CONTEXT. Pneumococcal conjugate bacterial vaccines that are able to prevent invasive disease and mucosal infections have been developed.
OBJECTIVE. A meta-analysis of published data from trials on pneumococcal conjugate vaccine was performed to determine the efficacy in reducing the incidence of invasive disease caused by Streptococcus pneumoniae, pneumonia, and acute otitis media in healthy infants younger than 24 months.
METHODS. A systematic search of the literature was conducted. Controlled clinical trials had to compare the protective efficacy of the pneumococcal conjugate vaccine in reducing the incidence of invasive disease caused by S pneumoniae, pneumonia, and acute otitis media in healthy infants with placebo or control vaccines. Information was extracted by using a standardized protocol.
RESULTS. The efficacy of pneumococcal conjugate vaccine in the reduction of invasive pneumococcal disease was 89% involving vaccine serotypes in both the intention-to-treat and per-protocol analyses and ranged from 63% to 74% for all serotypes. The efficacy to prevent acute otitis media sustained by vaccine serotypes was 55% in the intention-to-treat and 57% in the per-protocol analyses, whereas it was 29% to prevent otitis involving all serotypes in the per-protocol analysis. Finally, in the intention-to-treat and per-protocol analyses, the efficacy to prevent clinical pneumonia was 6% and 7%, respectively, whereas for the prevention of radiograph-confirmed pneumonia it was 29% and 32%, respectively.
CONCLUSIONS. The pneumococcal conjugate vaccine produces a significant effect regarding prevention of invasive pneumococcal disease. Results on prevention of otitis or pneumonia have been less striking, but considering the high burden of these diseases in infants, even a low efficacy has potential for tremendous impact on the health of infants in developing and industrialized countries.
- acute otitis media
- invasive pneumococcal disease
- pneumococcal conjugate vaccine
Streptococcus pneumoniae is one of the major bacterial pathogens responsible for a wide spectrum of invasive disease and acute respiratory tract infections such as community-acquired pneumonia, acute otitis media, bacteremia, and meningitis, especially in children younger than 2 years in both developing and industrialized countries.1 The high morbidity and mortality rates resulting from these diseases2 and the increase of multidrug-resistant pneumococcal strains3,4 have emphasized the urgent need for introduction of effective vaccines against diseases caused by S pneumoniae.5–7
Pneumococcal conjugate bacterial vaccines that are able to prevent invasive disease and mucosal infections have been developed. In the United States, the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention and the American Academy of Pediatrics have recommended routine administration of a heptavalent pneumococcal conjugate vaccine (PCV-7), which contains the 7 serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F) that are the most prevalent in causing invasive diseases among young children, concurrently with other childhood immunizations for all infants younger than 2 years as well for older children (aged 2–5 years) at greater risk of developing invasive pneumococcal disease (IPD).8–10
Since the current PCV-7 was introduced in many industrialized countries, several studies have been performed on populations of infants and toddlers more representative of those for whom the vaccine is recommended in the Western world. These studies have evaluated the immunogenicity, reactogenicity, safety, and efficacy of this vaccine in preventing IPD, pneumonia, and acute otitis media and its complications in healthy children. However, there is still discussion about the efficacy of PCV-7, especially for the prevention of acute otitis media. Moreover, vaccines prepared with a higher number of serotypes (ie, 9 or 11) have been produced and evaluated for their efficacy toward the same outcomes.
Therefore, we performed a meta-analysis of all available published data from controlled clinical trials of any-valency PCV to determine the protective clinical efficacy in reducing the incidence of IPD, pneumonia, and acute otitis media in healthy infants younger than 24 months.
