High-Dose Influenza Vaccine Reduces Risk of Myocarditis and Pericarditis in Older Adults

Use of a high-dose inactivated influenza vaccine (HD-IIV) was associated with reduced risk of myocarditis or pericarditis compared with a standard-dose influenza vaccine (SD-IIV) in adults aged 65 years or older, according to a prespecified secondary analysis of the randomized DANFLU-2 trial.

"The [HD-IIV] significantly reduces the incidence of laboratory-confirmed influenza infection compared with [SD-IIVs] among older adults. However, it is unknown whether HD-IIV reduces the risk of myocarditis or pericarditis, and it has not previously been possible to explore this hypothesis given the large sample size needed," Tor Biering-Sørensen, MD, PhD, of the University of Copenhagen in Denmark, and colleagues wrote in the study published online August 30, 2025, in JAMA Network Open.

DANFLU-2 was a pragmatic, registry-based, open-label randomized trial conducted in Denmark across the 2022–2023, 2023–2024, and 2024–2025 influenza seasons. A total of 332 438 participants were randomized 1:1 to HD-IIV or SD-IIV. Mean age was approximately 74 years, and 51% were men. Baseline characteristics were balanced across treatment groups, though participants with a history of myocarditis or pericarditis were older, more often men, and had higher rates of cardiovascular comorbidity.

Follow-up extended from day 14 post-vaccination through the end of each influenza season. The prespecified exploratory endpoint for this analysis was hospitalization for myocarditis or pericarditis identified by International Classification of Diseases, Tenth Revision (ICD-10) codes.

Over follow-up, 19 myocarditis or pericarditis events were recorded in the HD-IIV group versus 35 in the SD-IIV group, corresponding to a relative vaccine effectiveness (rVE) of 45.7% (95% CI, 2.5%-70.7%; P = .04). Results were consistent when including events that occurred within the first 14 days after vaccination. Rates of discontinuation and adverse events were low and similar between groups, according to the study results.

"Despite sporadic reports of myocarditis and pericarditis associated with influenza vaccination, the consistency of our results with vs without inclusion of events occurring immediately after vaccination negates a dose-response association and a causal link," Biering-Sørensen and colleagues wrote.

Subgroup analysis showed that associations were consistent across baseline characteristics. No dose-response signal was detected when comparing events with or without the early post-vaccination period, suggesting the findings were not attributable to vaccine-related inflammatory cardiac reactions. Only two myocarditis events occurred, limiting interpretation for this specific outcome.

Influenza infection has been linked with an increased risk of myocarditis and pericarditis, but vaccine-related cardiac inflammation is rare and typically mild. The authors emphasized that this is the largest randomized study to assess cardiac outcomes with an enhanced influenza vaccine and that HD-IIV may provide an added benefit in reducing inflammatory cardiac events in older adults.

Limitations. The number of events was small, and severity or etiology could not be determined. The analysis did not include comparison with unvaccinated individuals, and generalizability to younger populations remains uncertain.

Source: Pareek M, Johansen ND, Modin D, et al. Risk of myocarditis or pericarditis with high-dose vs standard-dose influenza vaccine: a prespecified secondary analysis of the randomized DANFLU-2 trial. JAMA Netw Open. 2025;8(8):e2536889. doi:10.1001/jamanetworkopen.2025.36889