Pneumococcal serotypes missing prespecified efficacy threshold in immunogenicity trials: real-world evidence from national immunization programs

The 13-valent (PCV13) and 10-valent (PCV10) pneumococcal conjugate vaccines missed non-inferiority for certain 7-valent (PCV7) serotypes in immunogenicity trials. This study examines the population-level IPD case trends for these serotypes. We identified six countries with national IPD surveillance data that introduced PCV13 (Canada, Germany, Israel, Italy, South Africa, and the United States) and three with PCV10 (Finland, Brazil, and the Netherlands). We extracted country-specific annual IPD case counts for serotypes that met non-inferiority (4, 14, 18C, 19F, 9 V [PCV10 only]) and missed non-inferiority (6B, 23F, 9 V [PCV13 only]) for different age groups (<5 and ≥5 years) for eight years following PCV13/PCV10 introduction. For all ages and countries, IPD cases due to PCV7 serotypes that missed non-inferiority either decreased or remained suppressed following PCV13/PCV10 introduction. Similar trends were found for PCV7 serotypes that met non-inferiority in those <5 years. Paradoxically, cases increased in those ≥5 years in Canada, Italy, and the US, primarily driven by increases in serotypes 4 and 19F disease. Despite missing non-inferiority for serotypes in immunogenicity trials, higher-valent PCVs effectively suppressed these serotypes across all ages. Non-inferiority criteria from immunogenicity trials may not fully predict real-world disease impact after PCV implementation.