radiologically confirmed pneumonia, 2 on pneu-
mococcal pneumonia and 2 on empyema (Table 3). All studies eval-
uating the effectiveness of 2+1 PCV against clinical and radiologi-
cally confirmed pneumonia showed evidence of significant disease
reduction after PCV introduction into the national immunization
program. Results of the limited number of studies on pneumococ-
cal pneumonia and empyema were mixed (Table 3). Of the 2 studies
on pneumococcal pneumonia following 2+1 PCV dosing, 1 from
Italy found a significant decline in hospitalizations for pneumococ-
cal pneumonia after PCV introduction,
30
while the other from Bel-
gium found no significant decrease in incidence of pneumococcal
pneumonia in children <2 years of age and a significant increase in
incidence in children 2–4 years of age.
16
Of the two 2+1 studies on
empyema, one found a 22% decline in empyema,
50
while the other
found no significant change in empyema rates following PCV intro-
duction into the national immunization program.
34
Three-dose Primary Schedules, With or Without Booster,
in the General Population (n = 28 Studies)
Of studies assessing a single schedule, 5 (6 citations) evalu-
ated a 3+0 schedule and 23 (24 citations) evaluated a 3+1 sched-
ule on various pneumonia disease endpoints. Of the 3+0 schedule
studies, we identified 3 RCTs
22,23,25,26
from various regions (Table 2)
and 2 observational studies, both from Australia
45,49
(Table 4). Each
of the RCTs showed efficacy against clinical or radiologically
confirmed pneumonia; the clinical trial in the Philippines showed
impact of PCV11 (Sanofi Pasteur, Lyon, France) on radiologically
confirmed pneumonia but not clinical pneumonia.
25
Both observa-
tional studies showed significant reductions in disease burden fol-
lowing PCV introduction into the Australian national immunization
program, with reductions ranging from 28% to 38% for clinical
pneumonia and from 45% to 77% for pneumococcal pneumonia
depending on the age group (Table 4).
We identified 3 clinical trials
29,31,38,57
and 20 observational
studies that evaluated the impact of a 3+1 schedule on pneumonia end-
points (8 on clinical pneumonia,
19,21,27,36,37,43,48,51
4 on radiologically
confirmed pneumonia,
40,43,52,55
7 on empyema
24,32,33,39,44,48,51
and 12
on pneumococcal pneumonia
17,19,21,33,37,41,42,44,46–48,51
) (Tables 2 and 5).
All clinical trials and observational studies showed evidence of
PCV benefit on clinical and radiologically confirmed pneumonia;
however, 1 German study was a nonrandomized, single-blinded
clinical trial, which limits interpretation of their findings,
29
and
in some observational studies, the results did not reach statistical
significance
36,43
or found significant reductions only in children
<2 years of age
19,37,48
(Tables 2 and 5). Of the 7 observational stud-
ies that evaluated a 3+1 schedule on all-cause empyema, 5 found
a significant increase in empyema rates after PCV introduction,
with many attributing these increases to pneumococcal serotypes
TABLE 1. Characteristics of Citations Included in Analysis
Characteristic
Complete Dosing Schedule*
Total† 2+1 3 + 0 3 + 1‡
n = 42 (%) n = 6 (%) n = 7 (%) n = 29 (%)
Year of publication
1994–1998 1 (2) 0 0 1 (3)
1999–2002 2 (5) 0 0 2 (7)
2003–2006 12 (29) 0 3 (43) 9 (31)
2007–2011 27 (64) 6 (100) 4 (57) 17 (59)
Study type
Clinical trial 11 (26) 1 (17) 5 (71) 5 (17)
Observational 31 (74) 5 (83) 2 (29) 24 (83)
Case-control 0 0 0 0
Region
Africa 3 (7) 0 3 (43) 0
Asia 1 (2) 0 1 (14) 0
Australia/Oceania 5 (12) 0 3 (43) 2 (7)
Europe 9 (22) 5 (83) 0 4 (14)
Latin America 1 (2) 0 0 1 (3)
North America 23 (55) 1 (17) 0 22 (76)
PCV product
PCV7 37 (88) 6 (100) 3 (43) 28 (97)
PCV9 3 (7) 0 3 (43) 0
PCV10 1 (2) 0 0 1 (3)
PCV11 1 (2) 0 1 (14) 0
PCV13 0 0 0 0
High-risk population
HIV 2 (5) 0 2 (29) 0
Indigenous 3 (7) 0 0 3 (10)
Neonates 1 (2) 0 1 (14) 0
Endpoint
Clinical pneumonia (including lower
respiratory tract infections) 20 (47) 3 (50) 5 (71) 12 (39)
Radiologically confirmed
pneumonia 13 (30) 3 (50) 3 (43) 7 (23)
Pneumococcal pneumonia 16 (37) 2 (33) 2 (29) 12 (39)
Empyema 9 (21) 2 (33) 0 7 (23)
*There were no citations that evaluated a 2+0 schedule.
†Numbers are not mutually exclusive as some citations presented findings on multiple characteristics.
‡3+1 schedules include 3+PPV23.
Loo et al The Pediatric Infectious Disease Journal Volume 33, Number 1, Supplement 2, January 2014
S144 | www.pidj.com © 2013 Lippincott Williams & Wilkins
TABLE 2. Summary Characteristics of Controlled Trials Evaluating a Pneumonia Endpoint, by Schedule
Country Reference Study Design
Vaccine
Product
Dosing Schedule Population
Endpoint and Case
Definition
Vaccine Efficacy (95% CI)
Intent to Treat Per Protocol
2+1 schedule
Italy Esposito et al.
35
Nonrandomized,
single-blind
cohort
PCV7 (Wyeth) 3, 5 and 11 months 1555 Children
(75–105 days)
followed to
29 months of age
CXR pneumonia
(non-WHO
clinical reading)
65% (47–78%)
3+0 schedule
Papua New
Guinea
Richmond et al.
18
Randomized,
nonblind
PCV7 (Wyeth) 0, 1 and 2 months
1, 2 and 3 months
Neonates and
infants followed to
18 months of age
Clinical pneumonia
(syndromic
diagnosis)
18% (4–31%)*
Philippines Lucero et al.
25
Randomized,
double-blind
PCV11 (Sanofi) 6, 10 and 14 weeks 12,191 Children
(<2 years of age)
followed to
24 months of age
Clinical pneumonia
(WHO IMCI),
CXR pneumonia
(WHO reading)
Clinical: –0.8% (−9.6% to 7.4%)
CXR: 16% (−7.3% to 34.2%)
Clinical: 0.1% (−9.4%
to 8.7%)
CXR: 22.9% (−1.1% to
41.2%)
South Africa Klugman et al.
22
Randomized,
double-blind
PCV9 (Wyeth) 6, 10 and 14 weeks 39,836 HIV− and
HIV+ Children
(<2 years of age)
CXR pneumonia
(WHO reading)
HIV−: 20% (2–35%)
HIV+: 13% (−7% to 29%)
HIV−: 25% (4–41%)
HIV+: not reported
South Africa Madhi et al.
26
Randomized,
double-blind
PCV9 (Wyeth) 6, 10 and 14 weeks 39,836 HIV− and
HIV+ Children
(<2 years of age)
Clinical pneumonia
(WHO IMCI)
HIV−: 17% (7–26%)
HIV+: 15% (5–24%)
HIV−: 23% (11–33%)
HIV+: 14% (−4% to
28%)
The Gambia Cutts et al.
