Bivalent RSVpreF Effectiveness Against Respiratory Syncytial Virus (RSV)-Related Respiratory Disease Hospitalization and Emergency Department Visits Across Three RSV Seasons

INTRODUCTION: Respiratory syncytial virus (RSV) protein subunit vaccines reduce the risk of severe outcomes such as hospitalization and emergency department (ED) visits for at least two RSV seasons following vaccination. No data have been published on real-world RSV vaccine effectiveness (VE) beyond the second season after vaccination. This study evaluates bivalent RSVpreF VE against RSV-related respiratory disease hospitalizations/ED visits throughout three seasons after vaccination. METHODS: This retrospective test-negative case-control study evaluates bivalent RSVpreF VE among adults aged ≥60 years at Kaiser Permanente Southern California, USA, with lower respiratory tract disease (LRTD) or acute respiratory illness (ARI) over three RSV seasons (11/24/2023-4/18/2026). Cases were RSV-positive without coinfection. Controls were negative for RSV, hMPV, influenza, SARS-CoV-2, and positive for a non-vaccine preventable disease pathogen. Exposure was bivalent RSVpreF (Abrysvo) receipt ≥ 21 days before LRTD/ARI. Adjusted VE was estimated using odds ratios from multivariable logistic regression or generalized estimating equations. RESULTS: Overall adjusted VE against RSV-related LRTD hospitalization/ED visits was 80% (95% CI 68-87), 70% (95% CI 53-81), and 51% (95% CI -12-78) in the first, second, and third season after vaccination, respectively. Overall adjusted VE against RSV-related ARI hospitalization/ED visits was 81% (71-87), 64% (48-75), and 60% (15-81), respectively. Adjusted VE among non-immunocompromised individuals trended 4-7% higher than corresponding overall estimates. Overall adjusted VE across the three combined seasons was 73% (95% CI 64-80) and 73% (95% CI 65-79) against RSV-related LRTD and ARI, respectively. CONCLUSION: Bivalent RSVpreF provides protection against RSV-related respiratory hospitalization/ED visits for at least three seasons after vaccination in this population of older adults with a high prevalence of comorbidities. Estimates in the third season for ARI were more definitive, while those for LRTD were imprecise due to limited event numbers. This suggests bivalent RSVpreF vaccination results in substantial individual and public health benefit. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT06077968.