Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Aug 30:e253460.
doi: 10.1001/jamacardio.2025.3460. Online ahead of print.

High-Dose vs Standard-Dose Influenza Vaccine and Cardiovascular Outcomes in Older Adults: A Prespecified Secondary Analysis of the DANFLU-2 Randomized Clinical Trial

Niklas Dyrby Johansen  1   2 , Daniel Modin  1   2 , Matthew M Loiacono  3   4 , Rebecca C Harris  5 , Marine Dufournet  6 , Carsten Schade Larsen  7   8 , Lykke Larsen  9 , Lothar Wiese  10 , Michael Dalager-Pedersen  11   12 , Brian L Claggett  13 , Kira Hyldekær Janstrup  1   2 , Katja Vu Bartholdy  1   2 , Katrine Feldballe Bernholm  1   2 , Julie Inge-Marie Helene Borchsenius  1   2 , Filip Soeskov Davidovski  1   2 , Lise Witten Davodian  1   2 , Maria Dons  1   2 , Lisa Steen Duus  1   2 , Caroline Espersen  1   2 , Frederik Holme Fussing  1   2 , Anne Marie Reimer Jensen  1   2 , Nino Emanuel Landler  1   2 , Adam Cadovius Femerling Langhoff  1   2 , Mats Christian Højbjerg Lassen  1   2 , Anne Bjerg Nielsen  1   2 , Camilla Ikast Ottosen  1   2 , Morten Sengeløv  1   2 , Kristoffer Grundtvig Skaarup  1   2 , Manan Pareek  1   2 , Scott D Solomon  13 , Martin J Landray  14 , Gunnar H Gislason  1   15   16 , Lars Køber  15   17 , Pradeesh Sivapalan  15   18 , Cyril Jean-Marie Martel  19 , Jens Ulrik Stæhr Jensen  15   18 , Tor Biering-Sørensen  1   2   17   20
Affiliations

High-Dose vs Standard-Dose Influenza Vaccine and Cardiovascular Outcomes in Older Adults: A Prespecified Secondary Analysis of the DANFLU-2 Randomized Clinical Trial

Niklas Dyrby Johansen et al. JAMA Cardiol. .

Abstract

Importance: The high-dose inactivated influenza vaccine (HD-IIV) has demonstrated superior protection against laboratory-confirmed influenza infection vs standard-dose IIV (SD-IIV); however, data regarding its effectiveness against cardiovascular (CV) outcomes are mainly from observational studies or specific high-risk groups.

Objective: To investigate the relative vaccine effectiveness (rVE) of HD-IIV vs SD-IIV against CV outcomes in the general older adult population in Denmark.

Design, setting, and participants: This was a prespecified secondary analysis of DANFLU-2, a pragmatic, open-label, individually randomized clinical trial (RCT) using nationwide administrative health registries in Denmark during the 2022/2023 to 2024/2025 influenza seasons. Older adults (age ≥65 years) were eligible for inclusion regardless of comorbidity. The trial design specified that if the primary end point was neutral, no hypothesis testing would be performed for secondary or exploratory end points. Data were analyzed from June 29 to August 12, 2025.

Interventions: Individual-level 1:1 randomization to HD-IIV or SD-IIV. Participants re-enrolling in additional seasons were rerandomized.

Main outcomes and measures: Severe CV outcomes were prespecified secondary and exploratory end points in the trial, occurring from 14 days after vaccination through May 31 the following year.

Results: A total of 332 438 participants (170 900 [51.4%] male; mean [SD] age, 73.7 [5.8] years) were randomized (166 218 to HD-IIV and 166 220 to SD-IIV), of whom 91 026 (27.4%) had a history of CV disease. HD-IIV did not significantly reduce the trial's primary end point of hospitalization for influenza or pneumonia. The incidence of hospitalization for any cardiorespiratory disease was lower in the HD-IIV group than the SD-IIV group (rVE, 5.7% [95% CI, 1.4% to 9.9%]; absolute difference, -0.13 [95% CI, -0.24 to -0.03] percentage points), and rVE did not differ by history of CV disease compared with no CV disease at baseline. Hospitalization for any CV disease occurred in fewer participants in the HD-IIV group than the SD-IIV group (rVE, 7.5% [95% CI, 1.5% to 12.5%]; absolute difference, -0.10 [95% CI, -0.18 to -0.02] percentage points) as did hospitalization for heart failure (rVE, 19.5% [95% CI, 3.3% to 33.1%]; absolute difference, -0.03 [95% CI, -0.06 to -0.01] percentage points).

Conclusions and relevance: This study found reduced incidence of cardiorespiratory hospitalization among those who received HD-IIV vs SD-IIV, driven by a lower incidence of CV hospitalizations, and particularly heart failure hospitalizations. These differences should be interpreted as exploratory findings in the setting of a large RCT with a neutral primary outcome.