23
Randomized,
double-blind
PCV9 (Wyeth) 11, 15 and 24 weeks 16,340 Children
(6–51 weeks of age)
followed for 2 years
Clinical pneumonia
(WHO IMCI),
CXR pneumonia
(WHO reading)
Clinical: 6% (1–11%)
CXR: 35% (26–43%)
Clinical: 7% (1–12%)
CXR: 37% (27–45%)
3+1 schedule
Latin America Tregnaghi et al.
57
Randomized,
double-blind
PCV10 (GSK) 2, 4, 6 and
15–18 months
23,738 Children
(6–16 weeks of age
at enrollment)
CXR pneumonia
(WHO reading)
23% (9–36%)
United States Black et al.
31
Randomized,
double-blind
PCV7 (Wyeth) 2, 4, 6 and
12–15 months
37,868 Children
(<3 years of age)
Clinical pneumonia
(study defined)
6.0% (−1.5% to 11.0%) 4.3% (−3.5% to 11.5%)
United States Hansen et al.
38
Randomized,
double-blind
PCV7 (Wyeth) 2, 4, 6 and
12–15 months
37,868 Children
(<3 years of age)
CXR pneumonia
(WHO reading)
25.5% (6.5–40.7%) 30.3% (10.7–45.7%)
United States O’Brien et al.
56
Randomized PCV7 (Wyeth) 2, 4, 6 and
12–15 months
8292 Native
American children
CXR pneumonia
(WHO reading);
inpatient cases
only
–11.0% (−39.3% to 11.5%) –8.0% (−37.0 to 14.9%)
Germany Adam and Fehnle
29
Nonrandomized,
nonblind
PCV7 (Wyeth) 2, 3, 4 and
12–15 months
5984 Children
(2–6 months of age)
followed until 1 year
after booster dose
Clinical pneumonia
(syndromic
diagnosis)
6.3% (−15.9% to 23.7%)
CXR, radiologically confirmed pneumonia; IMCI, Integrated Management of Childhood Illness.
*Vaccine efficacy was calculated VE = (1-incidence rate ratio) X 100.
The Pediatric Infectious Disease Journal Volume 33, Number 1, Supplement 2, January 2014 PCV Dosing and Pneumonia
© 2013 Lippincott Williams & Wilkins
www.pidj.com | S145
TABLE 3. Summary Characteristics and Findings of Observational Studies Evaluating a Pneumonia Endpoint, 2+1 Schedules
Country Reference Case Definition Study Design
Dosing Schedule
for PCV*
Age Groups
Evaluated
(Years)
Years
Baseline
Data
Baseline Measure
(Per Year)
Years
Postintroduction
Data
Percent Change at
Latest Year Post-PCV
Introduction†¶
Clinical pneumonia
Canada De Wals et al.
34
ICD-9 or
ICD-10 codes
Passive, sentinel
surveillance
2, 4, 12 months <5 7 3803 cases 2 −13.2‡
Italy Ansaldi et al.
30
ICD-9 or
ICD-10 codes
Sentinel
surveillance
3, 5, 11–12 months <2 3 642.2 cases/100,000 3 −15.2
United Kingdom Koshy et al.
50
ICD-9 or
ICD-10 codes
Population-based
surveillance
2, 4, 13 months <15 10 1335 admissions/
1,000,000
(standardized by
age and sex)
2 −19
CXR pneumonia
Canada De Wals et al.
34
ICD-9 or
ICD-10 codes
Passive, sentinel
surveillance
2, 4, 12 months <5 7 1660 cases 2 −72.3‡
Poland Patrzałek et al.
54
Clinical reading
(not WHO) by
2 independent
radiologists
Sentinel
surveillance
3, 5, 13 months <2
2–4
2 <2 years: 41.3
cases/1000
2–4 years: 6.1
cases/1000
2 <2 years: −10
2–4 years: −18
Pneumococcal pneumonia
Belgium Hanquet et al.
16
Radiograph
confirmation +
isolation of
S. pneumoniae
from blood or
pleural fluid
Active, popu-
lation-based
surveillance
8, 16 weeks;
12 months
<2, 2–4 1 <2 years: 25.5
cases/100,000
2–4 years: 20.1
cases/100,000
2 <2 years: −7.4§
2–4 years: 45.3
Italy Ansaldi et al.
30
ICD-9 or
ICD-10 codes
Sentinel
surveillance
3, 5 and
11–12 months
<2 3 19.1 cases/100,000 3 −70.5
Empyema
Canada De Wals et al.
34
ICD-9 or
ICD-10 codes
Passive, sentinel
surveillance
2, 4 and 12 months <5 7 0.8/100,000 average
annual rate
2 No change
United Kingdom Koshy et al.
50
ICD-9 or
ICD-10 codes
Population-based
surveillance
2, 4 and 13 months <15 10 18 admissions/
1,000,000
(standardized by
age and sex)
2 −22
*All studies evaluated PCV7.
†All percent changes are statistically significant (P < 0.05) unless otherwise noted.
‡NR, statistical significance not reported.
§NS, not significant.
¶Negative percent change indicates a percent reduction; positive percent change indicates a percent increase.
Loo et al The Pediatric Infectious Disease Journal Volume 33, Number 1, Supplement 2, January 2014
S146 | www.pidj.com © 2013 Lippincott Williams & Wilkins
not found in PCV7 or other pathogens such as multi-drug resist-
ant Staphylococcus aureus.
32,33,39,48,51
Evidence for the impact of a
3+1 schedule on pneumococcal pneumonia varied (Table 5). Eight
studies showed a decrease in pneumococcal pneumonia rates, 5
with significant findings.
17,19,21,37,48
Four studies found an increase, 2
with significant findings.
41,44
Of the 4 studies showing an increase in
pneumococcal pneumonia rates, 2 were conducted in Spain while
PCV7 coverage rates were <50%
44,47
and 1 was conducted in the
United States
41
that noted a PCV7 shortage limiting vaccine avail-
ability. Two of the 4 studies with increases in pneumococcal pneu-
monia rates also documented an increase in invasive disease rates
due to non-PCV7 serotypes.
41,44
PCV Dosing Schedules in High-Risk
Populations (n= 5 Studies)
Among 5 studies evaluating the impact of PCV on popula-
tions at high risk for pneumococcal disease, 2 (3 citations) used a
3+0 schedule and 3 used a 3+1 schedule. Two RCTs evaluated the
impact of PCV7 among a high-risk population using a 3+0 schedule
(Table 2).
18,22,26
One trial, conducted in South Africa, found a 13–15%
efficacy against clinical and radiologically confirmed pneumonia in
children with HIV. The other clinical trial, from Papua New Guinea,
found PCV7 to be 18% (95% CI: 4–31%) efficacious against clini-
cal pneumonia in neonates.
18
We identified 1 RCT
56
and 2 observa-
tional studies
20,52
from the United States and Australia that evaluated
a 3+1 (3+PPV23 for Australian Indigenous) schedule in indigenous
populations. The RCT, conducted among a population of American
Indians in the United States, showed no efficacy against the first
episode of radiologically confirmed pneumonia (authors' data, per
protocol vaccine efficacy: –8.0%, 95% CI: –37.0% to 14.9%); how-
ever, only inpatient pneumonia cases were included in this analysis
unlike other RCTs. One of the observational studies found a trend of
declining incidence for clinical pneumonia in Australian Indigenous
children; however, this finding was not significant (P = 0.13), and
study investigators speculate the lack of sufficient follow-up time as
a possible reason.
