Pneumococcal conjugate vaccines (PCV) have been available for use in infants for over a decade and have played an integral role in the prevention of disease caused by Streptococcus pneumoniae in children in higher income settings.1 However, until recently, availability of PCV for children living in lower income countries has been limited. This situation is now changing. In 2011, 18 GAVI-eligible countries were approved to introduce PCV; an additional 19 have been approved.2 As the feasibility of introducing PCV into childhood immunization programs has grown, the need to understand the number and the timing of doses, which will maximize both direct and indirect effects, has become a key question.
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 Because pneumococci are transmitted through respiratory secretions, reductions in NP carriage of pneumococci are a key factor toward indirect effects of vaccine introduction and the establishment of “herd” protection. Through herd protection, infant immunization indirectly protects groups not targeted to receive the vaccine by reducing the circulation of vaccine-type bacteria. Prevention of disease among adults through herd protection has been shown to be an important benefit and a powerful driver of the cost effectiveness of a PCV program in high-income settings.7 Whether different PCV dosing schedules may translate into noticeable differences in herd effects is unknown. Here, we present a systematic review of the literature summarizing the evidence on the indirect effects of PCV dosing schedules on VT-IPD, VT-NP-carriage and syndromic pneumonia among groups not targeted to receive the vaccine.
MATERIALS AND METHODS
This analysis is part of a larger project describing the impact of PCV dosing schedules on IPD, immunogenicity, nasopharyngeal carriage, pneumonia and indirect effects.3–6 Details on the literature search terms and methods used in this systematic review are described elsewhere (see Methods Appendix8). In brief, a systematic 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, NP colonization, invasive pneumococcal disease, pneumonia and on indirect effects among unvaccinated populations. Articles published in 14 databases, from ad hoc unpublished sources and abstracts from meetings of the International Symposium 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 trials, surveillance database analyses and observational studies of any PCV schedule on 1 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 relevant 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 the relevant data for this project. Details on the search methods are provided in the Methods Appendix.8
Citations recovered through the literature search went through several stages of independent review to determine their eligibility, as described elsewhere.8 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, population, surveillance system or other data collection system relevant to that outcome. Investigators identified the 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” asa group of children distinguished by immunization schedule or PCV product.
We abstracted core information on the following: number 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. To assess indirect effects, we abstracted additional data from studies of the effects of PCV in unimmunized populations on VT-IPD, VT-NP carriage and syndromic pneumonia and included information on study design, case definitions and trends in the outcome of interest.
Inclusion and Exclusion Criteria
We included the data published during or after 1994 from clinical trials, surveillance database analyses and observational studies of PCV schedules on VT-IPD, VT-NP carriage and syndromic pneumonia. 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 the observational studies that only reported data before or after PCV introduction but not for both periods. Unless ≥50% vaccination coverage was documented, the observational studies were also excluded if vaccination was only available through a private sector or only recommended for high-risk groups. Studies that only provided incidence rates during the year of vaccine introduction, or did not specify a time period, were excluded.
For IPD, we focused the analysis on the indirect effects among adults by including studies that reported data on specific age groups between 18 and 64 years (eg, 18–35 and 36–64 years), and those that were inclusive of age groups ≥65 or <18 years (eg, the “general population”). Studies that only reported data on age groups <18 or ≥65 years were excluded.
Pneumococcal Vaccine Dosing Schedules
We included PCV schedules with 2 or 3 primary doses without a booster dose (2+0 and 3+0) and with a booster dose (2+1 and 3+1). Schedules with either PCV or PPV23 boosters were included (2+PPV23 and 3+PPV23).
Because the included studies used a variety of designs and methods, we were unable to perform a formal meta-analysis. Thus, we summarized the data across studies in descriptive analyses to provide an overview of the amount and variability of data by outcome and schedule. For VT-NP carriage, each study was divided into arms, defined as a unique combination of vaccine schedule, age at NP specimen collection and vaccine product used. Studies could have multiple arms. Vaccine-type pneumococci were defined as each study defined them, based on the product used. For carriage, no studies included serotype 19A in VT and 1 included serotype 6A in VT.9 For IPD, no studies included serotypes 19A or 6A in VT. We defined VT-NP carriage prevalence as the percentage of those sampled who carried VT pneumococci, except in 2 studies that only reported the percentage of pneumococcal isolates found that were VT.9,10 The syndromic pneumonia endpoint included clinical pneumonia, radiologically confirmed pneumonia and pneumococcal (eg, bacteremic) pneumonia.
