Bivalent RSVpreF effectiveness against RSV-associated hospital or emergency department care over two seasons: a retrospective test-negative case control study

<h2>Summary</h2><h3>Background</h3> Since RSV vaccine licensure in 2023, vaccine effectiveness (VE) studies demonstrated first season protection against severe RSV disease including RSV-related hospitalization/emergency department (ED) visits. Here, we estimate VE over two seasons, by RSV subtype, and for additional high-risk subgroups. <h3>Methods</h3> This retrospective test-negative case–control study included adults ≥60 years at Kaiser Permanente Southern California with lower respiratory tract disease (LRTD) or acute respiratory illness (ARI) hospitalization/ED during 24 November 2023─09 April 2024 and 05 November 2024─26 April 2025. In primary analyses, cases were RSV-positive and controls were negative for: RSV, SARS-CoV-2, influenza, and positive for a non-vaccine-preventable pathogen. Exposure was bivalent RSVpreF receipt ≥21 days before LRTD/ARI. VE was calculated using adjusted odds ratios from multivariable logistic regression. "First season after vaccination" includes events in the same RSV season as vaccination; "second season" includes events in 2024–25 among those vaccinated in 2023–24. <h3>Findings</h3> VE against RSV-associated LRTD hospitalizations/ED was 81% (95% CI: 68–89) and 76% (95% CI: 48–89) for first and second seasons after vaccination, respectively. Limiting to those vaccinated in 2023/2024, VE was 87% (95% CI: 37–97) 0–<6 and 77% (95% CI: 54–89) 6–18 months post-vaccination. Protection persisted across both seasons for adults aged ≥75 years, those with risk factors, frailty, immunocompromise, and by RSV A/B. VE in immunocompromised adults appeared to decrease more quickly: 74% (95% CI: 37–89) first season to 54% (95% CI: −48 to 85) second season. <h3>Interpretation</h3> RSVpreF vaccination was associated with protection against RSV-associated severe respiratory illness, overall and among the most vulnerable patients. VE appeared to decline modestly across two seasons in most populations, this finding was more pronounced among immunocompromised adults. Our VE estimates indicate potentially substantial public health benefit of RSV vaccination. <h3>Funding</h3> This was a Pfizer-sponsored study.