Trial registration: ClinicalTrials.gov Identifier: NCT05517174.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Loiacono reported being employed by Sanofi during the conduct of the study. Dr Harris reported being employed by Sanofi during the conduct of the study; and holding shares in Sanofi outside the submitted work. Dr Dufournet being employed by Sanofi during the conduct of the study. Dr Claggett reported personal fees from Alnylam Pharmaceuticals, Cardior Pharmaceuticals, Cardurion, Cytokinetics, CVRx, Intellia Therapeutics, Rocket Pharmaceuticals, Eli Lilly, and Alexion outside the submitted work. Dr Bartholdy reported receiving grants from Danish Cardiovascular Academy outside the submitted work. Dr Langhoff reported receiving grants from Novo Nordisk Foundation and personal fees from Novo Nordisk outside the submitted work. Dr Skaarup reported receiving personal fees from Sanofi and AstraZeneca outside the submitted work. Dr Pareek reported receiving personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Janssen-Cilag, and Novo Nordisk, and grants from Danish Cardiovascular Academy and Danish Heart Foundation outside the submitted work. Dr Solomon reported receiving grants from Alexion, Alnylam Pharmaceuticals, Applied Therapeutics, AstraZeneca, Bellerophon Therapeutics, Bayer, Bristol Myers Squibb, Boston Scientific, Cytokinetics, Edgewise, Eidos/BridgeBio, Gossamer, GSK, Ionis, Lilly, National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Tenaya, Theracos, Us2.ai and personal fees from Abbott, Action Pharma, Akros, Alexion, Alnylam Pharmaceuticals, Amgen, Arena Pharmaceuticals, Askbio, AstraZeneca, Bayer, Bristol Myers Squibb, BridgeBio, Cardior Pharmaceuticals, Cardurion, Corvia Medical, Cytokinetics, GSK, Intellia Therapeutics, Lilly, Novartis, Roche, Theracos, Quantum Genomics, Tenaya Therapeutics, Sanofi-Pasteur, Dinaqor, Tremeau Pharmaceuticals, CellProThera, Moderna, American Regent, Sarepta Therapeutics, Lexicon Pharmaceuticals, AnaCardio, Akros, Valo, Synhale Therapeutics, and Recordati outside the submitted work. Dr Landray reported receiving grants from GSK, Sanofi, Regeneron, and Moderna outside the submitted work. Dr Køber reported receiving personal fees Novo Nordisk, Novartis, AstraZeneca, and Boehringer Ingelheim outside the submitted work. Dr Biering-Sørensen reported receiving grants from Sanofi during the conduct of the study and grants from AstraZeneca, Bayer, Boston Scientific, GE Healthcare, GSK, Novartis, Novo Nordisk Pfizer, and Sanofi-Pasteur and personal fees from Amgen, AstraZeneca, Bayer, CSL Seqirus, GE Healthcare, GSK, IQVIA, Novartis, Parexel, and Sanofi outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Relative Vaccine Effectiveness (rVE) of High-Dose vs Standard-Dose Influenza Vaccine Against Hospitalization for Cardiorespiratory Disease Across Prespecified Subgroups
Figure 2.
Figure 2.. Relative Vaccine Effectiveness (rVE) of High-Dose vs Standard-Dose Influenza Vaccine Against Additional Cardiorespiratory Outcomes According to Established Disease at Baseline
See this image and copyright information in PMC

Comment in

  • doi: 10.1001/jamacardio.2025.3521

References

    1. Kwong JC, Schwartz KL, Campitelli MA, et al. Acute myocardial infarction after laboratory-confirmed influenza infection. N Engl J Med. 2018;378(4):345-353. doi: 10.1056/NEJMoa1702090 - DOI - PubMed
    1. Kytömaa S, Hegde S, Claggett B, et al. Association of influenza-like illness activity with hospitalizations for heart failure: the Atherosclerosis Risk in Communities Study. JAMA Cardiol. 2019;4(4):363-369. doi: 10.1001/jamacardio.2019.0549 - DOI - PMC - PubMed
    1. Chang TY, Chao TF, Liu CJ, et al. The association between influenza infection, vaccination, and atrial fibrillation: A nationwide case-control study. Heart Rhythm. 2016;13(6):1189-1194. doi: 10.1016/j.hrthm.2016.01.026 - DOI - PubMed
    1. Johnstone J, Loeb M, Teo KK, et al. ; Ongoing Telmisartan Alone and in Combination With Ramipril Global EndPoint Trial (ONTARGET); Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND) Investigators . Influenza vaccination and major adverse vascular events in high-risk patients. Circulation. 2012;126(3):278-286. doi: 10.1161/CIRCULATIONAHA.111.071100 - DOI - PubMed
    1. Modin D, Jørgensen ME, Gislason G, et al. Influenza vaccine in heart failure. Circulation. 2019;139(5):575-586. doi: 10.1161/CIRCULATIONAHA.118.036788 - DOI - PubMed

Associated data