52
The other observational study, evaluating empy-
ema in a US Alaskan Native pediatric population, found no change
in empyema-associated hospitalizations following PCV introduc-
tion and rates remained higher than those for children in the general
US population.
20
Study investigators did note an apparent increased
rate in empyema due to S. pneumoniae and, in particular, episodes
due to nonvaccine serotypes, which could explain the lack of change
in overall empyema rates.
DISCUSSION
This analysis found strong evidence of PCV benefit against
both clinical and radiologically confirmed pneumonia in the age
group targeted for vaccination using 2+1, 3+0 and 3+1 schedules.
Data from several RCTs, including trials in low-income settings,
strongly support use of 3 primary dose schedules with or without
a booster (ie, 3+0 or 3+1) for prevention of pneumonia. A large
number of observational studies support use of either 3 primary
doses, with or without a booster, or 2 primary doses plus 1 booster
(2+1), which demonstrates the benefits of these schedules for pneu-
monia prevention in a routine immunization setting. Overall, half
(21 of 42) of the studies in our review provided evidence for sig-
nificant reductions in 1 or more disease endpoints. The evidence
for 1 schedule over another and the impact of PCV in preventing
pneumococcal pneumonia and empyema were less clear, given the
small number of studies and their conflicting findings.
Immunization with PCV is critical to provide protection
against pneumonia in the first year of life. However, quantifying the
differences in benefit between 2-dose and 3-dose primary immuni-
zation schedules against pneumonia was difficult as only 2 studies
TABLE 4. Summary Characteristics and Findings of Observational Studies Evaluating a Pneumonia Endpoint, 3+0 Schedules
Country Reference
Case
Definition
Study Design
Dosing
Schedule for
PCV*
Age Groups
Evaluated
(Years)
Years
Baseline
Data
Baseline
Measure (per
year)
Years
Postintroduction
Data
Percent Change at
Latest Year Post-PCV
Introduction†
Clinical pneumonia
Australia Jardine et al.
49
ICD-9 or ICD-10 codes Population-based
surveillance
2, 4 and 6 months <2, 2–4 7 No baseline
measure
reported
2 <2 years: −38‡
2–4 years: −28‡
Pneumococcal pneumonia
Australia Jardine et al.
49
ICD-9 or ICD-10 codes Population-based
surveillance
2, 4 and 6 months <2, 2–4 7 No baseline
measure
reported
2 <2 years: −77‡
2–4 years: −67‡
Australia Roche et al.
45
Isolation of S. pneumoniae
from blood or nucleic
acid test + clinical or
radiological confirmation
Passive,
population-based
surveillance
2, 4 and 6 months <2 3 44 cases 2 −45§
*All studies evaluated PCV7.
†Negative percent change indicates a percent reduction; positive percent change indicates a percent increase.
P < 0.05.
§NR, statistical significance not reported.
The Pediatric Infectious Disease Journal Volume 33, Number 1, Supplement 2, January 2014 PCV Dosing and Pneumonia
© 2013 Lippincott Williams & Wilkins
www.pidj.com | S147
TABLE 5. Summary Characteristics and Findings of Observational Studies Evaluating a Pneumonia Endpoint, 3+1 Schedules
Country Reference Case Definition Study Design
Dosing Schedule
for PCV*
Age Groups
Evaluated
Years
Baseline
Data
Baseline
Measure (Per Year)
Years
Postintroduction
Data
Percent Change
at Latest Year
Post-PCV
Introduction†
Clinical pneumonia
United States Balazs et al.
27
Clinician diagnosis Retrospective
cohort
2, 4, 6 and
12–15 months
<3 years 3 0.60 episodes 2 −35 (P = 0.06)
United States Grijalva et al.
36
ICD-9 or ICD-10 codes Passive,
population-based
surveillance
2, 4, 6 and
12–15 months
<2 years
(outpatient
only)
6 80 visits/1000 4 −31‡
United States Grijalva et al.
37
ICD-9 or ICD-10 codes Sentinel
surveillance
2, 4, 6 and
12–15 months
<2 years
2–4 years
3 <2 years: 1296.9
cases/100,000
2–4 years: 417.6 cases/100,000
4 <2 years: −39
2–4 years: −17‡
United States Grijalva et al.
48
ICD-9 or ICD-10 codes Sentinel
surveillance
2, 4, 6 and
12–15 months
<2 years
2–4 years
4 <2 years: 1267
hospitalizations/100,000
2–4 years: 402
hospitalizations/100,000
7 <2 years: −33
2–4 years: no
change
United States Li and Tancredi
51
ICD-9 or ICD-10 codes Population-based
surveillance
2, 4, 6 and
12–15 months
<18 years 2 281.1 hospitalizations/100,000 2 −13§
United States Nelson et al.
43
ICD-9 or ICD-10 codes Cohort study 2, 4, 6 and
12–15 months
<1 year
1–2 years
3–4 years
3 <1 year: 6.6 cases/1000
1–2 years: 4.7 cases/1000
3–4 years: 1.9 cases/1000
4 <1 year: −19‡
1–2 years: −15 ‡
3–4 years: +2‡
United States Simonsen et al.
19
ICD-9 or ICD-10 codes Sentinel
surveillance
2, 4, 6 and
12–15 months
<2 years
2–4 years
4 <2 years: 1026.5
cases/100,000
2–4 years: 307.5 cases/100,000
7 <2 years: −28
2–4 years: −1‡
United States Zhou et al.
21
ICD-9 or ICD-10 codes Cohort study 2, 4, 6 and
12–15 months
<2 years 3 11.5 hospitalizations/1000
person-years
3 −52.4
CXR pneumonia
Canada Twele et al.
55
WHO-standardized
trained readers or
WHO-adjudication of
radiographs
Sentinel
surveillance
2, 4, 6 and
12–15 months
<5 years 2 <1 year: 24.6% of admissions
1–2 years: 32.9% of
admissions
2–5 years: 41.5% of
admissions
2 <1 year: −4.6‡
1–2 years: −12.2
2–-5 years: −9.6
United States Nelson et al.
43
ICD-9 or ICD-10 codes
+ clinical radiograph
reading (not WHO)
Cohort study 2, 4, 6 and 12–15
months
<1 year
1–2 years
3–4 years
3 <1 year: 3.8 cases/1000
1–2 years: 3.2 cases/1000
3–4 years: 1.2 cases/1000
4 <1 year: −10‡
1–2 years: −9‡
3–4 years: −10‡
United States Rutman et al.
40
Clinical reading (not
WHO)
Cohort study 2, 4, 6 and 12–15
months
<2 years
2–4 years
All <5 years
4 <2 years: 17% (121/709) of
admissions
2–5 years: 38% (69/180) of
admissions
<5 years: 21% (190/889) of
admissions
5 <2 years: −41‡
2–4 years: +13‡
<5 years: −81‡
Australia O’Grady et al.
52
WHO-standardized
trained readers or
WHO-adjudication of
radiographs
Cohort study 3+PPV23
2, 4, 6 and 18
months
<18 months,
Indigenous
3 3.5 cases/1000 child-months 4 −12.3‡
(Continued)
Loo et al The Pediatric Infectious Disease Journal Volume 33, Number 1, Supplement 2, January 2014
S148 | www.pidj.com © 2013 Lippincott Williams & Wilkins
Pneumococcal pneumonia
Spain Aristegui et al.
