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Comparative Study

High-Dose Versus Standard-Dose Influenza Vaccine and Cardiovascular Outcomes in Older Adults: The FLUNITY-HD Prespecified Pooled Analysis

Niklas Dyrby Johansen et al. Circulation. .

Abstract

Background: The high-dose inactivated influenza vaccine (HD-IIV) has demonstrated superior protection against a range of hospitalization end points versus standard-dose inactivated influenza vaccine (SD-IIV), but its effectiveness against specific cardiovascular outcomes and in those with pre-existing cardiovascular disease (CVD) is not well elucidated.

Methods: In a prespecified secondary analysis of the FLUNITY-HD (Pooled Analysis of Methodologically Harmonized Pragmatic Randomized Trials of High-Dose vs. Standard-Dose Influenza Vaccine Against Severe Clinical Outcomes) individual-level pooled data set integrating 2 methodologically harmonized pragmatic, individually randomized trials conducted in Denmark and Spain, we investigated the relative vaccine effectiveness of HD-IIV versus SD-IIV against severe cardiovascular outcomes and according to pre-existing CVD among adults ≥65 years of age. Data were primarily obtained from routine health care databases, with follow-up from 14 days after vaccination to May 31 the following year.

Results: The pooled data set encompassed 466 320 individually randomized participants, of whom 107 700 (23.1%) had a history of CVD. HD-IIV reduced the incidence of hospitalization for influenza or pneumonia, cardiorespiratory disease, laboratory-confirmed influenza, and any cause compared with SD-IIV, irrespective of the presence or absence of pre-existing CVD (Pinteraction>0.66 for all outcomes). Compared with the SD-IIV group, the HD-IIV group had a significantly lower incidence of hospitalization for any CVD (HD-IIV, 1.15%, versus SD-IIV, 1.24%; relative vaccine effectiveness, 6.6% [95% CI, 1.6-11.4]; P=0.010), hospitalization for any respiratory disease (HD-IIV, 0.92%, versus SD-IIV, 0.98%; relative vaccine effectiveness, 6.5% [95% CI, 0.7-11.9]; P=0.027), and hospitalization for heart failure (HD-IIV, 0.11%, versus SD-IIV, 0.15%; relative vaccine effectiveness, 21.3% [95% CI, 7.6-33.0]; P=0.003).

Conclusions: In a prespecified pooled analysis of 466 320 individually randomized older adults, HD-IIV reduced the incidence of a wide range of severe cardiovascular and respiratory outcomes compared with SD-IIV, with consistent findings regardless of previous history of CVD. Among cardiovascular outcomes, the protective effect of HD-IIV versus SD-IIV was particularly pronounced against hospitalization for heart failure.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT06506812.

Keywords: effectiveness; high-dose; hospitalization; individual participant data; individual randomization; influenza; meta-analysis; pooled analysis; pragmatic; randomized controlled trial; registry; vaccine.

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Conflict of interest statement

M.M.L., R.C.H., M.D., R.v.A., and A.C. are full-time employees of Sanofi and may own shares or stock options in the company. C.S.L. has received speaker fees and served on advisory boards for GSK, MSD, Pfizer, Takeda, and Valneva. B.L.C. has received consulting fees from Amgen, Cardurion, Corvia, Myokardia, and Novartis. S.D.S. has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi, Theracos, and US2.AI and consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Puretech Health. F.M.-T. has acted as principal investigator for other studies sponsored by AstraZeneca, GlaxoSmithKline, Janssen, Medimmune, Moderna, MSD, Novavax, Novartis, Pfizer, Regeneron, Roche, Sanofi Pasteur, and Seqirus, with honoraria paid to his institution; and has consulting or advisory relationships with GlaxoSmithKline, Janssen, Medimmune, Moderna, MSD, Pfizer, Sanofi Pasteur, and Seqirus. T.B.-S. has received research grants from Bayer, Novartis, Pfizer, Sanofi Pasteur, GSK, Novo Nordisk, AstraZeneca, Boston Scientific, and GE Healthcare; consulting fees from Novo Nordisk, IQVIA, Parexel, Amgen, CSL Seqirus, GSK, and Sanofi Pasteur; and lecture fees from AstraZeneca, Bayer, Novartis, Sanofi Pasteur, GE Healthcare, and GSK. The other authors report no conflicts.

