Effectiveness of the mRNA-1345 Vaccine Against Respiratory Syncytial Virus in US Veterans

Importance: In clinical trials, the messenger RNA (mRNA)-1345 vaccine provided protection against respiratory syncytial virus (RSV) illness. Data on mRNA-1345 effectiveness in broader patient populations are needed. Objective: To estimate the effectiveness of mRNA-1345 vaccination during a single respiratory illness season. Design, Setting, and Participants: This cohort study used a target trial emulation framework to assess veterans 50 years and older receiving care in the Veterans Health Administration. Eligible vaccine recipients were matched with up to 4 unvaccinated individuals in 4 monthly, nested, sequential trials from October 1, 2025, to January 31, 2026. Outcomes were ascertained through May 31, 2026, or 24 weeks. Exposure: A single dose of mRNA-1345 RSV vaccine vs no RSV vaccination. Main Outcomes and Measures: The primary outcome was any positive RSV test result from day 14 after the matched index date. Secondary outcomes included RSV-associated emergency department (ED) or urgent care (UC) encounters and RSV-associated hospitalizations. Vaccine effectiveness was estimated as 100 × (1 - risk ratio). A sensitivity analysis comparing veterans who received same-day mRNA-1345 and influenza vaccination to influenza vaccination alone (active comparator arm) was performed to explore potential bias from differences in health care-seeking behavior and outcome ascertainment between comparator groups. Results: A total of 74 926 vaccinated veterans were matched to 286 425 unique control individuals, weighted to represent 74 926 individuals, for a total of 149 852 study participants (median [IQR] age, 73.0 [63.3-78.6] years; 136 756 [91.3%] male). During a median (IQR) follow-up of 160 (130-168) days, estimated vaccine effectiveness was 60.3% (95% CI, 49.0%-70.4%) against any documented infection, 60.2% (95% CI, 47.2%-71.5%) against RSV-associated ED or UC encounters, and 81.8% (95% CI, 58.1%-99.9%) against RSV-associated hospitalizations. Estimated effectiveness against documented infections decreased with increasing age, from 82.9% (95% CI, 64.0%-96.7%) in the 50- to 59-year age group to 28.6% (95% CI, -12.0% to 60.4%) in the 80-year or older age group. With an active comparator arm, estimated effectiveness was 67.1% (95% CI, 48.9%-82.6%) against documented RSV infections, 69.5% (95% CI, 49.7%-85.4%) against RSV-associated ED and UC encounters, and 86.9% (95% CI, 56.5%-100.0%) against RSV-associated hospitalizations. Conclusions and Relevance: In this cohort study using a target trial emulation of mRNA-1345 vaccine effectiveness during 24 weeks, vaccination was associated with protection against RSV illness and associated health care use in adults 50 years and older. Comparative effectiveness studies are needed to determine the relative benefits of available RSV vaccine products.