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

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 ug/mL), but varied by serotype, lowest for serotype 3-PCV20 (0.84 ug/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.