This study was performed with a prospectively developed protocol that prespecified the research objective, literature-search strategy, study-inclusion criteria, methods of quality assessment, data extraction, and statistical analysis. All subgroup variables were defined before analysis. Reporting of the study's findings was in accordance with the Quality of Reporting of Meta-analyses (QUORUM) conference statement.11
A detailed literature-search strategy was developed to identify published reports of controlled trials that evaluated the protective efficacy of the PCV (any valency) in reducing the incidence of IPD, pneumonia, and acute otitis media in healthy infants younger than 24 months. A systematic bibliographic search of the medical literature between January 2000 and June 2008 was conducted through electronic databases, including the National Library of Medicine (Medline) and Embase. To achieve the maximum sensitivity of the search strategy and identify all trials, the search was performed by exploring and combining the following medical subject headings (MeSH) terms and text words: “respiratory tract infections,” “respiratory infections,” “pneumonia,” “otitis media,” “acute otitis media,” “recurrent otitis media,” “consolidation,” “invasive pneumococcal disease,” “pneumococcal conjugate vaccine,” “pneumococcal vaccine,” “efficacy,” “effectiveness,” “effect,” “effects,” “child,” “children,” “infant,” “infants,” “toddler,” and “toddlers.” Titles and abstracts of trials generated by electronic search were reviewed, and hard copies of potentially suitable reports were retrieved for detailed assessment. In an effort to identify other possibly undetected published articles, a systematic manual search of bibliographies of every relevant trial retrieved from the electronic search and from review articles was performed.
To be eligible for inclusion in the meta-analysis, controlled clinical trials had to compare the protective efficacy of the PCV (any valency) in reducing the incidence of IPD, pneumonia, and acute otitis media in healthy infants younger than 24 months with placebo or control vaccines, irrespective of number of events and duration of follow-up. The contents of all potentially relevant abstracts or full-text articles identified through the literature search were reviewed independently by 2 investigators in duplicate to determine if they met eligibility criteria for inclusion. When discrepancies between investigators occurred for inclusion or exclusion, additional evaluation of the study was conducted, and disagreements were resolved by consensus. Studies were included in the meta-analysis if they met all of the following prespecified criteria: (1) the study was a randomized, controlled trial; (2) healthy infants younger than 24 months were enrolled; (3) the intervention consisted of a primary series of immunizations (3–4 doses) of PCV (any valency) given before 12 months of age and a control group with placebo or with other vaccines; (4) the study measured at least 1 of the following outcomes, through intention-to-treat (ITT) or per-protocol (PP) analysis, that occurred during the study in the intervention and control groups: (a) number of events of IPD, to include all or specific serotypes; (b) number of events of pneumonia (of unspecified etiology) with or without radiograph confirmation; and (c) number of events of acute otitis media; (5) the study was published in the English language; and (6) the study was published through June 2008. Clinical pneumonia was defined by the treating physician on the basis of an individual appraisal of a physical examination including or not ancillary laboratory data, or as history of cough or breathing difficulty of <14 days' duration, with a raised respiratory rate for age or lower chest-wall indrawing. Acute otitis media was defined as a visually abnormal tympanic membrane (color, position, and/or mobility) suggesting middle-ear effusion, with at least 1 or 2 of the following symptoms or signs of acute infection: fever, earache, irritability, diarrhea, vomiting, acute otorrhea not caused by otitis externa, and other symptoms of respiratory infection. If the same population appeared in more than 1 report and there was a possibility of overlapping data, the most recent report and/or the one with the largest number of observations was used.
Two investigators independently assessed the quality of each individual trial included in the meta-analysis. Each trial was read and scored for quality, and all studies had blinded investigators, institutions, country, and journal, thereby reducing the possibility of detection bias. The quality assessment of the trials was performed according to the widely used methods of Chalmers et al12 and Jadad et al.13 A Jadad et al score ranging from 0 to 5 points was assigned to the included trials according to whether the investigators described the study as randomized and double-blind, reported the methods used to randomly assign patients and blind the intervention, and reported the number of withdrawals and dropouts and the reason. Higher scores indicate higher quality in the conduct or reporting of trials. The readers discussed their evaluation, and discrepancies in quality ratings were resolved by consensus between the 2 reviewers. To avoid selection bias, no study was rejected because of these quality criteria.
