We performed a systematic literature review to identify all available data between January 1994 and September 2010 from published and selected unpublished sources on the immunogenicity and direct and indirect effects on NP carriage, IPD and pneumonia of various PCV schedules for healthy children as well as children with underlying medical conditions (eg, sickle cell disease and HIV). We reviewed all data from clinical trials (both randomized controlled trials and other designs), other clinical studies (eg, observational studies) and surveillance database analyses performed in the setting of PCV use. Only studies published in the English language were considered for review because of the low likelihood that such studies had been published in non-English journals.

Specific search terms and choice of databases were developed with the advice of a professional librarian from Johns Hopkins University and used to identify articles (Table 1). To be identified in the search, each article had to include a minimum of one “narrow vaccine term” and one “pneumococcal term.” Terms were listed as Medical Subject Headings (MeSH) or other categories specific to each database. The following 14 electronic databases were used in this analysis:

In addition to the electronic literature search, all abstracts from meetings of the International Symposium on Pneumococci and Pneumococcal Disease (1998–2010) and the Interscience Conference on Antimicrobial Agents and Chemotherapy (1994–2010) were also searched. Additional articles in 2010–2011 included after the end date of the electronic literature search (September 2010), were identified on an ad hoc basis.

We included all data published from January 1994 to September 2010 including any PCV schedule on one or more outcomes of interest (IPD, pneumonia, NP carriage, immunogenicity [antibody concentrations and functional antibody measures]) in children less than 15 years of age targeted to receive vaccine. Fifteen years of age was selected to allow for inclusion of data on catch-up schedules. We also included studies reporting indirect effects (NP colonization, IPD and pneumonia) of PCV on groups not targeted to receive vaccine, including unvaccinated children, older children and adult populations.

Data on licensed or about-to-be licensed products (eg, from Wyeth [now Pfizer, New York, NY] and GlaxoSmithKline, Philadelphia, PA) as well as products that are no longer being pursued (eg, products from Merck and Aventis [now Sanofi Pasteur, Swiftwater, PA]) were included. We included the latter products, because many attributes of dosing and relative immunogenicity may be generalizable across PCV products.

We excluded any studies that focused on vaccine target groups older than 15 years of age or that evaluated pneumococcal polysaccharide vaccine (PPV) in a primary series or as a single dose, although we included studies using PPV as a booster dose. We also excluded studies published before 1994 as these studies are likely to evaluate product formulations that differ too much from licensed products to provide relevant information for our study objectives. Studies with non-analyzable data (eg, from cross-sectional studies that only report data before or after PCV introduction and would not allow for calculating impact), studies focusing on maternal doses of pneumococcal vaccine (PPV or PCV), dose ranging studies and review articles were also excluded.

Two independent reviewers with expertise in pneumococcal disease (J.D.L. and L.C.) screened the titles and abstracts of all references identified by the search strategy to create a master list of potentially relevant references for full-text review. To identify any missing relevant references, the list was then reviewed by senior staff members (C.G.W. and K.O.B.) and a second pass through the original title/abstract list was performed. Abstracts for all references flagged for inclusion were reviewed to determine if the full report was eligible to be included in the analysis. Full-text articles or abstracts (ie, from International Symposium on Pneumococci and Pneumococcal Disease and Interscience Conference on Antimicrobial Agents and Chemotherapeutics) from all eligible references were abstracted for a predetermined set of variables and data recorded directly into a 2003 Microsoft Access (Microsoft Corporation, Redmond, WA) database. This information was used to generate “groups” of reports based on outcome of interest: IPD, pneumonia, immunogenicity and NP carriage.

A full-text review was then performed on all citations (both articles and conference abstracts) within each “group,” and detailed information from the citations was abstracted into a larger standardized database (2007 Microsoft Access). All citations were independently double abstracted for quality control. To guide abstractors in the review of citations, standard operating procedures and data collection forms with standardized variables were developed and reviewers were trained on abstraction methods. All abstractors participated in weekly calls with the project team to troubleshoot issues and discuss progress updates or receive other relevant information.

We defined “study families” as abstracts or articles generated from a single protocol, population, or surveillance system or other data collection system. For each study family, we identified a single “primary study” or main publication, which was identified through de-duplication of the data following the full double abstraction of each citation. For all outcomes, we identified “primary data” since data were sometimes found across >1 publication. Abstracts and articles containing supplemental data or substudies were considered secondary citations. All abstractions were then adjudicated and data cleaned to create an analyzable dataset.

We summarized the data in descriptive analyses to provide an overview of the amount and variability of the data by schedules and outcomes. All analyses were conducted using SAS 9.2 and 9.3 (SAS Institute Inc., Cary, NC). Outcome-specific inclusion criteria and analyses are described in each outcome-specific publication.