Effectiveness of RSV vaccine against cardio-respiratory hospitalizations in heart failure: a prespecified analysis of the DAN-RSV trial

Background Individuals living with heart failure (HF) are predisposed to severe cardio-respiratory disease (CRD) complications following respiratory syncytial virus (RSV) infection. A bivalent RSV prefusion F protein-based (RSVpreF) vaccine reduced the risk of hospitalization for RSV-related respiratory tract disease (RTD), all-cause RTD, and all-cause CRD in the first season of the DAN-RSV trial (adults ≥60 years). A prespecified secondary analysis demonstrated no appreciable differences in vaccine effectiveness (VE) across HF status. However, the study was not adequately powered to detect potential differences in CV events. Purpose This prespecified analysis combining data from two seasons of the DAN-RSV trial will evaluate VE of RSVpreF vs. no vaccine against severe CRD outcomes according to HF status. Methods DAN-RSV is a pragmatic, open-label, parallel-group, individually randomized trial conducted during the 2024-2025 and 2025-2026 winter seasons, enrolling individuals regardless of preexisting comorbidities. In season 1, individuals aged ≥60 years were enrolled in Denmark. In season 2, individuals aged ≥18 years are being enrolled in Denmark and Galicia, Spain. Recruitment is digital via the national governmental electronic mail system in Denmark and predominantly in-person during primary care and hospital-based visits in Galicia. Participants are randomized 1:1 to receive RSVpreF vaccine or no vaccine. Routine health-care databases are used to obtain baseline characteristics, outcome, and safety data. Participants are followed for outcomes from 14 days after booked study visit until the end of the RSV season. Primary outcome is RSV-related RTD hospitalization. This prespecified analysis will also evaluate prespecified CRD outcomes, including HF hospitalization, among individuals with and without pre-existing HF. VE will be examined across relevant HF subgroups, including HF severity and treatment status. Long-term VE will be examined by baseline HF status among season 1 participants. Results Among 131,276 participants (mean age, 69.4±6.5 years; 50.3% male) randomized in season 1, 2,973 had HF at baseline. In season 2, 331,601 participants (mean age, 57.4±14.3 years; 43.9% male) were recruited in Denmark and >49,000 in Galicia, resulting in a combined population of >510,000 (Figure). At 1.4% HF prevalence, ≈5,300 participants in season 2 have HF. Baseline and endpoint data will be available for presentation at ESC 2026. Conclusions This prespecified analysis will provide the most robust evaluation of RSVpreF VE against severe CRD outcomes, including HF hospitalizations overall, among individuals with baseline HF, and across key HF subgroups. The results will provide VE for adults aged ≥18 years and ≥60 years. Additionally, long-term VE estimates will be available among those aged ≥60 years.