Two investigators independently assessed articles according to the predetermined eligibility criteria, and information was extracted by using a standardized protocol and a data-collection form that was created for this study. Differences between reviewers' data were resolved through discussion until a consensus was reached. Because agreement was by consensus, no formal methods to assess interobserver agreement were used. We did not contact authors to request additional information. The following information was recorded from each trial: (1) first author's name, year of publication, and geographic setting of the population studied; (2) study design; (3) description of intervention; (4) type of controls; (5) total number and ages of study participants in each treatment group; (6) outcomes data (including the number of IPD cases, to include all or specific serotypes; the number of clinical pneumonia cases [of unspecified etiology] with or without radiograph confirmation; the number of clinical episodes of acute otitis media, of first episode of acute otitis media, of acute otitis media cases caused by S pneumoniae [to include serotypes present in the vaccine], of acute otitis media cases caused by all pneumococcal serotypes, and of recurrent episodes of otitis media and of tympanoplasty); and (7) type of analysis (ITT or PP).
The efficacy of PCV (any valency) was evaluated in several meta-analyses by combining the results regarding the reported number of events caused by vaccine serotypes of IPD, the number of pneumonia cases, and the number of clinical episodes of acute otitis media in infants who received PCV compared with those who received placebo or another vaccine. In every study, the efficacy of PCV on each end point of interest was expressed as 1 minus relative risk (RR) along with the 95% confidence interval (CI). When data on efficacy were not available, the number of events and number of participants or participants/years in the vaccine as well as in the control group was extracted, and RRs and 95% CIs were calculated. The outcome measures were pooled by use of the random-effects model by the method of DerSimonian and Laird,14 with which it is assumed that there is variation between studies and the calculated risk ratio, thus, has a more conservative value. A statistically significant heterogeneity was considered when the P value was <.1 among the results of the included studies. In cases with heterogeneity, a random-effects model was applied, as opposed to a fixed-effects model,15 because it includes both within-study sampling error (variance) and between-study variation in the assessment of the uncertainty (CI) of the results of a meta-analysis. In the absence of significant heterogeneity, overall results led by fixed-effects models were preferred only when they were substantially similar to those emerging from random-effects model meta-analyses.
To explore the reasons for observed heterogeneity, sensitivity analyses were performed by grouping studies that used only the PCV-7. Finally, the presence of publication bias was assessed with a funnel plot for asymmetry, a scatter plot of individual studies that related the magnitude of the treatment effect against a measure of its precision,16 using for formal statistical testing an adjusted rank correlation test.17,18
All P values are 2-sided. Results were considered to be statistically significant at a P value of ≤.05. All statistical analyses were performed with the use of Stata 10 software.19
Figure 1 summarizes the flowchart of studies from identification through final inclusion in the meta-analysis. A total of 370 citations were identified through electronic database searching and scanning reference lists. Of these, 356 abstracts were screened and identified and retrieved potentially relevant studies for further scrutiny. Forty-nine retrieved articles were reviewed for inclusion criteria and data extraction. A total of 9 articles fulfilled all inclusion criteria and were included in the meta-analysis.20–28
Table 1 shows the principal characteristics of the included clinical trials. The trials were undertaken between 2000 and 2008, were all randomized on an individual basis except for 1 study23 that was group-randomized, varied in participant size from 856 to 39 836, all but 1 study provided data on the ITT and PP populations, and the end-point of IPD was assessed in 6 trials, radiograph-confirmed pneumonia of unspecified etiology in 3 trials, clinical pneumonia with or without radiograph confirmation in 2 trials, and acute otitis media in 5 trials. Some of the trials reported 2 outcomes (IPD and acute otitis media; IPD and clinical/radiograph-confirmed pneumonia). One study included HIV-1–negative and –positive infants, and the results regarding those who tested negative were included and pooled,25 and 1 study was performed with a high-risk population (Navajo American Indian children).23,28 All but 3 of the studies used PCV-7: 2 used the 9-valent vaccine25,26 and 1 used the 11-valent vaccine.27
Table 2 lists selected items of the quality-assessment systems used, along with the number of articles that scored “adequate” (ie, completely addressed the issue) on each item. The mean quality scores of the individual studies using the Chalmers et al12 scale ranged from 0.24 to 0.74 (mean: 0.53), for the protocol from 0.19 to 0.79 (mean: 0.54), and for the data analysis and presentation from 0.3 to 0.74 (mean: 0.49). All trials received full credit for description of therapeutic regimens, start and stop dates, CIs of trials end points, and laboratory tests to evaluate the adsorption or pharmacologic effect of the treatment. A few trials reported adequate methods of randomization (33.3%) or correct techniques of allocation concealment, such as assignment via telephone communication by an individual not involved in the actual treatment or treatments randomly precoded by the pharmacy (55.6%) and could be considered double-blinded (55.6%). No trials reported both test statistics and P values. With regard to the Jadad et al13 criteria, the mean score was 3.89 (median: 4), and most trials were classified as double-blinded (88.9%); a few trials addressed adequately the problems of withdrawals or dropouts after randomization (44.4%).
