Effectiveness of bivalent RSV prefusion F protein-based vaccine in individuals with and without atrial fibrillation: a prespecified analysis of the DAN-RSV trial

Background Respiratory syncytial virus (RSV) has been linked to an elevated risk of cardiovascular (CV) events, including arrythmias. Pre-existing atrial fibrillation (AF) may further increase the risk of RSV-related CV events. Recently, a bivalent RSV prefusion F protein based (RSVpreF) vaccine demonstrated significant protection against RSV-related respiratory and cardio-respiratory hospitalizations in the first season of the DAN-RSV trial. Nevertheless, the trial was not adequately powered to assess for vaccine effectiveness (VE) against key CV endpoints, including AF hospitalizations. Purpose In this pre-specified analysis of the complete two-season cohort of the DAN-RSV trial, we will evaluate the VE of RSVpreF versus no RSV vaccine against respiratory and CV outcomes overall, and among participants with and without pre-existing AF. Methods DAN-RSV is a pragmatic, open-label trial in which participants were individually randomized 1:1 to RSVpreF or no vaccine during the 2024/2025 and 2025/2026 winter seasons. In the first season, individuals ≥60 years of age were enrolled in Denmark, whereas in the second season, individuals ≥18 years of age were enrolled in Denmark and Galicia, Spain (Figure). Baseline and outcome data will be retrieved through linkage to regional and national registries. Clinical endpoints are ascertained from 14 days after vaccination/booked study visit through May 31 of the corresponding year. The primary endpoint is RSV-related respiratory tract disease hospitalization. This pre-specified analysis will additionally evaluate VE against CV outcomes, including CV hospitalization, stroke hospitalization, AF hospitalization, and major adverse cardiovascular events overall, and among individuals with or without a history of AF. We will report both incidence rates and VE by AF status and test for effect modification by baseline AF status. Results A total of 131,276 participants (50% women) were randomized in the first season of the DAN-RSV trial. Among these, 10,126 (7.7%) participants had a history of AF. The results demonstrated a reduction in RSV-related respiratory tract disease hospitalization, irrespective of AF history. Moreover, RSVpreF was associated with a reduction in RSV-related and all-cause cardio-respiratory hospitalizations with similar VE in both individuals with and without AF. In the second season, 331,601 participants (56% women) have been randomized in Denmark and >49,000 (52% women) in Spain, resulting in a combined study population of >510,000 participants. The AF cohort is expected to exceed 25,000 individuals. Final outcome data will be available for presentation at the ESC Congress. Conclusions This pre-specified analysis of the largest individually randomized RSV vaccine trial will provide important information on RSVpreF VE against major respiratory and CV outcomes in individuals with and without AF and may help inform future RSV prevention strategies.