47
Isolation of S. pneumoniae
from sterile site
Population-based
surveillance
2, 4, 6 and 15–18
months
<2 years 3 14.4 cases/100,000 2 +8‡
Spain Calbo et al.
33
Isolation of S. pneumoniae
from sterile site
Population-based
surveillance
2, 4, 6 and 15–18
months
<5 years 3 32.32 cases/100,000 3 −2.9‡
Spain¶ Munoz et al.
44
Isolation of S. pneumoniae
from sterile site + clinical
diagnosis (ICD-9 codes)
Active, sentinel
surveillance
2, 4, 6 and 15–18
months
<2 years
2–4 years
5 <2 years: 3.4 episodes/100,000
2–4 years: 3.8 episodes/
100,000
5 <2 years: +289
2–4 years: +344
United States Grijalva et al.
37
ICD-9 or ICD-10 codes Sentinel
surveillance
2, 4, 6 and 12–15
months
<2 years
2–4 years
3 <2 years: 26.2 cases/100,000
2–4 years: 27.1 cases/100,000
4 <2 years: −65
2–4 years: −73
United States Grijalva et al.
48
ICD-9 or ICD-10 codes Sentinel
surveillance
2, 4, 6 and 12–15
months
<2 years
2–4 years
4 <2 years: 27 hospitaliza-
tions/100,000
2–4 years: 12 hospitaliza-
tions/100,000
7 <2 years: −61
2–4 years: −26
United States Kaplan et al.
46
Isolation of S. pneumoniae
from blood, pleural fluid
or lung + radiological
confirmation
Active, sentinel
surveillance
2, 4, 6 and 12–15
months
<5 years 6 30.5 pneumococcal isolates/yr 2 −39‡
United States Liand Tancredi
51
ICD-9 or ICD-10 codes Population-based
surveillance
2, 4, 6 and 12–15
months
<18 years 2 8.9 hospitalizations/100,000 2 −45§
United States Moore et al.
17
Isolation of S. pneumoniae
from sterile site +
clinical or radiological
confirmation
Active,
population-based
surveillance
2, 4, 6 and 12–15
months
<5 years 2 16.3 cases/100,000 6 −52
United States Schutze et al.
41
Isolation of S. pneumoniae
from sterile site + clinical
diagnosis
Cohort study 2, 4, 6 and 12–15
months
<20 years 7 13% (16 of 128) of invasive
cases
2 +24
United States Shafinoori et al.
42
Isolation of S. pneumoniae
from blood or cerebral
spinal fluid + clinical
diagnosis
Active, sentinel
surveillance
2, 4, 6 and 12–15
months
“Children” 2 24% (19 of 80) of invasive
cases
4 +5‡
United States Simonsen et al.
19
ICD-9 or ICD-10 codes Sentinel
surveillance
2, 4, 6 and 12–15
months
<2 years 4 <2 years: 25.9 cases/100,000
2–4 years: 11.8 cases/100,000
7 <2 years: −51
2–4 years: −17
United States Zhou et al.
21
ICD-9 or ICD-10 codes Cohort study 2, 4, 6 and 12–15
months
<2 years 3 0.63 hospitalizations/1000
person-years
3 −57.6
Empyema
Spain Calbo et al.
33
Isolation of S. pneumoniae
from sterile site
Population-based
surveillance
2, 4, 6 and 15–18
months
<5 years 3 1.7 cases/100,000 3 +400 (P = 0.06)
United States Byington et al.
32
ICD-9 or ICD-10 codes Active, sentinel
surveillance
2, 4, 6 and 12–15
months
<18 years 4 38 cases/yr 3 +88.1
(Continued)
TABLE 5. Continued
Country Reference Case Definition Study Design
Dosing Schedule
for PCV*
Age Groups
Evaluated
Years
Baseline
Data
Baseline
Measure (Per Year)
Years
Postintroduction
Data
Percent Change
at Latest Year
Post-PCV
Introduction†
The Pediatric Infectious Disease Journal Volume 33, Number 1, Supplement 2, January 2014 PCV Dosing and Pneumonia
© 2013 Lippincott Williams & Wilkins
www.pidj.com | S149
directly compared different schedules within the same study. Pelton
et al.
28
directly compared 2 versus 3 primary doses in an observa-
tional study of an immature immunization program and found that
3 primary doses were superior to 2 doses in preventing hospitaliza-
tions for clinical pneumonia before a booster dose, but only early
in the vaccination program (presumably before the indirect effect
matured). The other study, conducted among Australian Indigenous
infants, also found that 3 primary doses were superior to 2 doses,
but under the condition of almost no effect from receipt of 3 pri-
mary doses compared with receipt of 0 doses in preventing clinical
pneumonia and an increased risk with receipt of 2 primary doses.
53
Study investigators speculated that replacement of vaccine sero-
types with either nonvaccine serotypes or other respiratory patho-
gens carried in the nasopharynx may have increased clinical pneu-
monias among infants. The remaining studies evaluating a single
schedule compared with no vaccination showed evidence of impact
on pneumonia burden using 2+1, 3+0 or 3+1 schedules; there were
no discernible differences in the magnitude of that impact accord-
ing to a specific dosing schedule. Findings from individual stud-
ies were not comparable with each other as the measured impact
was dependent on a variety of study methods, case definitions and
populations, which, due to the heterogeneity of the data, we were
unable to control for in analysis. Despite this limitation, our find-
ings support the use of PCV in effectively reducing disease burden
and complement a recent systematic review that evaluated the sub-
set of PCV studies making direct schedule comparisons; because of
limited or no data meeting inclusion criteria, that review was unable
to assess clinical outcomes regarding pneumonia.
58
In addition to the heterogeneity of study designs evaluating
different PCV schedules, the nonspecificity of pneumonia endpoints
and myriad case definitions complicated the ability to adequately
summarize and interpret findings regarding impact of PCV sched-
ules on pneumonia. Studies using more narrow and specific end-
points and case definitions, such as World Health Organization
(WHO)–standardized definitions, likely provide a more accurate
picture of PCV impact on disease specifically caused by pneumo-
coccus. Studies that use a more generic endpoint, such as clinical
pneumonia, are more prone to include cases caused by pathogens
other than pneumococcus and mask any true impact. A few stud-
ies have assessed the impact of specificity of disease endpoints by
retrospectively applying more specific case definitions and re-eval-
uating PCV impact. In each case, a higher efficacy was measured
with increased specificity for the disease endpoint.
26,38,59,60
However,
capturing cases with a more specific case definition is not always
appropriate or feasible given limited resources (ie, access to labora-
tory or clinical diagnostics, population access to care, limited sur-
veillance area) and confounding factors (ie, high burden of underly-
ing conditions such as malaria or HIV) in many studies evaluating
implementation in routine settings. We found evidence of this in our
review of case definitions; the most rigorous and specific case defi-
nitions were more often used in the setting of controlled trials while
observational studies were more likely to use nonspecific case defi-
nitions. Case definitions ranged in specificity and inclusion criteria
with some studies using International Classification of Diseases,
9th edition (ICD-9) or International Classification of Diseases, 10th
edition (ICD-10) administrative database codes or clinician diagno-
sis, while others used WHO-standardized definitions or laboratory
confirmation. This lack of specificity and standardization within
case definitions may explain some of the variability in findings and
the inability to interpret reductions in certain disease endpoints.