For observational studies reporting VT-IPD incidence over time, we calculated percent reduction by defining baseline incidence as the mean of all data points reported prior to introduction. When annual data on post introduction incidence were available, we calculated percent reduction from baseline using the data point given for each year reported. In cases where only the average post introduction incidence rate over a period was provided, we calculated percent reduction 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. Percent reduction reported by the study was only used if no incidence rates were provided. Therefore, the percent reduction over time presented in this review may not always be identical to that reported by the study.
We used Microsoft Access 2003 and 2007 (Microsoft Corporation, Redmond, WA) for data abstraction and SAS 9.2 and 9.3 (SAS Institute Inc., Cary, NC) to perform all analyses.
Of 12,980 citations reviewed, 36 studies (38 citations) met inclusion criteria for PCV indirect effects; of these, 21 were VT-IPD studies,11–31 9 were pneumonia syndrome studies11,32–39 and 6 were VT-NP carriage studies9,10,40–45 (Fig. 1). Among the 36 studies, all were published in 2003 or later, and 28 (78%) were from Europe or North America (Table 1). Almost all (95%) studies evaluated PCV7; none evaluated PCV10 or PCV13.
This review identified 6 studies that evaluated the indirect impact of PCV on VT-NP carriage. All but 1 study were from North America, Europe or Australia. Five studies (83%) evaluated PCV7, including one with a PPV23 booster dose; 1 study (17%) evaluated PCV9. Three studies (50%) evaluated the impact of PCV on VT-NP carriage in indigenous populations.
Two studies (3 citations) among nonhigh-risk populations evaluated the indirect effects of either a 2+0 or 2+1 schedule (Table 2) on VT-NP carriage.41,44,45 One individual RCT in the Netherlands found no VT-NP carriage indirect effect of PCV7 given in 2+0 and 2+1 dosing schedules among parents and siblings of vaccinated and unvaccinated children.44,45 One pre/postvaccine introduction observational study in the United Kingdom using a 2+1 schedule with catch-up through 2 years of age found a nonsignificant reduction in VT-NP carriage 2–3 years after PCV7 introduction among children and adults ≥5 years of age (Table 2).41 There were no studies that evaluated 2+0 or 2+1 schedules in high-risk populations, such as indigenous and immunocompromised populations.
One study evaluated a 3+0 (Table 2) schedule on VT-NP carriage. This individual RCT found no effect on VT-NP carriage among unvaccinated younger siblings of children vaccinated with PCV9 or placebo in The Gambia.40 There was 1 RCT and 2 observational studies that evaluated a 3+1 or 3+PPV23 schedule in high-risk populations; no studies evaluated a 3+0 schedule in high-risk populations (Table 2). The observational carriage study in Australia among Aboriginals with 3+PPV23 found a significant indirect reduction of VT-carriage among older children, but no difference among adults.10 A cluster-randomized, placebo-controlled trial evaluated VT-carriage indirect effects among the Navajo Nation and White Mountain Apache people.9,43 During the trial, VT-carriage was reduced among household contacts (older and younger siblings) of PCV7 vaccinees, but reached statistical significance only for daycare-attending contacts.9 However, at 3–15 months after completion of the trial, significant reductions were seen in VT-carriage among unvaccinated children <5 years of age and adults living in communities randomized to PCV7 compared with placebo.43 Another observational study demonstrated a highly significant trend in reduction of VT-carriage prevalence among Alaskan Native adults in the 4 years following the introduction of PCV7 with a 3+1 schedule.42
Invasive Pneumococcal Disease
We identified 21 studies documenting the impact of PCV introduction on incidence of VT-IPD among adult age groups, including 4 studies that specifically reported data on VT-meningitis (Table 3). All these studies were observational studies using either population-based surveillance or sentinel site data. No clinical trials of indirect effects among adults were identified in the published literature; we are aware of 1 such unpublished trial result that showed no effect in any age group (author data).46 Six studies provided data on a high-risk population, either indigenous (n = 4; 19.0%) or HIV-infected (n = 2, 9.5%) persons. The definition of adult age group varied across studies; however, 4 (19.0%) reported data from the total population, including children <18 and adults ≥65 years of age.
