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. 2025 Aug 30:e2515405.
doi: 10.1001/jama.2025.15405. Online ahead of print.

Bivalent RSV Prefusion F Protein-Based Vaccine for Preventing Cardiovascular Hospitalizations in Older Adults: A Prespecified Analysis of the DAN-RSV Trial

Mats C Højbjerg Lassen  1   2 , Niklas Dyrby Johansen  1   2 , Sine H Christensen  1   2 , Negar Aliabadi  3 , Kristoffer G Skaarup  1   2 , Daniel Modin  1   2 , Brian L Claggett  4 , Carsten S Larsen  5   6 , Lykke Larsen  7 , Lothar Wiese  8 , Michael Dalager-Pedersen  9   10 , Matias G Lindholm  11 , Anne Marie R Jensen  1   2 , Maria Dons  1   2 , Katrine F Bernholm  1   2 , Filip S Davidovski  1   2 , Lisa S Duus  1   2 , Camilla I Ottosen  1   2 , Anne B Nielsen  1   2 , Julie H Borchsenius  1   2 , Caroline Espersen  1   2 , Güldas Köse  1   2 , Frederik H Fussing  1   2 , Manan Pareek  1   2 , Lars Køber  12   13 , Scott D Solomon  4 , Jens Ulrik Stæhr Jensen  12   14 , Cyril Jean-Marie Martel  15 , Bradford D Gessner  3 , Claudia Schwarz  3 , Elisa Gonzalez  3 , Mette Skovdal  3 , Lawrence H Moulton  16 , Pingping Zhang  3 , Elizabeth Begier  3 , Tor Biering-Sørensen  1   2   13   17
Affiliations

Bivalent RSV Prefusion F Protein-Based Vaccine for Preventing Cardiovascular Hospitalizations in Older Adults: A Prespecified Analysis of the DAN-RSV Trial

Mats C Højbjerg Lassen et al. JAMA. .

Abstract

Importance: Respiratory syncytial virus (RSV) infection is linked to elevated cardiovascular risk, particularly in individuals with preexisting cardiovascular disease (CVD). A bivalent RSV prefusion F protein (RSVpreF) vaccine was recently approved for preventing RSV-related lower respiratory tract illness, but its effectiveness against cardiovascular outcomes has not been evaluated in a randomized trial.

Objective: To investigate the vaccine effectiveness of RSVpreF compared with no vaccine against cardiovascular outcomes among adults aged 60 years or older.

Design, setting, and participants: Prespecified secondary analysis of the DAN-RSV trial, a pragmatic, open-label, individually randomized clinical trial conducted in Denmark during the 2024-2025 winter season. The first participant was enrolled on November 18, 2024. Adults aged 60 years or older were eligible for inclusion regardless of comorbidity status.

Interventions: Participants were randomized 1:1 to receive RSVpreF (n = 65 642) or no vaccine (n = 65 634).

Main outcomes and measures: Hospitalization for any cardiorespiratory disease was a prespecified secondary outcome, and hospitalizations for any CVD, heart failure, myocardial infarction, stroke, and atrial fibrillation were prespecified exploratory outcomes. Outcomes were assessed from 14 days after booked study visit through May 31, 2025. Vaccine effectiveness was calculated as 1 - incidence rate ratio, expressed as a percentage.

Results: Of 131 276 participants included (mean age, 69.4 [SD, 6.5] years; 50.3% male), 28 662 (21.8%) had preexisting CVD. All-cause cardiorespiratory hospitalization incidence was lower in the RSVpreF group compared with the control group (26.3 vs 29.2 events per 1000 participant-years [PY]; absolute rate reduction, 2.90 [95% CI, 0.10-5.71] per 1000 PY; vaccine effectiveness, 9.9% [95% CI, 0.3%-18.7%]; P = .04). There was no significant interaction by baseline CVD status (CVD at baseline: vaccine effectiveness, 5.0% [95% CI, -11.2% to 16.7%]; no CVD at baseline: vaccine effectiveness, 15.2% [95% CI, 2.2%-27.1%]; P = .27 for interaction). For the RSVpreF group vs control group, respectively, incidence rates of all-cause cardiovascular hospitalization were 16.4 vs 17.7 events per 1000 PY (vaccine effectiveness, 7.4% [95% CI, -5.5% to 18.8%]; P = .24), and incidence rates of stroke were 3.0 vs 3.8 events per 1000 PY (vaccine effectiveness, 19.4% [95% CI, -8.6% to 40.4%]; P = .14). There were also no statistically significant between-group differences for myocardial infarction, heart failure hospitalization, and atrial fibrillation.

Conclusions and relevance: In adults aged 60 years or older, all-cause cardiorespiratory hospitalization was significantly lower with RSVpreF than with no vaccine. The findings suggest potential downstream cardiorespiratory benefits of RSV immunization, although the effect on all-cause cardiovascular hospitalization was not statistically significant.

Trial registration: ClinicalTrials.gov Identifier: NCT06684743.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Aliabadi reported being an employee of Pfizer Inc and owning Pfizer stock. Dr Skaarup reported receipt of personal fees for advisory board membership from Sanofi and travel support for congress participation from AstraZeneca. Dr Claggett reported receipt of personal fees for consulting from Alnylam, Cardior, Cardurion, Cytokinetics, CVRx, Intellia, Rocket, Lilly, and Alexion. Dr Pareek reported receipt of personal fees for advisory board membership and/or speaker fees from AstraZeneca, Bayer, Boehringer Ingelheim, Janssen-Cilag, and Novo Nordisk and grants from the Danish Cardiovascular Academy and the Danish Heart Foundation. Dr Køber reported receipt of speaker honoraria from Novo Nordisk, Novartis, AstraZeneca, and Boehringer Ingelheim. Dr Solomon reported receipt of grants to his institution from Alexion, Alnylam, Applied Therapeutics, AstraZeneca, Bellerophon, Bayer, BMS, Boston Scientific, Cytokinetics, Edgewise, Eidos/BridgeBio, Gossamer, GSK, Ionis, Lilly, the National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Tenaya, Theracos, and US2.AI and personal fees from Abbott, Action, Akros, Alexion, Alnylam, Amgen, Arena, AskBio, AstraZeneca, Bayer, BMS, BridgeBio, Cardior, Cardurion, Corvia, Cytokinetics, GSK, Intellia, Lilly, Novartis, Roche, Theracos, Quantum Genomics, Tenaya, Sanofi Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, Valo, Synhale, and Recordati. Dr Gessner, Dr Schwarz, Ms Gonzalez, Ms Skovdal, Dr Moulton, Ms Zhang, and Dr Begier reported being employees of Pfizer Inc and owning Pfizer stock. Dr Biering-Sørensen reported receipt of personal fees for consulting and/or lectures from Sanofi Pasteur, GSK, Novo Nordisk, IQVIA, Parexel, Amgen, CSL Seqirus, Bayer, Novartis, and GE Healthcare and grants from Sanofi Pasteur, Pfizer, AstraZeneca, Boston Scientific, GE Healthcare, Novartis, Novo Nordisk, Bayer, and AstraZeneca. No other disclosures were reported.

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