Nevertheless, our review found sufficient evidence of PCV impact
against pneumonia outcomes: 12/20 (60%) studies found significant
reductions in clinical pneumonia, 6/11 (55%) radiologically con-
firmed pneumonia and 7/16 (44%) pneumococcal pneumonia. It is
United States Hendrickson
et al.
39
ICD-9 or ICD-10 codes Cohort study 2, 4, 6 and 12–15
months
<18 years 5 13 total cases during baseline
period
5 +80
United States Grijalva et al.
48
ICD-9 or ICD-10 codes Sentinel
surveillance
2, 4, 6 and 12–15
months
<2 years
2–4 years
4 <2 years: 3.5 hospitaliza-
tions/100,000
2–4 years: 3.7 hospitaliza-
tions/100,000
7 <2 years: +100‡
2–4 years: +178
United States Li and Tancredi
51
ICD-9 or ICD-10 codes Population-based
surveillance
2, 4, 6 and 12–15
months
<18 years 2 2.2 hospitalizations/100,000 2 +70§
United States Schultz et al.
24
ICD-9 or ICD-10 codes Active, sentinel
surveillance
2, 4, 6 and 12–15
months
<18 years 2 29 S. pneumoniae isolates 2 −86.2
United States Singleton et al.
20
ICD-9 or ICD-10 codes Active,
population-based
surveillance
2, 4, 6 and 12–15
months
<10 years,
Alaskan
native
5 46.3 average annual
empyema-associated
hospitalization rate
4 No change
*All studies evaluated PCV7.
†All percent changes are statistically significant (P < 0.05) unless otherwise noted.
‡NS, not significant.
§NR, statistical significance not reported.
¶Endpoint also includes empyema.
Negative percent change indicates a percent reduction; positive percent change indicates a percent increase.
TABLE 5. Continued
Country Reference Case Definition Study Design
Dosing Schedule
for PCV*
Age Groups
Evaluated
Years
Baseline
Data
Baseline
Measure (Per Year)
Years
Postintroduction
Data
Percent Change
at Latest Year
Post-PCV
Introduction†
Loo et al The Pediatric Infectious Disease Journal Volume 33, Number 1, Supplement 2, January 2014
S150 | www.pidj.com © 2013 Lippincott Williams & Wilkins
essential for future studies to consider more pneumococcal-specific
and standardized case definitions to accurately and consistently
measure the impact of PCV against pneumonia.
The studies included in this analysis represent a number of dif-
ferent settings and populations, which, while providing a breadth of
data, also made it difficult to discern differences between schedules.
Many data collected from settings of routine immunization focused
on PCV7 and were from low disease burden, higher income countries,
complicating the ability to extrapolate findings to other PCV products
and to low- and middle-income countries, which often have higher
rates of disease burden and more constrained resources. In addition,
many populations in lower income countries have higher rates of
underlying health conditions (eg, HIV or sickle cell disease) that can
increase risk of developing pneumonia. We found only 6 studies that
evaluated the impact of PCV in populations at higher risk for disease
and magnitude of disease reduction varied greatly. Despite this limita-
tion in geographical representation in settings of routine immuniza-
tion, all RCTs evaluating 3+0 schedules were from low-income or
lower-middle income countries and showed impact of PCV in these
populations. As a greater number of countries have now introduced
PCV into national immunization programs, ongoing studies in lower
income settings and studies using various PCV products (PCV10 or
PCV13) will contribute to additional evidence of impact.
61,62
Our review of the literature on impact of PCV dosing sched-
ules found evidence of impact on varying pneumonia endpoints
using 2+1, 3+0 and 3+1 schedules, although the preponderance of
evidence informed 3+1 schedules, with fewer data available regard-
ing 2+1 and 3+0 schedules. Our findings support recommendations
by the Pan American Health Organization and WHO for using a
3-dose regimen, which can be given as either 3+0 or 2+1, and given
a lack of evidence supporting 2+0 schedules, choosing a schedule
that ensures high coverage with a third dose is essential.
63,64
Further-
more, due to current data limitations and heterogeneity of the data,
the optimal schedule in a given epidemiological setting for those 3
doses is dependent on a range of disease impact and programmatic
considerations. As more countries make a decision to introduce
PCV into national immunization programs, it will be essential for
policy makers to consider programmatic and epidemiologic factors
when making decisions regarding the ideal dosing schedule for their
program. To ensure stakeholders are well-informed, more data are
needed to evaluate PCV10 and PCV13 and the impact of these vac-
cines on pneumonia in developing countries. For all such studies, use
of specific, standardized case definitions and evaluations that include
direct schedule comparisons will greatly enhance the strength of evi-
dence on which to formulate optimal dosing policies and achieve the
greatest disease reductions for the doses administered.
ACKNOWLEDGMENTS
We gratefully acknowledge the tremendous support from the
following: Becky Roberts, Karrie-Ann Toews and Carolyn Wright
from the Centers for Disease Control and Prevention, Respiratory
Diseases Branch; Catherine Bozio, Rose Chang, Jamie Felzer, Amy
Fothergill, Sara Gelb, Kristen Hake, Sydney Hubbard, Grace Hunte
and Shuling Liu from Emory University Rollins School of Public
Health; T. Scott Johnson from Biostatics Consulting and Bethany
Baer, Subhash Chandir, Stephanie Davis, Sylvia Kauffman, Min
Joo Kwak, Paulami Naik and Meena Ramakrishnan from The Johns
Hopkins Bloomberg School of Public Health.
REFERENCES
1. O’Brien KL, Wolfson LJ, Watt JP, et al.; Hib and Pneumococcal Global
Burden of Disease Study Team. Burden of disease caused by Streptococcus
pneumoniae in children younger than 5 years: global estimates. Lancet.
2009;374:893–902.
2. World Health Organization. Estimated Hib and pneumococcal deaths for
children under 5 years of age. 2008. Available at: http://www.who.int/
immunization_monitoring/burden/Pneumo_hib_estimates/en/index.html.
Accessed March 18, 2013.
3. Lucero MG, Dulalia VE, Parreno RN, et al. Pneumococcal conjugate vac-
cines for preventing vaccine-type invasive pneumococcal disease and
pneumonia with consolidation on x-ray in children under two years of age.
Cochrane Database Syst Rev. 2004:CD004977.
4. World Health Organization. Pneumococcal conjugate vaccine for child-
hood immunization—WHO position paper. Wkly Epidemiol Rec. 2007;12:
93–104.
5. World Health Organization and UNICEF. Global Action Plan for Prevention
and Control of Pneumonia (GAPP). 2009. Available at: http://whqlibdoc.
who.int/hq/2009/WHO_FCH_CAH_NCH_09.04_eng.pdf. Accessed
March 18, 2013.
6. Johnson HL, Deloria-Knoll M, Levine OS, et al. Systematic evaluation of
serotypes causing invasive pneumococcal disease among children under five:
the pneumococcal global serotype project. PLoS Med. 2010;7:e1000348.
7. European Medicines Agency. Prevenar. 2011. Available at: http://www.ema.
europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000323/
human_med_000987.jsp&jsenabled=true. Accessed March 12, 2012.
8. European Medicines Agency. Prevenar 13. 2013. Available at: http://
www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medi-
cines/001104/human_med_001220.jsp&mid=WC0b01ac058001d124.