Figures

Figure 1.
Figure 1.
Primary and secondary end points according to history of cardiovascular disease. Hospitalization for influenza or pneumonia was the primary end point of the study; the remaining end points in this figure were secondary. Relative vaccine effectiveness was calculated as 1 minus the relative risk. P values for interaction were estimated by including interaction terms in log-binomial regression models adjusted for trial and season. Number needed to vaccinate corresponds to the number of individuals needed to be vaccinated with HD-IIV instead of SD-IIV to prevent one additional event and was calculated only for end points with statistically significant overall crude relative vaccine effectiveness estimates. Number needed to vaccinate within subgroups was calculated using the overall relative vaccine effectiveness estimate for the outcome in case no significant effect modification was observed. HD-IIV indicates high-dose inactivated influenza vaccine; and SD-IIV, standard-dose inactivated influenza vaccine.
Figure 2.
Figure 2.
High-dose vs standard-dose influenza vaccine against additional cardiorespiratory outcomes according to established disease at baseline. Relative vaccine effectiveness was calculated as 1 minus the relative risk. P values for interaction were estimated by including interaction terms in log-binomial regression models adjusted for trial and country and season. Number needed to vaccinate corresponds to the number of individuals needed to be vaccinated with HD-IIV instead of SD-IIV to prevent one additional event and was calculated only for end points with statistically significant overall crude relative vaccine effectiveness estimates. Number needed to vaccinate within subgroups was calculated using the overall relative vaccine effectiveness estimate for the outcome in case no significant effect modification was observed. HD-IIV indicates high-dose inactivated influenza vaccine; and SD-IIV, standard-dose inactivated influenza vaccine.
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References

    1. Iuliano AD, Roguski KM, Chang HH, Muscatello DJ, Palekar R, Tempia S, Cohen C, Gran JM, Schanzer D, Cowling BJ, et al. ; Global Seasonal Influenza-Associated Mortality Collaborator Network. Estimates of global seasonal influenza-associated respiratory mortality: a modelling study. Lancet. 2018;391:1285–1300. doi: 10.1016/S0140-6736(17)33293-2 - PMC - PubMed
    1. CDC. People at increased risk for flu complications. Influenza (Flu). 2025. Accessed April 21, 2025. https://www.cdc.gov/flu/highrisk/index.htm
    1. Kwong JC, Schwartz KL, Campitelli MA, Chung H, Crowcroft NS, Karnauchow T, Katz K, Ko DT, McGeer AJ, McNally D, et al. Acute myocardial infarction after laboratory-confirmed influenza infection. N Engl J Med. 2018;378:345–353. doi: 10.1056/NEJMoa1702090 - PubMed
    1. Kytömaa S, Hegde S, Claggett B, Udell JA, Rosamond W, Temte J, Nichol K, Wright JD, Solomon SD, Vardeny O. Association of influenza-like illness activity with hospitalizations for heart failure: the Atherosclerosis Risk in Communities Study. JAMA Cardiol. 2019;4:363–369. doi: 10.1001/jamacardio.2019.0549 - PMC - PubMed
    1. Chang T-Y, Chao T-F, Liu C-J, Chen S-J, Chung F-P, Liao J-N, Tuan T-C, Chen T-J, Chen S-A. The association between influenza infection, vaccination, and atrial fibrillation: a nationwide case-control study. Heart Rhythm. 2016;13:1189–1194. doi: 10.1016/j.hrthm.2016.01.026 - PubMed

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