Many studies reporting indirect effects of PCV on VT-IPD occurred in the setting of a 3+1 national immunization program (n = 12; 61.9%). Six studies (12.9%), conducted in the United Kingdom, Scotland, Italy, Denmark and Norway, occurred in a 2+1 setting. Three studies, all conducted in Australia, used a 3+PPV23 (among indigenous groups) and/or 3+0 (among nonindigenous groups) dosing schedule.23,26 No studies used a 2+0 schedule and no direct comparisons among dosing schedules were identified.
Nearly all studies (n = 20; 95.2%) demonstrated a reduction in VT-IPD among at least 1 adult age group, regardless of dosing schedule (2+1, 3+0, 3+PPV23 and 3+1). The degree of impact varied by a specific age group, the outcome measured and the number of years post introduction (Fig. 2). Reductions in VT-IPD were observed as early as 1 year after introduction. In general, reductions for all schedules were larger ≥3 years after introduction compared with reductions seen within 3 years of introduction (Fig. 3A, B).
Of the 12 studies, 9 (75.0%) using a 3+1 or 3+PPV23 schedule took place in countries where catch-up campaigns were implemented during national introduction. Reductions in VT-IPD among healthy adult groups in countries using 3+1 schedules ranged from 13% in Spain, 6 years after PCV introduction, to 92% in the United States, 7 years after introduction.11,25 Vaccine-type meningitis was reduced by 73% among the general population in Canada and by 67% among adults ages 18–39 years in the United States, both within 5 years after PCV introduction.12,19 One study conducted in the United States demonstrated a 67% reduction in VT-IPD among Alaskan Natives ages 18–44 years, also within 5 years after introduction.
Two studies identified in this review did not show a reduction in VT-IPD among a reported adult group using a 3+1 schedule. In Spain, a 25% increase in VT-meningitis was observed among all adults, which was accompanied by a 13% reduction in VT-IPD among adults ages 18–64 years.11 Factors cited as possibly contributing to this finding included a low PCV coverage (50% within 6 years after introduction for high-risk groups) and an increase in in-migration to the area that could have impacted the indirect effects of vaccine introduction. In the Netherlands, no change (0%) in VT-IPD was observed among 5–49 year olds 2 years following introduction.27 Authors attributed the apparent absence of herd immunity despite high vaccine uptake among children (94%) to the lack of a catch-up campaign and short evaluation period.
We identified 2 studies reporting indirect effects of PCV on VT-IPD among adults with HIV. Both studies took place in settings using a 3+1 schedule. In the United States, Cohen et al. reported a 91% reduction in the incidence of VT-IPD among HIV-infected persons, from 681 per 100,000 persons 18–64 years of age living with AIDS in 1998/1999 to 64 per 100,000 persons in 2007. In Spain, Grau et al. reported a 67% reduction in VT-IPD among 4011 HIV-infected adults receiving care at a teaching hospital in Barcelona 6 years after vaccine introduction.
Of the 5 countries reporting data on the indirect effects of PCV on adult groups using a 2+1 schedule, all except Italy implemented some type of catch-up campaign among young children. Reported indirect effects on VT-IPD with a 2+1 schedule ranged from 15% among the general population in Italy to 88% among 15–44 year olds in England and Wales.14,24 A 70% reduction in VT-meningitis was also observed among adults 5–64 years of age in England and Wales within 4 years after vaccine introduction.24
The 3 studies using either a 3+0 or a 3+PPV23 schedule all took place in Australia, where catch-up campaigns were conducted for both indigenous and nonindigenous children.23,26 These studies demonstrated similar reductions in VT-IPD among indigenous (range 43–75%) and nonindigenous adults (range 35–62%) over 15 years of age, although 1 study demonstrated a 6% increase in VT-IPD among indigenous adults 15–29 years of age. In this study, other indigenous adults 30–49 and 50–64 years of age experienced reductions of 54% and 43%, respectively.23
Nine observational studies in this review evaluated the impact of PCV dosing schedules on clinical or radiologically confirmed pneumonia in older children or adults (Table 4). Most studies (n = 7, 78%) were conducted in Europe, North America or Australia; the remaining 2 studies were from South Africa32 and Taiwan.35 There were no studies that evaluated indirect pneumonia effects on high-risk populations. Additionally, no studies directly compared various dosing schedules on indirect populations and no RCTs have evaluated the impact of PCV on pneumonia in unvaccinated populations.