Accessed October 16, 2013.
9. European Medicines Agency. Synflorix. 2011. Available at: http://www.ema.
europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000973/
human_med_001071.jsp&mid=WC0b01ac058001d124. Accessed March
12, 2012.
10. IVAC, Johns Hopkins Bloomberg School of Public Health. Vaccine
Information Management System (VIMS) Global Vaccine Introduction
Report. March, 2013. Available at: www.jhsph.edu/ivac/vims.html.
Accessed April 15, 2013.
11. Conklin L, Loo JD, Kirk J, et al. Systematic review of the effect of pneu-
mococcal conjugate vaccine dosing schedules on vaccine-type invasive
pneumococcal disease among young children. Pediatr Infect Dis J. 2014;33
(Suppl 2):S109–S118.
12. Fleming-Dutra KE, Conklin L, Loo JD, et al. Systematic review of the effect
of pneumococcal conjugate vaccine dosing schedules on vaccine-type naso-
pharyngeal carriage. Pediatr Infect Dis J. 2014;33 (Suppl 2):S152–S160.
13. Deloria Knoll M, Park D, Johnson TS, et al. Systematic review of the effect
of pneumococcal conjugate vaccine dosing schedules on immunogenicity.
Pediatr Infect Dis J. 2014;33 (Suppl 2):S119–S129.
14. Loo JD, Conklin L, Fleming-Dutra KE, et al. Systematic review of the indi-
rect effect of pneumococcal conjugate vaccine dosing schedules on pneu-
mococcal disease and colonization. Pediatr Infect Dis J. 2014;33 (Suppl
2):S161–S171.
15. Loo JD, Conklin L, Deloria Knoll M, et al. Methods for a systematic review
of pneumococcal conjugate vaccine dosing schedules. Pediatr Infect Dis J.
2014;33 (Suppl 2):S182–S187.
16. Hanquet G, Lernout T, Vergison A, et al.; Belgian IPD Scientific Committee.
Impact of conjugate 7-valent vaccination in Belgium: addressing methodo-
logical challenges. Vaccine. 2011;29:2856–2864.
17. Moore M, Pilishvili T, Farley M, et al. Trends in invasive pneumococcal
pneumonia, selected US sites, 1998–2006. 6th International Symposium
on Pneumococci and Pneumococcal Disease; June 8–12, 2008. Reykjavik,
Iceland. Abstract 371.
18. Richmond P, Phuanukoonnon S, Jacoby P, et al. Effect of neonatal and early
immunisation with heptavalent pneumococcal conjugate vaccine on mor-
bidity and pneumonia in Papua New Guinea. 6th International Symposium
on Pneumococci and Pneumococcal Disease; June 8–12, 2008. Reykjavik,
Iceland. Abstract 345.
19. Simonsen L, Taylor RJ, Young-Xu Y, et al. Impact of pneumococcal
conjugate vaccination of infants on pneumonia and influenza hospi-
talization and mortality in all age groups in the United States. MBio.
2011;2:e00309–e00310.
20. Singleton R, Holman R, Yorita K, et al. Pneumococcal empyema and pleu-
ral effusion among Alaska Native children less than 10 yrs of age. 6th
International Symposium on Pneumococci and Pneumococcal Disease;
June 8–12, 2008. Reykjavik, Iceland. Abstract 87.
21. Zhou F, Kyaw MH, Shefer A, et al. Health care utilization for pneumonia
in young children after routine pneumococcal conjugate vaccine use in the
United States. Arch Pediatr Adolesc Med. 2007;161:1162–1168.
The Pediatric Infectious Disease Journal Volume 33, Number 1, Supplement 2, January 2014 PCV Dosing and Pneumonia
© 2013 Lippincott Williams & Wilkins
www.pidj.com | S151
22. Klugman KP, Madhi SA, Huebner RE, et al.; Vaccine Trialists Group. A trial
of a 9-valent pneumococcal conjugate vaccine in children with and those
without HIV infection. N Engl J Med. 2003;349:1341–1348.
23. Cutts FT, Zaman SM, Enwere G, et al.; Gambian Pneumococcal Vaccine
Trial Group. Efficacy of nine-valent pneumococcal conjugate vaccine against
pneumonia and invasive pneumococcal disease in The Gambia: randomised,
double-blind, placebo-controlled trial. Lancet. 2005;365:1139–1146.
24. Schultz KD, Fan LL, Pinsky J, et al. The changing face of pleural empyemas in
children: epidemiology and management. Pediatrics. 2004;113:1735–1740.
25. Lucero MG, Nohynek H, Williams G, et al. Efficacy of an 11-valent
pneumococcal conjugate vaccine against radiologically confirmed pneu-
monia among children less than 2 years of age in the Philippines: a ran-
domized, double-blind, placebo-controlled trial. Pediatr Infect Dis J.
2009;28:455–462.
26. Madhi SA, Kuwanda L, Cutland C, et al. The impact of a 9-valent pneu-
mococcal conjugate vaccine on the public health burden of pneumonia in
HIV-infected and -uninfected children. Clin Infect Dis. 2005;40:1511–1518.
27. Balazs GC, Garcia FJ, Yamamoto LG. Conjugate heptavalent pneumococcal
vaccine outcome improvements. Hawaii Med J. 2006;65:288–289.
28. Pelton SI, Weycker D, Klein JO, et al. 7-Valent pneumococcal conjugate
vaccine and lower respiratory tract infections: effectiveness of a 2-dose ver-
sus 3-dose primary series. Vaccine. 2010;28:1575–1582.
29. Adam D, Fehnle K. Safety and effectiveness against respiratory tract infec-
tions for pneumococcal conjugate vaccine co-administered with routine
vaccine combinations. Vaccine. 2008;26:5944–5951.
30. Ansaldi F, Sticchi L, Durando P, et al. Decline in pneumonia and acute oti-
tis media after the introduction of childhood pneumococcal vaccination in
Liguria, Italy. J Int Med Res. 2008;36:1255–1260.
31. Black SB, Shinefield HR, Ling S, et al. Effectiveness of heptavalent pneu-
mococcal conjugate vaccine in children younger than five years of age for
prevention of pneumonia. Pediatr Infect Dis J. 2002;21:810–815.
32. Byington CL, Korgenski K, Daly J, et al. Impact of the pneumococcal conju-
gate vaccine on pneumococcal parapneumonic empyema. Pediatr Infect Dis
J. 2006;25:250–254.
33. Calbo E, Díaz A, Cañadell E, et al.; Spanish Pneumococcal Infection Study
Network. Invasive pneumococcal disease among children in a health dis-
trict of Barcelona: early impact of pneumococcal conjugate vaccine. Clin
Microbiol Infect. 2006;12:867–872.
34. De Wals P, Robin E, Fortin E, et al. Pneumonia after implementation of
the pneumococcal conjugate vaccine program in the province of Quebec,
Canada. Pediatr Infect Dis J. 2008;27:963–968.
35. Esposito S, Lizioli A, Lastrico A, et al. Impact on respiratory tract infections
of heptavalent pneumococcal conjugate vaccine administered at 3, 5 and 11
months of age. Respir Res. 2007;8:12.
36. Grijalva CG, Poehling KA, Nuorti JP, et al. National impact of universal
childhood immunization with pneumococcal conjugate vaccine on outpa-
tient medical care visits in the United States. Pediatrics. 2006;118:865–873.
