Flu Vaccination Associated With Lower Risk of Major Cardiovascular Events in Older Adults

Influenza (flu) vaccination was associated with a reduced risk of major adverse cardiovascular events (MACE) in older adults, according to results from a retrospective cohort study presented at Infectious Disease Week 2025.¹

MACE risk reduction was garnered primarily through direct, non-infectious mechanisms, rather than flu prevention, according to the study authors.¹

Why is Flu Vaccination Important for Cardiovascular Risk?

Clinical guidance recommends an annual flu vaccination for all adults based on its ability to reduce cardiovascular and all-cause morbidity and mortality. Past researchers have demonstrated the importance of flu vaccination in this setting; one meta-analysis including over 6000 individuals found a 36% lower risk of MACE in vaccine recipients compared with placebo or unvaccinated patients.^1,2

Novel investigations are ongoing to further elucidate the impact of flu vaccination on cardiovascular outcomes. For example, the recent DANFLU-2 trial results suggest that high-dose flu vaccination confers protection against specific cardiovascular outcomes, such as myocarditis and pericarditis. Flu vaccination has also been shown to protect against influenza-related hospitalizations and pneumonia, especially high doses.^1,3

Although flu vaccination has consistently been associated with reduced cardiovascular risk, investigators have struggled to determine whether the benefit is incurred due to infection prevention, moderation of disease severity, or other behavioral or biological explanations.¹

What Did the Investigators Find?

Using a novel mediation analysis, the current study authors sought to unravel the mechanisms behind MACE reductions following influenza vaccination. A retrospective cohort analysis of adults aged 65 and older with at least 1 polymerase chain reaction (PCR) flu test during the 2023-2024 influenza season. Electronic health record data was utilized to identify vaccination status and laboratory-confirmed influenza infection.¹

MACE, which was the study’s primary outcome, was defined as any diagnosis of acute myocardial infarction (AMI) or stroke as per the International Classification of Diseases, 10^th Revision within 7 days of influenza testing. Using a counterfactual framework, causal mediation analysis was employed to determine the total effect of vaccination on MACE and its decomposition into indirect, direct, and interaction effects.¹

Cross-tabulation of patient demographics provided 7-day incidence of acute myocardial infarction (AMI), stroke, and composite MACE across 4 groups, separated according to vaccination and influenza status. The lowest rate of MACE (2.1%) occurred among vaccinated, flu-positive individuals, while the highest (6.8%) was observed among unvaccinated, flu-negative individuals. These preliminary data indicate the potential vaccine-associated cardiovascular protection, regardless of flu infection positivity.¹

A total of 15,793 participants were deemed eligible and included in the analysis. Of these, 2973 (19%) were vaccinated, while 982 (6.2%) were positive for influenza. Across the entire cohort, 6.4% of enrollees experienced a MACE event.¹

Vaccinated individuals reported lower MACE incidence than unvaccinated individuals (5.2% vs 6.6%; P = .003). A multivariable analysis was employed to confirm the protective effect of vaccination (odds ratio [OR] = 0.71; P < .001). Mediation analysis indicated that most of this effect was direct (OR = 0.71; P < .001), while the indirect effect—through flu infection—was deemed negligible (OR = 1.005).¹

There was a small, albeit statistically significant, mediated interaction observed (OR = 1.008; P = .04), indicating minimal modification of flu-related cardiovascular risk by vaccination.¹

What Are the Implications of This Data?

These insights provide critical background to how influenza vaccination works to reduce the risk of MACE. Rather than garnering effects through flu prevention, influenza vaccination provides direct, non-infectious protection through reductions in systemic inflammation, improvements in endothelial function, and plaque stabilization.^1,4,5

More research into these mechanisms is essential given the limited number of corresponding studies that describe specific pathways for non-infectious protection. However, these results provide positive indications for the vast benefits that influenza vaccination can give patients beyond infection prevention. As guidelines already suggest, routine influenza vaccination should be a hallmark of cardiovascular protection in at risk patients.^1,2

REFERENCES

1. Khoury AE, Martin E, Ladikos CD, Albar Z, Farah JA. P-1433: Direct vs. indirect effects of influenza vaccination on cardiovascular risk: A causal mediation study. Poster Session: Vaccines for All Ages. Presented: IDWeek 2025, Atlanta, Georgia. October 21, 2025. Accessed Online October 16, 2025. https://idweek2025.eventscribe.net/searchbyposterbucket.asp?f=PosterSessionName&pfp=BrowsebyPosterSession

2. Ferruggia K. New clinical guidance recommends vaccines to protect cardiovascular patients from respiratory illness. Pharmacy Times. Published September 2, 2025. Accessed October 16, 2025. https://www.pharmacytimes.com/view/new-clinical-guidance-recommends-vaccines-to-protect-cardiovascular-patients-from-respiratory-illness

3. Valletti D. High-dose influenza vaccine linked to lower risk of myocarditis, pericarditis in older adults. Pharmacy Times. September 4, 2025. Accessed October 17, 2025. https://www.pharmacytimes.com/view/high-dose-influenza-vaccine-linked-to-lower-risk-of-myocarditis-pericarditis-in-older-adults

4. Talaat KR, Halsey NA, Cox AB, et al. Rapid changes in serum cytokines and chemokines in response to inactivated influenza vaccination. Influenza Other Respir Viruses. 2018;12(2):202-210. doi:10.1111/irv.12509

5. Bermudez-Fajardo A, Oviedo-Orta E. Influenza vaccination promotes stable atherosclerotic plaques in apoE knockout mice. Atherosclerosis. 2011;217(1):97-105. doi:10.1016/j.atherosclerosis.2011.03.019