Table 3 shows the overall preventive effect led by the fixed-effects models comparing the reduction in the risk of IPD, otitis, and pneumonia by PCV (any valency) with that by placebo or other vaccines recommended for healthy infants. The estimate of treatment effect on IPD favoring PCV-7 was 89% involving vaccine serotypes in both the ITT (95% CI: 73%–96%) and PP (95% CI: 65%–96%) analyses, whereas the reduction of IPD caused by all serotypes was still significant, although with a lower efficacy, with values of 74% (95% CI: 54%–85%) in the ITT and 63% (95% CI: 4%–85%) in the PP analyses. Additional meta-analyses were performed by pooling data from studies testing the efficacy against IPD of any valency of the PCV compared with that in the control group. The pooled RR estimate was significant for the vaccine versus control either for vaccine serotypes or all serotypes in both the ITT (efficacy: 80% [95% CI: 66%–88%] vs 62% [95% CI: 33%–78%], respectively) and PP (efficacy: 82% [95% CI: 67%–90%] vs 53% [95% CI: 28%–69%], respectively) analyses, although the efficacy was always lower than that observed with the PCV-7.
The efficacy of PCV-7 against acute and recurrent otitis was less striking, and several specific outcomes could be investigated. The efficacy to prevent acute otitis sustained by vaccine serotypes was 55% (95% CI: 43%–64%) in the ITT and 57% (95% CI: 48%–64%) in the PP analyses, whereas it was substantially lower, although still significant, with a value of 29% (95% CI: 20%–38%) to prevent otitis involving all serotypes in the PP analysis. Even lower efficacy (6%) resulted from the pooled analysis of both the ITT (95% CI: 4%–9%) and PP (95% CI: 4%–9%) analyses regarding prevention of all acute otitis episodes, whereas the prevention of first episode of otitis was more effective in the PP analysis, with a value of 51% (95% CI: 42%–59%). Moreover, in the meta-analyses performed to investigate the efficacy of PCV-7 in the prevention of recurrent otitis, a significant efficacy of 9% for the ITT (95% CI: 4%–14%) and 10% (95% CI: 4%–15%) for the PP analyses was observed, whereas for the prevention of tube placement, the efficacy was 20% in both the ITT and PP analyses. The results of the meta-analyses conducted by pooling data from studies with PCV-7 and PCV-11 with regards to acute otitis media and recurrent otitis were not substantially changed, but for all episodes, no significant efficacy was observed.
The protective efficacy of the PCV in reducing the incidence of pneumonia was established by pooling data from trials testing the 7-valency and 9-valency vaccines. The results showed that in the ITT and PP analyses, the efficacy to prevent clinical pneumonia was 6% (95% CI: 2%–10%) and 7% (95% CI: 2%–11%), whereas for the prevention of radiograph-confirmed pneumonia it was 29% (95% CI: 22%–35%) and 32% (95% CI: 24%–39%), respectively.
Funnel plots did not show any significant asymmetry in studies that explored the effectiveness of PCV in the prevention of IPD and acute otitis media caused by vaccine serotypes, thus reducing the potential for publication bias.