37. Grijalva CG, Nuorti JP, Arbogast PG, et al. Decline in pneumonia admis-
sions after routine childhood immunisation with pneumococcal conjugate
vaccine in the USA: a time-series analysis. Lancet. 2007;369:1179–1186.
38. Hansen J, Black S, Shinefield H, et al. Effectiveness of heptavalent pneumo-
coccal conjugate vaccine in children younger than 5 years of age for prevention
of pneumonia: updated analysis using World Health Organization standardized
interpretation of chest radiographs. Pediatr Infect Dis J. 2006;25:779–781.
39. Hendrickson DJ, Blumberg DA, Joad JP, et al. Five-fold increase in pediat-
ric parapneumonic empyema since introduction of pneumococcal conjugate
vaccine. Pediatr Infect Dis J. 2008;27:1030–1032.
40. Rutman MS, Bachur R, Harper MB. Radiographic pneumonia in young,
highly febrile children with leukocytosis before and after universal conju-
gate pneumococcal vaccination. Pediatr Emerg Care. 2009;25:1–7.
41. Schutze GE, Tucker NC, Mason EO Jr. Impact of the conjugate pneumococ-
cal vaccine in Arkansas. Pediatr Infect Dis J. 2004;23:1125–1129.
42. Shafinoori S, Ginocchio CC, Greenberg AJ, et al. Impact of pneumococ-
cal conjugate vaccine and the severity of winter influenza-like illnesses on
invasive pneumococcal infections in children and adults. Pediatr Infect Dis
J. 2005;24:10–16.
43. Nelson JC, Jackson M, Yu O, et al. Impact of the introduction of pneumo-
coccal conjugate vaccine on rates of community acquired pneumonia in
children and adults. Vaccine. 2008;26:4947–4954.
44. Muñoz-Almagro C, Jordan I, Gene A, et al. Emergence of invasive pneumo-
coccal disease caused by nonvaccine serotypes in the era of 7-valent conju-
gate vaccine. Clin Infect Dis. 2008;46:174–182.
45. Roche PW, Krause V, Cook H, et al.; Enhanced Invasive Pneumococcal
Disease Surveillance Working Group; Pneumococcal Working Party of the
Communicable Diseases Network Australia. Invasive pneumococcal disease
in Australia, 2006. Commun Dis Intell Q Rep. 2008;32:18–30.
46. Kaplan SL, Mason EO Jr, Wald ER, et al. Decrease of invasive pneumococ-
cal infections in children among 8 children’s hospitals in the United States
after the introduction of the 7-valent pneumococcal conjugate vaccine.
Pediatrics. 2004;113(3 pt 1):443–449.
47. Aristegui J, Bernaola E, Pocheville I, et al. Reduction in pediatric invasive
pneumococcal disease in the Basque Country and Navarre, Spain, after
introduction of the heptavalent pneumococcal conjugate vaccine. Eur J Clin
Microbiol Infect Dis. 2007;26:303–310.
48. Grijalva CG, Nuorti JP, Zhu Y, et al. Increasing incidence of empyema com-
plicating childhood community-acquired pneumonia in the United States.
Clin Infect Dis. 2010;50:805–813.
49. Jardine A, Menzies RI, McIntyre PB. Reduction in hospitalizations for
pneumonia associated with the introduction of a pneumococcal conjugate
vaccination schedule without a booster dose in Australia. Pediatr Infect Dis
J. 2010;29:607–612.
50. Koshy E, Murray J, Bottle A, et al. Impact of the seven-valent pneumo-
coccal conjugate vaccination (PCV7) programme on childhood hospital
admissions for bacterial pneumonia and empyema in England: national
time-trends study, 1997-2008. Thorax. 2010;65:770–774.
51. Li ST, Tancredi DJ. Empyema hospitalizations increased in US children
despite pneumococcal conjugate vaccine. Pediatrics. 2010;125:26–33.
52. O’Grady KF, Carlin JB, Chang AB, et al. Effectiveness of 7-valent
pneumococcal conjugate vaccine against radiologically diagnosed pneu-
monia in indigenous infants in Australia. Bull World Health Organ.
2010;88:139–146.
53. O’Grady KA, Lee KJ, Carlin JB, et al. Increased risk of hospitalization for
acute lower respiratory tract infection among Australian indigenous infants
5–23 months of age following pneumococcal vaccination: a cohort study.
Clin Infect Dis. 2010;50:970–978.
54. Patrzałek M, Albrecht P, Sobczynski M. Significant decline in pneumonia
admission rate after the introduction of routine 2+1 dose schedule heptava-
lent pneumococcal conjugate vaccine (PCV7) in children under 5 years of
age in Kielce, Poland. Eur J Clin Microbiol Infect Dis. 2010;29:787–792.
55. Twele L, Haider S, Nettel-Aguirre A, et al. Has the 7-valent pneumococcal
conjugate vaccine (PCV7) reduced hospital visits and admissions for pneu-
monia in young children in Calgary? Int J Antimicrob Agents. 2009;34:S5-S6.
56. O’Brien KL. The effect of conjugate pneumococcal vaccine on pneumo-
nia and otitis media among Navajo and White Mountain Apache children.
3rd International Symposium on Pneumococci and Pneumcooccal Disease;
May 5-8, 2002, Anchorage, AK.
57. Tregnaghi MW, Sáez-Llorens X,López P, et al. Evaluating the efficacy of
10-valent pneumococcal non-typeable Haemophilus influenzae protein-d
conjugate vaccine (PHID-CV) against community-acquired pneumonia
in Latin America. European Society of Pediatric Infectious Disease; June
7–11, 2011. The Hague, Netherlands.
58. Scott P, Rutjes AW, Bermetz L, et al. Comparing pneumococcal conjugate
vaccine schedules based on 3 and 2 primary doses: systematic review and
meta-analysis. Vaccine. 2011;29:9711–9721.
59. Cheung YB, Zaman SM, Ruopuro ML, et al. C-reactive protein and pro-
calcitonin in the evaluation of the efficacy of a pneumococcal conjugate
vaccine in Gambian children. Trop Med Int Health. 2008;13:603–611.
60. Madhi SA, Kohler M, Kuwanda L, et al. Usefulness of C-reactive protein to
define pneumococcal conjugate vaccine efficacy in the prevention of pneu-
monia. Pediatr Infect Dis J. 2006;25:30–36.
61. Cohen C, von Mollendorf C, Naidoo N, et al. South African IPD Case-
Control Study Group. Effectiveness of seven-valent pneumococcal conjugate
vaccine (PCV7) against invasive pneumococcal disease in South Africa: a
matched case-control study. 8th International Symposium on Pneumococci
and Pneumococcal Disease; March 11–15, 2012, Igacu Falls, Brazil.
62. Madhi SA, Groome M, Zar H, et al. Effectiveness of pneumococcal conju-
gate vaccine (PCV) against presumed bacterial pneumonia (PBP) in South
African HIV-uninfected children: a case-control study. 8th International
Symposium on Pneumococci and Pneumococcal Disease; March 11–15,
2012, Igacu Falls, Brazil. Abstract 8.
63. Pan American Health Organization. Technical Advisory Group on Vaccine-
Preventable Diseases. Final Report; July 6–8, 2011, Buenos Aires, Argentina.
64. World Health Organization. Meeting of the Strategic Advisory Group of
Experts on Immunization, November 2011—conclusions and recommenda-
tions. Wkly Epidemiol Rec. 2012:1–16.
