Highlight
- In the DAN‑RSV randomized cohort (adults ≥60 years), the bivalent prefusion F RSV vaccine reduced RSV‑related respiratory hospitalizations with similar point estimates whether participants had pre‑existing ASCVD or not.
- Vaccine effectiveness (VE) for the primary respiratory outcome was 80.0% (95% CI, 29.3–96.3) among those without ASCVD and was estimated as 100% (95% CI, −141.3 to 100.0) among those with ASCVD; the interaction by ASCVD status was not statistically significant.
- No convincing evidence emerged that RSVpreF vaccination reduces short‑term major adverse cardiovascular events (composite of hospitalization for myocardial infarction, stroke, or heart failure) compared with no vaccine.
Background: clinical context and unmet need
Respiratory syncytial virus (RSV) has long been recognized as an important cause of lower and upper respiratory tract disease in infants; in recent years, its role in older adults and those with chronic cardiopulmonary disease has gained increasing attention. RSV infection in older adults can precipitate severe lower respiratory disease and hospitalization, and respiratory viral infections more broadly are associated with transient increases in cardiovascular events, including myocardial infarction, stroke, and decompensated heart failure. Older adults with established atherosclerotic cardiovascular disease (ASCVD) are at higher baseline risk for both respiratory and cardiovascular complications, so evaluating whether RSV vaccination confers respiratory protection and whether that translates into fewer cardiovascular events is clinically relevant.
Study design: DAN‑RSV prespecified secondary analysis
The analysis reported by Pareek and colleagues is a prespecified secondary analysis of the DAN‑RSV randomized trial. Key design elements were:
- Population: Community‑dwelling adults aged ≥60 years enrolled in Denmark. Participants were categorized at baseline according to presence or absence of pre‑existing ASCVD (n = 14 241 with ASCVD; n = 117 035 without ASCVD).
- Intervention and comparator: Randomization 1:1 to receive the bivalent prefusion F protein‑based RSV vaccine (RSVpreF) versus no vaccine.
- Outcomes: Primary outcome for the trial was hospitalization for RSV‑related respiratory tract disease. A principal cardiovascular outcome was a composite major adverse cardiovascular event (MACE) defined as hospitalization for myocardial infarction, stroke, or heart failure. Baseline characteristics and outcomes were captured through nationwide registries enabling near‑complete follow‑up.
- Analysis: Vaccine effectiveness (VE) estimates were calculated overall and stratified by ASCVD status; heterogeneity of VE by ASCVD status was tested using interaction p‑values.
Key findings and interpretation
The principal results from the subgroup analysis can be summarized as follows.
Baseline risks
Participants with pre‑existing ASCVD had higher incidence rates for almost all measured outcomes compared with those without ASCVD. This is consistent with ASCVD being a marker of higher baseline vulnerability to both respiratory and cardiovascular complications.
Vaccine effectiveness against RSV‑related respiratory hospitalization
For the prespecified primary outcome of RSV‑related respiratory tract disease hospitalization, VE estimates were:
- Participants without ASCVD: VE 80.0% (95% CI, 29.3–96.3).
- Participants with ASCVD: VE estimated at 100.0% with a 95% CI of −141.3 to 100.0.
The interaction test for difference in VE by ASCVD status was not significant (Pinteraction > .99), indicating no statistically detectable heterogeneity: the protective effect against RSV hospitalization appeared similar across subgroups. The extremely wide and non‑informative CI in the ASCVD stratum reflects a low number of RSV hospitalizations in that subgroup (likely zero events in the vaccinated arm) and consequent statistical imprecision; a point estimate of 100% with a negative lower bound is a mathematical consequence of sparse data and should be interpreted cautiously.
Vaccine effectiveness against major adverse cardiovascular events (MACE)
- Participants without ASCVD: VE for MACE 9.3% (95% CI, −15.1 to 28.6).
- Participants with ASCVD: VE for MACE 12.0% (95% CI, −34.6 to 43.3).
These estimates are small in magnitude and not statistically significant, and the interaction by ASCVD status was nonsignificant (Pinteraction = .90). In short, there was no clear evidence from this analysis that RSVpreF vaccination reduces short‑term hospitalization for myocardial infarction, stroke, or heart failure in older adults, irrespective of baseline ASCVD status.
Safety and secondary outcomes
The secondary analysis focused on effectiveness outcomes using registry capture and did not report novel safety signals that would alter clinical interpretation. The absence of a reduction in MACE does not imply safety concerns; it primarily reflects lack of measurable cardiovascular benefit in this dataset and follow‑up duration.
Expert commentary: strengths, limitations, and biological plausibility
Strengths of the analysis include randomized allocation, very large sample size overall, and use of nationwide registries to obtain near‑complete outcome ascertainment—features that reduce selection and ascertainment bias. The prespecified nature of the subgroup analysis and formal interaction testing are additional strengths.