This meta-analysis provides an up-to-date summary of average effect of all the relevant randomized, controlled trials that have assessed the efficacy of the PCV (any valency) in reducing the incidence of IPD caused by S pneumoniae, pneumonia, and clinical episodes of acute otitis media in healthy infants and reliable guidance for clinical practice and future research. It demonstrated that the PCV-7 was highly effective in the prevention of IPD serotypes included in the vaccine (89%) and by all serotypes (63%–74%). This may be partly because of the high incidence of circulating S pneumoniae that belong to serotypes in the vaccine and/or to cross reactions of antibodies produced against the vaccine with other serotypes. In the analysis including all trials regardless of the type of vaccine used (any valency), the results showed a lower efficacy ranging from 80% to 82% against vaccine serotypes and from 53% to 62% for all serotypes. Therefore, although the efficacy of different vaccine preparation could not formally be compared by pooling data from “head-to-head” trials, we may indirectly suggest a lower efficacy of PCV-9 compared with PCV-7. However, the 9-valent studies occurred in Africa, where the incidence of disease is greater and the age at which children contract the disease is different, the range of infecting serotypes is broader, the population is potentially sicker (with poor nutritional status and more comorbidities, with higher infection pressure, including HIV, diarrhea, and measles), and serotype-specific protection even for the PCV-7 is lower than that in the developed country studies. A previous meta-analysis was performed without restrictions to type of vaccines involved, and data were pooled on efficacy toward IPD caused by serotypes of S pneumoniae not included in the vaccine or cross-reacting with those included.29 Therefore, our meta-analysis provided data specifically concerning efficacy of PCV-7 that were not available in the previous one, and the meta-analysis on all vaccines comprised also data from a PCV-9 trial,26 which was not available at that time. In another meta-analysis that involved 3 of the trials included in ours,20,23,26 the minimum protective antibody concentration that correlates with clinical protection from IPD after immunization with PCV was derived.30
In this meta-analysis, the results regarding the several outcomes involving prevention of acute otitis media showed a modest, although significant, efficacy toward prevention of all episodes of acute otitis media (<10%). This was consistent in all studies involving the PCV-7, whereas a recent trial on the efficacy of PCV-11 yielded a considerably higher estimate (34%); indeed, in the meta-analysis including all types of vaccines, a significant heterogeneity was detected. There were a number of methodologic differences among these studies, including case definitions, case detection, time periods, and sites of investigation. A recent study verified whether the differences in efficacy could depend on the case definition used and reanalyzed the data of a trial21 by using a definition by Prymula et al.27 However, the efficacy did not vary significantly, and it was concluded that differences may be related to varying epidemiology of S pneumoniae and its serotypes and/or different case-detection methods.31 It should be noted that the inclusion in the meta-analyses of the study by Prymula et al27 always strikingly influenced the overall results. This is of concern, because the vaccine used was formulated by using the H influenzae–derived protein D as a carrier protein for pneumococcal polysaccharides; therefore, it protected also against acute otitis media caused by nontypeable H influenzae.
Another meta-analysis addressed the effect of PCV on acute otitis media32 by pooling studies that evaluated conjugate and polysaccharide vaccines on infants, toddlers, and children in day care centers, and only 2 of the studies included20,21 were also pooled in this meta-analysis. Therefore, the comparison is difficult, although the results on the prevention of all episodes of otitis were very similar to ours, regardless of the differences in the inclusion criteria used.
The findings on the effectiveness toward prevention of pneumonia must be interpreted within the context of certain limitations. Only 3 published randomized, controlled trials have investigated this outcome, and it never was the primary outcome. To offset this limitation, however, our analysis was performed by pooling the data, whenever possible, from all 3 trials. Moreover, despite results of single trials being very similar, 1 of them did not follow the World Health Organization's standardized criteria for the radiologic diagnosis of pneumonia in children.22 However, the data were recently reanalyzed according to World Health Organization criteria, and the results were not very dissimilar from those of the original one.33 To assess whether these changes would have an impact on the meta-analysis, these data were pooled, but results were almost identical, demonstrating the robustness of analysis and that the diagnostic criteria seem to have had a small impact on overall results. A previous meta-analysis,29 on the prevention of radiograph-confirmed pneumonia pooling from 2 studies,22,25 demonstrated a 22% efficacy in the ITT and 24% in the PP analyses. In our meta-analysis, which includes also data from Cutts et al,26 the efficacy was higher in both the ITT (29%) and PP (32%) analyses.