Of the observational studies, 2 studies using 2+138 and 3+034 schedules showed almost no impact on clinical or radiologically confirmed pneumonia (Table 4). Of 5 studies using a 3+1 schedule,11,33,35,37,39 3 showed any impact on pneumonia (Table 4). The study conducted in Taiwan35 found significant reductions in pneumonia only in adults ≥65 years of age, although the authors noted an increase in use of PPV23 among this population during the study period.
This analysis also found 2 case-control studies evaluating PCV impact on pneumonia in unvaccinated populations (Table 5). One study, conducted in South Africa, evaluated the impact of a 3+0 schedule on adults residing with children enrolled in an RCT for PCV9.32 This study found no impact against pneumonia in adults during the clinical trial. The authors noted possible reasons for a lack of impact, including a large burden of HIV among adults in South Africa, timing of doses given in the infant schedule, the lack of a booster dose and <20% coverage in <5 year olds in the community during the trial. Another case-control study conducted in the United States after implementation of PCV7 into the national immunization program showed an 80% reduction in the odds of getting bacteremic pneumococcal pneumonia in adults that resided with a vaccinated child.36
Our review identified a substantial body of research evaluating whether PCV use in young children leads to indirect effects in other age groups, although there are more data supporting some schedules than others. Most of the data were from studies evaluating 2 or 3 primary dose schedules with a booster dose (2+1, 3+1 or 3+PPV23), and among these, studies evaluating a 3+1 dosing schedule were most common. While studies have evaluated pneumonia, VT-NP carriage and VT-IPD, the demonstration of indirect effects was most consistent across studies and for all schedules for VT-IPD.
Because the first countries to introduce PCV used a 3+1 schedule, most of the available literature on indirect effects is for that schedule. The weight of evidence suggests that the use of a 3+1 schedule as part of a routine vaccination program for all infants will result in reduction of carriage and disease in age groups not targeted to receive PCV. Of 12 studies that we identified evaluating the 3+1 schedule for VT-IPD, only 2 showed no evidence of reductions in VT-IPD in unimmunized age groups; both took place in countries without catch-up campaigns and vaccine coverage in the population may have been insufficient to demonstrate indirect effects.11,27 VT-NP carriage studies have also shown indirect effects with 3+1 schedules. The impact on VT-NP carriage was observed in high-risk populations; no NP carriage studies with indirect effects were conducted in general populations. Studies of syndromic pneumonia only showed an impact with 3+1 schedules. Among 6 studies evaluating the 3+1 schedule, only 2, from Spain11 and the United States,37 observed increases in overall trends of pneumonia (pneumococcal, clinical and radiologically confirmed), with authors of both studies speculating that the overall increases were due to increases in nonvaccine serotype disease, although other secular trends could have contributed.
A smaller but growing number of studies have examined 3-dose (2+1 and 3+0) schedules. Most policy makers recently adopting PCV have used 1 of these schedules and the World Health Organization recently updated their recommendation for PCV to be used on either of these 3-dose schedules.47 Our review did not find sufficient data to directly compare these 2 schedules or to make conclusions regarding the impact of these schedules on VT-NP carriage or syndromic pneumonia; statistically significant indirect effects for pneumonia and VT-NP carriage using 2+1 and 3+0 schedules were not observed in any of the 6 studies of these outcomes identified by our review, although many of these studies were conducted early in the immunization programs or evaluated nonspecific endpoints. Despite these limitations, both 3-dose schedules appear to have indirect effects on VT-IPD when introduced nationally. Substantial reductions in VT-IPD were observed among young adult groups in 5 European countries using a 2+1 national immunization schedule.14–16,22,24,30 In countries with catch-up campaigns, this reduction was observed as early as 1 year after vaccine introduction. Two studies evaluated 3+0 schedules for indirect effects on VT-IPD and both found significant reductions. One 3+0 study in Australia did find 3–11% reductions in pneumonia; however, these findings were only borderline significant.34 Additionally, a 3+PPV23 schedule in Australia showed a decrease in VT-NP carriage among older children but not among adults.10 However, other studies suggest that PPV23 boosters do not affect VT-carriage,48 and thus a 3+PPV23 schedule likely approximates a 3+0 schedule in terms of benefits against VT-carriage.
