The impact of vaccine products, schedules and geographic regions on immunogenicity of pneumococcal vaccines in children under 2 years old: a systematic review and meta-analysis

Summary Background Pneumococcal conjugate vaccines (PCVs) cover only a proportion of disease-causing serotypes. In some settings, population-level introduction of PCVs has resulted in an increase in “non-vaccine” serotype incidence. Higher-valency PCVs were developed to address shifting disease-causing serotypes. We aim to systematically define the trends in vaccine immunogenicity and likely protection over time. Methods We conducted a systematic review and meta-analysis of studies published to Jan 7, 2025, reporting immunoglobulin G (IgG) responses after PCV vaccination in healthy children <2 years. Outcomes were serotype-specific IgG geometric mean concentration (GMC) and seroresponse rate. We performed random-effects meta-analyses using log-transformed GMCs and logit-transformed seroresponse rates to generate pooled estimates by vaccine product, dosing schedule, and World Health Organization (WHO) region. This study was registered with PROSPERO (CRD42024484824). Findings We included 250 articles from 138 study groups involving 244 study arms. Pooled IgG GMCs for vaccine-included serotypes post-childhood-schedule exceeded the WHO-defined protective threshold (0·35 μg/mL), but varied by serotype, lowest for serotype 3-PCV20 (0·84 μg/mL; 95% confidence interval: 0·60–1·17). Post-childhood-schedule seroresponse rates were >95% for all serotypes except serotype 3 (84–92%). A general “downward trend” in IgG GMCs was observed with the increasing vaccine valency. IgG responses increased with the number of primary doses, and were further enhanced by a booster, although magnitude varied by serotype and vaccine. IgG responses post 1-primary dose were low, whereas GMCs post 2- or 3-primary doses exceeded protective thresholds for most serotypes. Booster-containing schedules (3+1, 2+1, 1+1) generally elicited higher post-childhood-schedule IgG response than primary-only schedule (3+0). We observed substantial regional variation of post-childhood-schedule serotype-specific IgG GMCs, with highest GMCs in the Western Pacific Region. Interpretation Vaccine immunogenicity varied by serotype, vaccine product, schedule and WHO region, and should be carefully considered when evaluating potential vaccination programs. Funding PhD Scholarship; Australian Department of Foreign Affairs and Trade. Research in context Evidence before this study We implemented a targeted literature review strategy to identify prior evidence in PubMed on August 14, 2023, without time and language restrictions, using the following search strategies: ((streptococcus pneumoniae[Title]) OR (pneumococc*[Title]) AND (immun*[Title] OR antibod*[Title]) AND (review[Filter])). We identified six systematic reviews quantitatively evaluating the serotype-specific immune responses following pneumococcal conjugate vaccine (PCV) in infants. All reviews focused on PCV7, PCV10-GSK, and PCV13; none included the newer higher-valency PCVs (PCV15, PCV20) or the novel PCV10-SII. Two early reviews (2011) compared 2-dose versus 3-dose primary series in randomized clinical trials (RCTs), reporting differences in seroresponse rates — greatest for serotypes 6B and 23F — without accounting for specific vaccine products. Two reviews in 2014 further explored the impact of dosing schedules, vaccine product, and region on immune responses, but only a subset of vaccine-included serotypes was analysed. A 2020 review investigated regional variation in post-primary responses but was restricted to RCTs and did not assess post-booster immune responses. A 2023 review of head-to-head RCTs in infants comparing PCV7, PCV10-GSK and PCV13 found that 1-month post-primary serotype-specific IgG geometric mean ratios favoured PCV7 over either PCV13 or PCV10 for serotypes 4, 6B, 9V, 14, and 23F. Added value of this study PCV15 and PCV20 were developed in response to changes in patterns of disease-causing serotypes, whereas PCV10-SII was designed for developing countries with distinct serotype distribution. To date, however, no systematic review has synthesised all available PCV data and compared the immunogenicity of newer vaccines relative to earlier ones. As immunogenicity remains the cornerstone of vaccination recommendations in the absence of representative effectiveness studies, our study quantifies and compares immune responses to five widely used PCVs across alternative dosing regimens, populations, and epidemiological contexts. Implications of all the available evidence Vaccine immunogenicity varied by serotype, vaccine product, schedule and World Health Organization (WHO) region. Downward trend of serotype-specific IgG response was generally observed with increasing vaccine valency for most serotypes, indicating the importance of balancing vaccine serotype coverage and the magnitude of immune response for sustained population protection. This evidence should be considered when evaluating potential vaccination programs.

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