The results indicate that there is a reasonable amount of evidence to suggest that PCV produces a significant greater effect regarding prevention of IPD than did placebo or another vaccine and confirmed the current guidelines. Results on prevention of otitis or pneumonia are less striking, but considering the high burden of these diseases in infants, even a low efficacy has potential for tremendous impact on the health of infants in developing and industrialized countries. Indeed, a reduction of all-cause pneumonia hospitalizations among US children aged <24 months has been documented, and it has been associated to the introduction of routine PCV-7 use.34
A key finding from this meta-analysis is that the studies included differed in patient population and methodologies, rendering comparison difficult even with current meta-analysis techniques. Many different comparisons were used, and many different outcomes were reported, particularly on acute and recurrent otitis media, with considerable variability in the definitions used. One study included pediatric patients whose immune function may have differed from that of adults with HIV for a number of years,27 although removing this study from the analysis did not significantly affect the results. It is sometimes possible, when sources of variability are clearly identified, to conduct secondary analyses to determine the extent to which that covariate is contributing to the overall heterogeneity. In this article, however, the sources of variability were not reported with enough consistency to conduct such analysis, so subanalyses were not conducted to determine if 1 of these factors was influencing the results. It should be pointed out, however, that in all meta-analyses involving PCV-7, no significant heterogeneity was revealed regardless of the outcome investigated, whereas significant heterogeneity was observed in many of those involving any-valency vaccine, and this was the only source of heterogeneity.
Our meta-analysis has highlighted that the methodologic quality of the studies was variable, with several scoring <5 on the Jadad et al13 scale, particularly the first studies, whereas more recent trials gained full scores. However, there is still debate on the opportunity of using quality scores as an inclusion criterion in meta-analysis, and we pooled all studies regardless of their score. Sometimes subgroup analysis is performed according to quality score, but because studies were few, we preferred to avoid such analysis. This choice was supported by the fact that statistical heterogeneity can also be caused by defects of methodologic quality, but that was not our case, because in the meta-analysis restricted to PCV-7, no statistical heterogeneity was found and, as already stated, the only source of heterogeneity was related to vaccine valency.
This meta-analysis has several strengths and potential limitations. The strengths include the comprehensive literature search that improved the likelihood of identifying all the relevant published studies. Duplicate extraction of data reduced the potential for bias in this component of the synthesis process. By limiting this review only to randomized prospective trials, we ensured that the included studies would have reduced likelihood of systematic bias and, therefore, have high internal validity. The large number of patients provided an adequate statistical power to address the study questions, as reflected by the narrow CIs for RRs, whereas most individual trials were unable to do so because of their small sample sizes. The results are robust and consistent, as shown by the extensive search for potential bias by use of publication-bias analysis.
Meta-analysis also has inherent potential limitations. Only published trials have been included, and they have been judged according to what is recorded in the publication. The results might have been affected by publication bias, because positive studies are more likely than negative ones to be published, and so it is possible that other trials have been conducted and their results never published. However, because PCV is a relatively new vaccine, it is improbable that other negative studies exist. Moreover, results from the tests do not suggest publication bias as a main issue in this meta-analysis. We purposefully did not contact authors of the articles included in this meta-analysis, because we wished to assess the evidence as it stands in the public domain. The search was limited to articles published in the English language, so the possibility of quality studies in other languages does exist. Finally, the findings are affected by the limitations of the individual trials included.
Lessons about the reporting of studies also emerged from this meta-analysis. First, accurate, detailed descriptions of the source of patients are required in all reports so that readers can judge which studies are duplicate from a single sample and which are true replication from a new sample. When multiple reports are justified, they should be clearly cross-referenced. Second, many researchers describe their samples as consecutive series but provide no information on how many patients were excluded or refused to participate. Therefore, readers cannot judge whether samples are truly representative or whether an apparently consecutive series is merely a convenience sample. These problems could be limited if journals refused to publish articles that do not specify the dates of data collection or give the absolute number of patients who were potentially available for recruitment.