This review also found studies of indirect effects of PCV on high-risk populations, including 9 studies evaluating PCV on either VT-NP carriage9,10,42,43 or VT-IPD13,17,18,23,28,31; no studies evaluated pneumonia and all used 3+1 or 3+PPV23 schedules. Seven studies focused on the impact of PCV on indigenous populations, including Australian Indigenous, Alaskan Native and American Indian populations, and 2 focused on HIV-infected populations. Despite these varying populations, the findings were consistent. All studies noted reductions in disease in older children and adults, suggesting indirect impact of PCV on high-risk populations. These observations may be of relevance to countries with a high burden of HIV or vulnerable populations at higher risk of pneumococcal disease.
While the strength of this analysis is the diversity of settings and study designs included, both for high-risk and nonhigh-risk populations, there are some limitations to our analysis. The heterogeneity of the data did not allow for direct comparisons among schedules and since many factors contribute to the indirect impact of a vaccine schedule, this analysis was unable to fully address the wide variability in study settings and factors that may contribute to the relative impact of PCV schedules (eg, vaccine coverage, presence of a catch up campaign, proportion of the population under 5 years of age, HIV prevalence). Additionally, few data points exist for most of the outcomes we evaluated. Only 1 study directly compared impact among dosing schedules; this VT-NP study from the Netherlands showed no impact of either a 2+0 or a 2+1 schedule on NP carriage in older siblings and parents of vaccinated and unvaccinated children participating in an individual RCT. This study was the only study to evaluate a 2+0 schedule.44,45 Furthermore, some of the studies presented here were small and/or were substudies of clinical trials and therefore may not accurately represent the herd protection of vaccine introduction in a broad population. Many of the studies took place over relatively short periods; since full realization of herd effects in a population may take years,1 study periods of just a few years likely underestimate the measured herd effects in some studies. As PCV introductions in lower- and middle-income countries have only recently occurred,49 almost all data on impact from routine use came from high-income, early introducing countries with more mature immunization programs, which may be more likely to show indirect effects; however, a number of studies are ongoing and data will likely be available soon on the impact of routine use of PCV on unvaccinated older children and adults in lower- and middle-income settings.
The findings of our review suggest to policy makers that, should they adopt either a 3- or 4-dose PCV schedule, indirect effects are likely to add to the overall benefits seen from their program. The evidence to date is strong for the 3+1 schedule and is growing for the 3-dose schedules (2+1 and 3+0). More data to support evidence of herd effects from countries using either the 2+1 or 3+0 schedule would be useful, in particular for the outcomes of VT-NP carriage and pneumonia, from developing country settings where transmission may be more intense and across a wider age range than in high-income populations and for the new generation of conjugate vaccines (PCV10 and PCV13). Because studies of PCV effect on NP carriage in vaccinated children show that 3- and 4-dose schedules reduce colonization,4 we anticipate that with time and more study, vaccination of infants using all of these schedules will be found to prevent a variety of disease syndromes and colonization in unvaccinated age groups. For policy makers trying to determine the best schedule to adopt for their national PCV program, the evidence summarized here on indirect effects should provide an adjunct to data on the direct benefits of various PCV schedules for infants and to programmatic and epidemiologic factors specific to their situation that would drive their decisions on PCV use.
The authors gratefully acknowledge the tremendous support for abstracting data 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; Bethany Baer, Subash Chandir, Stephanie Davis, Sylvia Kauffman, Min Joo Kwak, Paulami Naik and Meena Ramakrishnan from The Johns Hopkins Bloomberg School of Public Health and T. Scott Johnson from Biostatistics Consulting.
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