Globally, 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 annually.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 Prevention 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 immunization 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 makers 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.
This analysis is part of a larger project describing the impact of PCV dosing schedules on invasive pneumococcal disease (IPD), immunogenicity, nasopharyngeal carriage, pneumonia and indirect effects.11–14 Details on the literature search terms and methods used in this systematic review are described elsewhere (see Methods Appendix15). 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, nasopharyngeal colonization, IPD, 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 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 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 relevant data for this project. Details on the search methods are provided in the Methods Appendix.15
Citations recovered through the literature search went through several stages of independent review to determine their eligibility, as described (see Methods Appendix15). 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 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: 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. Additional data abstracted for pneumonia included specific endpoints, case definitions, 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 pneumonia, pneumococcal pneumonia (including bacteremic pneumonia) and empyema.
Inclusion and Exclusion Criteria
We included data published during or after 1994 from clinical trials, surveillance database analyses and observational studies 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% vaccination 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 incidence 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 completion 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).
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 reporting 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 postintroduction incidence rate over a period of years was provided, we calculated 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).
Descriptive Characteristics of Included Studies
Of 12,980 citations reviewed, we identified 106 pneumonia outcome citations that met initial criteria for further evaluation (Fig. 1). After further review, 81 citations met inclusion criteria 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 published during or after 2004. Most citations were from North America (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 PCV1057 (Table 1).
Studies Directly Comparing Dosing Schedules (n = 2 Studies)
We identified only 2 studies, both observational, that compared the effectiveness of different PCV dosing schedules within the study itself. One study directly evaluated the impact of 2 versus 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 respiratory tract infections and found that children who received 3 primary PCV doses had fewer ambulatory visits and hospitalizations 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 difference 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 schedules, a retrospective cohort conducted among Australian Indigenous infants,53 evaluated risk of clinical and radiologically confirmed 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 trial35 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 radiologically 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 parents were not blinded to the intervention; these design limitations 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 pneumococcal pneumonia and 2 on empyema (Table 3). All studies evaluating the effectiveness of 2+1 PCV against clinical and radiologically confirmed pneumonia showed evidence of significant disease reduction after PCV introduction into the national immunization program. Results of the limited number of studies on pneumococcal 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 pneumococcal pneumonia after PCV introduction,30 while the other from Belgium 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 introduction 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) evaluated a 3+0 schedule and 23 (24 citations) evaluated a 3+1 schedule on various pneumonia disease endpoints. Of the 3+0 schedule studies, we identified 3 RCTs22,23,25,26 from various regions (Table 2) and 2 observational studies, both from Australia45,49 (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 observational studies showed significant reductions in disease burden following 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 trials29,31,38,57 and 20 observational studies that evaluated the impact of a 3+1 schedule on pneumonia endpoints (8 on clinical pneumonia,19,21,27,36,37,43,48,51 4 on radiologically confirmed pneumonia,40,43,52,55 7 on empyema24,32,33,39,44,48,51 and 12 on pneumococcal pneumonia17,19,21,33,37,41,42,44,46–48,51) (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 significance36,43 or found significant reductions only in children <2 years of age19,37,48 (Tables 2 and 5). Of the 7 observational studies 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 not found in PCV7 or other pathogens such as multi-drug resistant 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 States41 that noted a PCV7 shortage limiting vaccine availability. Two of the 4 studies with increases in pneumococcal pneumonia 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 populations 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 clinical pneumonia in neonates.18 We identified 1 RCT56 and 2 observational studies20,52 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%); however, 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 empyema in a US Alaskan Native pediatric population, found no change in empyema-associated hospitalizations following PCV introduction 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.
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 pneumonia prevention in a routine immunization setting. Overall, half (21 of 42) of the studies in our review provided evidence for significant 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 immunization schedules against pneumonia was difficult as only 2 studies directly compared different schedules within the same study. Pelton et al.28 directly compared 2 versus 3 primary doses in an observational study of an immature immunization program and found that 3 primary doses were superior to 2 doses in preventing hospitalizations 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 primary 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 serotypes with either nonvaccine serotypes or other respiratory pathogens carried in the nasopharynx may have increased clinical pneumonias 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 according to a specific dosing schedule. Findings from individual studies 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 findings support the use of PCV in effectively reducing disease burden and complement a recent systematic review that evaluated the subset 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 schedules on pneumonia. Studies using more narrow and specific endpoints 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 pneumococcus. 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 studies have assessed the impact of specificity of disease endpoints by retrospectively applying more specific case definitions and re-evaluating 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 laboratory or clinical diagnostics, population access to care, limited surveillance area) and confounding factors (ie, high burden of underlying 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 definitions were more often used in the setting of controlled trials while observational studies were more likely to use nonspecific case definitions. 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 diagnosis, 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 confirmed pneumonia and 7/16 (44%) pneumococcal pneumonia. It is 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 different 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 limitation in geographical representation in settings of routine immunization, 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 schedules 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 regarding 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 Furthermore, 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 vaccines 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 evidence on which to formulate optimal dosing policies and achieve the greatest disease reductions for the doses administered.
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.
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