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Background Pneumococcal conjugate vaccines (PCVs) have significantly reduced pneumococcal disease, but disease from non-PCV serotypes remains. Safety, tolerability, and immunogenicity of a 20-valent PCV (PCV20) were evaluated. Methods This pivotal phase 3, randomized, double-blind study enrolled adults into 3 age groups (≥60, 50-59, 18-49 years) at US and Swedish sites. Participants were randomized to receive one PCV20 or PCV13 dose. After 1 month, participants ≥60 years also received one dose of saline or 23-valent polysaccharide vaccine (PPSV23). Safety assessments included local reactions, systemic events, adverse events, serious adverse events, and newly diagnosed chronic medical conditions. Opsonophagocytic activity (OPA) geometric mean titers (GMTs) 1 month after PCV20 were compared to 13 matched serotypes after PCV13 and to 7 additional serotypes after PPSV23 in participants ≥60 years; noninferiority was declared if lower bound of the 2-sided 95% CI for OPA GMT ratio (PCV20/saline:PCV13/PPSV23 group) was >0.5. PCV20-elicited immune responses in younger participants were also bridged to those in 60-64-year-olds. Results Severity and frequency of prompted local reactions and systemic events were similar after PCV20 or PCV13; no safety concerns were identified. Primary immunogenicity objectives were met, with immune responses after PCV20 noninferior to 13 matched serotypes after PCV13 and to 6 additional PPSV23 serotypes in participants ≥60 years; serotype 8 missed the statistical noninferiority criterion. PCV20 induced robust responses to all 20 vaccine serotypes across age groups. Conclusions PCV20 was safe and well tolerated, with comparable immunogenicity to PCV13/PPSV23. PCV20 is anticipated to expand protection against pneumococcal disease in adults.

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