Effectiveness of 20-valent pneumococcal conjugate vaccine against pneumococcal pneumonia hospitalizations among U.S. adults: Test-Negative Design

Objective: This study estimated the vaccine effectiveness (VE) of 20-valent pneumococcal conjugate vaccine (PCV20) against culture-confirmed pneumococcal pneumonia hospitalizations among adults using a test-negative case-control design. Methods: We included adults ([≥]18 years) hospitalized with pneumonia in the U.S. Veterans Affairs Healthcare System between January 2023 and December 2025 who had respiratory cultures collected. VE was estimated using multivariable logistic regression adjusted for demographic and clinical characteristics. Subgroup analyses were conducted by age, risk group, and U.S. census region. Sensitivity analyses included inverse probability of treatment weighting (IPTW) and evaluation allowing previous PCV13 vaccination. Results: Among 34,009 pneumonia hospitalizations, 837 (2.5%) were Streptococcus pneumoniae culture-positive and 7,428 (21.8%) individuals had received PCV20. PCV20 vaccination was associated with lower odds of culture-confirmed pneumococcal pneumonia hospitalization among adults aged [≥]65 years (VE 20.4%; 95% CI: 2.1%, 35.3%), with greater effectiveness observed among those with chronic medical conditions (VE 24.4%; 95% CI: 0.7%, 42.4%). VE was highest in the Western region among adults aged [≥]65 years (39.6%; 95% CI: 3.2%, 62.3%), a region with a high burden of serotype 4 disease. Overall, VE among adults aged [≥]18 years was 8.8% (95% CI: -8.8%, 23.6%). Findings were consistent across multivariable and IPTW-adjusted analyses. Conclusion: PCV20 provided significant protection against pneumococcal pneumonia hospitalizations among older adults, with greater effectiveness in regions where vaccine-covered serotypes are more prevalent. These findings support the importance of aligning pneumococcal vaccination strategies with regional serotype distribution to maximize vaccine impact.