Key limitations that affect interpretation:
- Event rates for RSV hospitalizations and especially for RSV‑attributable cardiovascular events were low, yielding wide confidence intervals and imprecise VE estimates in subgroups (notably the ASCVD stratum). Point estimates such as 100% VE with a negative lower bound reflect sparse events rather than definitive perfect protection.
- The analysis compared vaccine versus no vaccine; while randomization preserves internal validity, generalizability to populations with different baseline immunization practices, comorbidities, or RSV epidemiology may be limited.
- MACE as an outcome was defined by hospitalization codes; although registry‑based definitions are pragmatic and informative for public health, they may misclassify events without central adjudication. The trial was not primarily powered to detect differences in cardiovascular outcomes, which are less frequent than respiratory hospitalizations even in high‑risk cohorts.
- Duration of follow‑up matters: vaccine effects on acute RSV infection are biologically plausible to reduce short‑term inflammation‑mediated cardiovascular triggers, but detecting such an effect requires both sufficient events and appropriate timing of observation.
Biological plausibility for cardiovascular benefit rests on the concept that acute respiratory infections can provoke systemic inflammation, prothrombotic states, and destabilization of atherosclerotic plaques—mechanisms implicated in triggering myocardial infarction and stroke. Preventing RSV may therefore plausibly reduce these transient risks; however, the magnitude and detectability of that effect depend on how often RSV is the trigger for cardiovascular events in the studied population and on the vaccine’s ability to prevent the infections most temporally linked to cardiovascular events.
Clinical and policy implications
From a clinical standpoint, the DAN‑RSV secondary analysis supports that older adults—whether or not they have established ASCVD—derive similar respiratory protection from the bivalent prefusion F RSV vaccine. Given the higher absolute risk of RSV complications among persons with ASCVD, the absolute benefit (prevented hospitalizations) would be expected to be greater in that subgroup even if relative VE is similar. These data therefore support inclusion of older adults with ASCVD as an important target population for RSV vaccination programs focused on preventing respiratory morbidity.
Conclusions about cardiovascular protection cannot be drawn from this analysis: the modest, nonsignificant VE point estimates for MACE and wide confidence intervals indicate insufficient evidence of a protective effect on short‑term cardiovascular hospitalizations. Policymakers and clinicians should therefore not expect robust cardiovascular risk reduction from RSV vaccination on the basis of current data, although preventing respiratory disease remains a valuable and independent goal.
Research implications and next steps
Future research to clarify whether RSV vaccination reduces cardiovascular events should consider:
- Larger or pooled randomized datasets designed and powered a priori to evaluate cardiovascular endpoints, with central adjudication of events where possible.
- Use of active surveillance for RSV infection with laboratory confirmation to relate individual infection episodes to subsequent cardiovascular events and permit causal inference.
- Mechanistic studies to define inflammatory and coagulation pathway changes after breakthrough RSV infection and whether these are mitigated by vaccination.
- Longer follow‑up to determine persistence of respiratory protection and any delayed cardiovascular effects.
Conclusion
In this prespecified secondary analysis of the DAN‑RSV randomized trial, the bivalent RSV prefusion F protein vaccine conferred substantial relative protection against RSV‑related respiratory hospitalizations in adults aged ≥60 years, with similar effectiveness estimates in those with and without pre‑existing ASCVD. There is no clear evidence from these data that vaccination significantly reduces short‑term hospitalization for myocardial infarction, stroke, or heart failure. Clinicians should consider RSV vaccination to reduce respiratory morbidity in older adults including those with ASCVD, while recognizing that demonstration of cardiovascular benefit will require larger or specifically designed studies.
Funding and trial registration
Funding details and trial registration are reported in the original publication: Pareek M et al., Eur Heart J. 2025 (see full citation below). Readers should consult the original DAN‑RSV report for complete sponsorship and protocol registration information.
Selected reference
Pareek M, Lassen MCH, Johansen ND, Christensen SH, Aliabadi N, Skaarup KG, Modin D, Claggett BL, Larsen CS, Larsen L, Wiese L, Dalager‑Pedersen M, Lindholm MG, Jensen AMR, Dons M, Bernholm KF, Davidovski FS, Duus LS, Ottosen CI, Nielsen AB, Borchsenius JH, Espersen C, Köse G, Fussing FH, Køber L, Solomon SD, Jensen JUS, Martel CJ, Gessner BD, Schwarz C, Gonzalez E, Skovdal M, Zhang P, Begier E, Biering‑Sørensen T. Effectiveness of bivalent respiratory syncytial virus prefusion F protein-based vaccine in individuals with or without atherosclerotic cardiovascular disease: the DAN‑RSV trial. Eur Heart J. 2025 Nov 3;46(41):4291-4298. doi: 10.1093/eurheartj/ehaf679. PMID: 40884439; PMCID: PMC12579979.
For further reading on RSV burden and vaccine development, consult recent reviews and guideline updates from public health authorities and specialty societies.