The findings of this meta-analysis offer a global estimate of overall response to PCV in healthy infants; given the incidence of S pneumoniae infection in developing and industrialized countries, accurate assessment of the probability of response to PCV is critical.
This study was supported by a research grant from the Second University of Naples (Naples, Italy). The funding source had no role in study design, data collection, data analysis, data interpretation, or writing of the report. All authors had access to all the data. Prof Angelillo had final responsibility for the decision to submit the manuscript for publication.
We express our appreciation to Prof. Pietro Crovari (Department of Health Sciences, University of Genoa, Genoa, Italy) for the thoughtful comments provided in the preparation of the manuscript.
- Accepted February 10, 2009.
- Address correspondence to Italo F. Angelillo, DDS, MPH, Second University of Naples, Department of Public, Clinical, and Preventive Medicine, Via Luciano Armanni, 5, 80138 Naples, Italy. E-mail:
Financial Disclosure: Prof Angelillo attended a consensus conference (Rome, Italy; November 26–27, 2007) on the pneumococcal vaccination in newborns as a speaker; the other authors have no financial relationships relevant to this article to disclose.
This work was presented in part as poster 343 at the 2nd Global Congress on Vaccine; December 7–9, 2008; Boston, MA.
- ↵O'Brien KL, Santosham M. Potential impact of conjugate pneumococcal vaccines on paediatric pneumococcal diseases. Am J Epidemiol.2004;159 (7):634– 644
- American Academy of Pediatrics, Committee on Infectious Diseases. Policy statement: recommendations for the prevention of pneumococcal infections, including the use of pneumococcal conjugate vaccine (Prevnar), pneumococcal polysaccharide vaccine, and antibiotic prophylaxis. Pediatrics.2000;106 (2 pt 1):362– 366
- ↵Centers for Disease Control and Prevention. Updated recommendation from the Advisory Committee on Immunization Practices (ACIP) for use of 7-valent pneumococcal conjugate vaccine (PCV7) in children aged 24–59 months who are not completely vaccinated. MMWR Morb Mortal Wkly Rep.2008;57 (13):343– 344
- ↵Sterne JA, Egger M, Smith GD. Systematic reviews in health care: investigating and dealing with publication bias and other biases in meta-analysis. BMJ.2001;323 (7304):101– 105
- ↵Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ.1997;315 (7109):629– 634
- ↵Stata Corp. 2007. Stata Statistical Software [computer program]. Release 10. College Station, TX: Stata Corp LP
- ↵Kilpi T, Åhman H, Jokinen J, et al. Protective efficacy of a second pneumococcal conjugate vaccine against pneumococcal acute otitis media in infants and children: randomized, controlled trial of a 7-valent pneumococcal polysaccharide-meningococcal outer membrane protein complex conjugate vaccine in 1666 children. Clin Infect Dis.2003;37 (9):1155– 1164
- ↵Cutts FT, Zaman SMA, Enwere G, et al. Efficacy of nine-valent pneumococcal conjugate vaccine against pneumonia and invasive pneumococcal disease in the Gambia: randomised, double-blind, placebo-controlled trial [published correction appears in Lancet. 2005;366(9479):28]. Lancet.2005;365 (9465):1139– 1146
- ↵Prymula R, Peeters P, Chrobok V, et al. Pneumococcal capsular polysaccharides conjugated to protein D for prevention of acute otitis media caused by both Streptococcus pneumoniae and non-typable Haemophilus influenzae: a randomised double-blind efficacy study. Lancet.2006;367 (9512):740– 748
- ↵Lucero MG, Dulalia VE, Parreno RN, et al. Pneumococcal conjugate vaccines 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;(4) :CD004977
- ↵Straetemans M, Sanders EAM, Veenhoven RH, Schilder AGM, Damoiseaux RAMJ, Zielhuis GA. Pneumococcal vaccines for preventing otitis media. Cochrane Database Syst Rev.2004;(1) :CD001480
- ↵Hansen J, Black S, Shinefield H, et al. Effectiveness of heptavalent pneumococcal 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 (9):779– 781
- Copyright © 2009 by the American Academy of Pediatrics