    • "PCV10 was also estimated to have a substantial effect on pneumonia deaths as well as on deaths due to all causes. For pneumonia hospitalizations, VE estimates are comparable—albeit on the lower end—to those presented in other observational studies in which the 3+1 schedule was used for different-valent vaccines, case definitions and study designs.[14, 15] A number of studies suggest that increasing the specificity of case definitions by applying more stringent and standardized diagnostic algorithms, including the use of radiological findings for example, increases estimates of vaccine effectiveness by increasing the number of pneumonias that are actually due to pneumococci.[4, "
    [Show abstract] [Hide abstract] ABSTRACT: Background: The ten-valent pneumococcal conjugate vaccine (PCV10) was introduced into the Chilean National Immunization Program (NIP) in January 2011 with a 3+1 schedule (2, 4, 6 and 12 months) without catch-up vaccination. We evaluated the effectiveness of PCV10 on pneumonia morbidity and mortality among infants during the first two years after vaccine introduction. Methods: This is a population-based nested case-control study using four merged nationwide case-based electronic health data registries: live birth, vaccination, hospitalization and mortality. Children born in 2010 and 2011 were followed from two moths of age for a period of two years. Using four different case definitions of pneumonia hospitalization and/or mortality (all-cause and pneumonia related deaths), all cases and four randomly selected matched controls per case were selected. Controls were matched to cases on analysis time. Vaccination status was then assessed. Vaccine effectiveness (VE) was estimated using conditional logistic regression. Results: There were a total of 497,996 children in the 2010 and 2011 Chilean live-birth cohorts. PCV10 VE was 11.2% (95%CI 8.5-13.6) when all pneumonia hospitalizations and deaths were used to define cases. VE increased to 20.7 (95%CI 17.3-23.8) when ICD10 codes used to denote viral pneumonia were excluded from the case definition. VE estimates on pneumonia deaths and all-cause deaths were 71.5 (95%CI 9.0-91.8) and 34.8 (95% CI 23.7-44.4), respectively. Conclusion: PCV10 vaccination substantially reduced the number of hospitalizations due to pneumonia and deaths due to pneumonia and to all-causes over this study period. Our findings also reinforce the importance of having quality health information systems for measuring VE.
    Full-text · Article · Apr 2016
    • "Vaccination with pneumococcal conjugate vaccines (PCV) reduces colonization rates of vaccine serotypes35363738. The protective effects of PCV were proven for invasive pneumococcal disease [12], pneumonia [11], and AOM [17, 39], while the PCV impact on sinusitis is not clearly defined [40] . The overall need of antimicrobial treatment is likely to be reduced with lower frequencies of these diseases caused by SPn. "
    [Show abstract] [Hide abstract] ABSTRACT: Background Streptococcus pneumoniae (SPn) is an important pathogen causing a variety of clinical manifestations. The effects of SPn nasopharyngeal colonization on respiratory tract infections are poorly studied. We evaluated the association of SPn colonization with features of respiratory tract infections. Methods Children under the age of 6 years who visited a primary care physician because of respiratory tract infections were enrolled in the study. History was taken, children were clinically assessed by the physician, and nasopharyngeal swabs were obtained and cultured for SPn. Positive samples were serotyped. Associations of SPn colonization with clinical signs and symptoms, recovery duration, absence from day care centre, frequencies of specific diagnoses, and treatment with antimicrobials were evaluated. Results In total 900 children were enrolled. The prevalence of SPn colonization was 40.8 % (n = 367). There were minor differences between male and female subjects (199 of 492, 40.4 % vs 168 of 408, 41.2 %, p = 0.825). Children with and without siblings had similar colonization rates (145 of 334, 43.4 % vs 219 of 562, 39.0 %, p = 0.187). Clinical signs and symptoms were not associated with SPn colonization. Children colonized with SPn had longer recovery duration compared to non-colonized children (114 of 367, 31.1 % vs 98 of 533, 18.4 %, p < 0.001) and were longer absent from day care (270 of 608, 44.4 % vs 94 of 284, 33.1 %, p = 0.001). Pneumonia, sinusitis, and acute otitis media were more frequently diagnosed in children colonized with SPn. Children attending day care centres had significantly higher prevalence of SPn colonization (270 of 367, 44.4 % vs 338 of 533, 33.1 %, p = 0.001). Children with pneumonia, sinusitis and acute otitis media were more frequently treated with antimicrobials than children with other diagnoses. Conclusions SPn nasopharyngeal colonization has a negative impact on the course of respiratory tract infection, likely because of SPn being the cause of the disease or a complicating factor. It is also associated with and may be responsible for higher frequencies of bronchitis, pneumonia, acute otitis media, sinusitis and the need of antimicrobial treatment.
    Full-text · Article · Sep 2015
    • "Much of the evidence regarding PCV impact has focused on young children targeted to receive vaccine using 2 primary doses plus a booster (2+1) or 3 primary doses with or without a booster (3+0 or 3+1).3–6 Clinical trials and observational studies have demonstrated a significant direct impact of PCV on both vaccine-type invasive pneumococcal disease (VT-IPD) and pneumococcal and syndromic pneumonia among children <5 years of age.3,6 Reductions in nasopharyngeal (NP) carriage of vaccine-type pneumococci (VT-NP), a necessary precursor to clinical disease, have also been demonstrated among young children receiving the vaccine.4 "
    [Show abstract] [Hide abstract] ABSTRACT: To aid decision making for pneumococcal conjugate vaccine (PCV) use in infant national immunization programs, we summarized the indirect effects of PCV on clinical outcomes among nontargeted age groups. We systematically reviewed the English literature on infant PCV dosing schedules published from 1994 to 2010 (with ad hoc addition of 2011 articles) for outcomes on children >5 years of age and adults including vaccine-type nasopharyngeal carriage (VT-NP), vaccine-type invasive pneumococcal disease (VT-IPD) and syndromic pneumonia. Of 12,980 citations reviewed, we identified 21 VT-IPD, 6 VT-NP and 9 pneumonia studies. Of these 36, 21 (58%) included 3 primary doses plus PCV or pneumococcal polysaccharide vaccine (PPV23) booster schedule (3+1 or 3+PPV23), 5 (14%) 3+0, 9 (25%) 2+1 and 1 (3%) 2+0. Most (95%) were PCV7 studies. Among observational VT-IPD studies, all schedules (2+1, 3+0 and 3+1) demonstrated reductions in incidence among young adult groups. Among syndromic pneumonia observational studies (2+1, 3+0 and 3+1), only 3+1 schedules showed significant indirect impact. Of 2 VT-NP controlled trials (3+0 and 3+1) and 3 VT-NP observational studies (2+1, 3+1 and 3+PPV23), 3+1 and 3+PPV23 schedules showed significant indirect effect. The 1 study to directly compare between schedules was a VT-NP study (2+0 vs. 2+1), which found no indirect effect on older siblings and parents of vaccinated children with either schedule. Indirect benefit of a 3+1 infant PCV dosing schedule has been demonstrated for VT-IPD, VT-NP and syndromic pneumonia; 2+1 and 3+0 schedules have demonstrated indirect effect only for VT-IPD. The choice of optimal infant PCV schedule is limited by data paucity on indirect effects, especially a lack of head-to-head studies and studies of PCV10 and PCV13.
    Full-text · Article · Jan 2014
Show more