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

Background Respiratory syncytial virus (RSV) is associated with an increased risk of cardiovascular (CV) events, particularly among individuals with pre-existing CV disease. A bivalent RSV prefusion F protein-based (RSVpreF) vaccine demonstrated effectiveness against RSV-related hospitalization outcomes in the first season of the DAN-RSV trial, without significant heterogeneity between participants with and without atherosclerotic CV disease (ASCVD). However, the study was not adequately powered to detect potential differences in CV events. Purpose This prespecified analysis of the complete two-season DAN-RSV trial cohort will examine the vaccine effectiveness (VE) of RSVpreF versus no vaccine on respiratory and CV events among participants with or without pre-existing ASCVD. Methods DAN-RSV (NCT06684743) is a pragmatic, open-label, individually randomized trial conducted during the 2024/2025 and 2025/2026 winter seasons. In season one, individuals aged ≥60 years were enrolled in Denmark. In season two, individuals aged ≥18 years are being enrolled in Denmark and Galicia, Spain (Figure). Across both seasons, recruitment in Denmark is mainly electronic, using the Danish governmental electronic mail system, while recruitment in Galicia is mainly in-person at primary care and hospital-based appointments. Participants are individually randomized 1:1 to RSVpreF or no vaccine. Baseline and outcome data are collected through linkage to regional and national registries. Participants are followed for clinical outcomes from 14 days after vaccination/booked study visit through May 31 of each season. The primary outcome is RSV-related respiratory tract disease hospitalization. This prespecified analysis will focus on a wide range of CV outcomes, e.g., CV hospitalization, major adverse cardiovascular events, and heart failure hospitalization, in individuals with or without a history of ASCVD. Incidence rates and VE, including the potential effect modification of ASCVD, will be reported. Results In season one of the DAN-RSV trial, 131,276 participants were randomized, of whom 14,241 (11%) had a history of ASCVD. The results suggested a potential reduction in all-cause CV hospitalization. The VE was similar among individuals with pre-existing ASCVD versus those without except for stroke, the risk of which was significantly reduced by the RSVpreF vaccine in persons with ASCVD. In season two, 331,601 participants (44% men) have been randomized in Denmark and >50,000 (48% men) in Galicia, rendering a total study population of >510,000. The ASCVD cohort is expected to exceed 35,000. The final outcome data will be available for presentation at the ESC Congress. Conclusions DAN-RSV is the first randomized RSV vaccine trial to evaluate VE against CV outcomes. Its large sample size, pragmatic design, and addition of diverse geographic locations support a robust assessment of RSVpreF VE in individuals with and without ASCVD.Trial Flow Diagram.