High-Dose Influenza Vaccine Linked to Lower Risk of Myocarditis, Pericarditis in Older Adults

Annual influenza vaccination remains a cornerstone of preventive care for older adults, but questions regarding the cardiovascular safety and efficacy of different vaccine formulations persist. A new analysis of the DANFLU-2 trial (NCT05517174) suggests that a high-dose inactivated influenza vaccine may confer greater protection not only against influenza infection but also against certain inflammatory cardiac complications, compared with the standard-dose vaccine.¹

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The DANFLU-2 trial was a randomized, open-label trial across 3 consecutive flu seasons, and it included more than 332,000 participants aged 65 and over in Denmark from 2022 to 2025. ¹ Participants were randomized to receive either a quadrivalent high-dose inactivated vaccine containing 60 mcg of hemagglutinin antigen per strain or the standard-dose quadrivalent vaccine containing 15 mcg.

A secondary analysis revealed that cases of myocarditis and pericarditis were less frequent in the high-dose vaccine group compared with the standard-dose group. Specifically, there were 19 events in the high-dose group versus 35 events in the standard-dose group, yielding a relative vaccine effectiveness of 45.7% (95% CI, 2.46-70.67; P = .04).¹ No myocarditis cases occurred in the high-dose group, whereas 2 were observed in the standard-dose group. Pericarditis accounted for the majority of cases, with 19 in the high-dose cohort and 33 in the standard-dose group.

Although myocarditis has occasionally been reported following influenza vaccination, the authors emphasized that their findings do not support a causal relationship, noting that results were consistent regardless of whether events occurring immediately after vaccination were included.¹

Notably, 68.3% of participants had myocarditis or pericarditis before vaccination. The group with preexisting conditions was mostly male and, on average, older and had a higher prevalence of other diseases such as chronic cardiovascular disease, atrial fibrillation, and hypertension.¹

Beyond potential cardiovascular safety advantages, prior studies have already demonstrated that high-dose influenza vaccines elicit stronger immune responses in older adults.² High-dose formulations have been associated with improved protection against influenza-related hospitalizations, pneumonia, and mortality compared with standard-dose shots.²^,³ The new DANFLU-2 analysis adds another dimension by suggesting reduced risks of cardiac inflammatory events—an important consideration in a population with elevated baseline cardiovascular risks.

The secondary analysis of the DANFLU-2 trial indicates that the administration of a high-dose flu vaccine to older adults may lessen the frequency of myocarditis and pericarditis, after which the standard-dose injection is the next best choice. Further research is required to validate the results and to investigate the extent to which these results apply to different populations, though the outcomes give an optimistic signal to the doctors and pharmacists making the decisions of whether to administer a high dose. In a population where flu-related complications and cardiovascular disease are the 2 major health problems, a high-dose vaccine may add a protective shield for vulnerable patients.

REFERENCES

1. Johansen ND, Modin D, Loiacono MM, et al. High-Dose vs Standard-Dose Influenza Vaccine and Cardiovascular Outcomes in Older Adults: A Prespecified Secondary Analysis of the DANFLU-2 Randomized Clinical Trial. JAMA Cardiol. Published online August 30, 2025. doi:10.1001/jamacardio.2025.3460

2. DiazGranados CA, Dunning AJ, Kimmel M, et al. Efficacy of High-Dose versus Standard-Dose Influenza Vaccine in Older Adults. New England Journal of Medicine. 2014;371(7):635-645. doi:https://doi.org/10.1056/nejmoa1315727

3. Izurieta HS, Chillarige Y, Kelman J, et al. Relative Effectiveness of Influenza Vaccines Among the United States Elderly, 2018-2019. J Infect Dis. 2020;222(2):278-287. doi:10.1093/infdis/jiaa080