High-Dose Influenza Vaccination Reduces Hospitalizations and Cardiovascular Events in Older Adults: Insights from the FLUNITY-HD Pooled Analysis

Introduction: The Intersection of Influenza and Cardiovascular Health

For decades, clinicians have observed a seasonal surge in cardiovascular events that parallels the peak of influenza activity. Influenza is not merely a respiratory pathogen; it acts as a systemic inflammatory trigger that can precipitate acute myocardial infarction, exacerbate heart failure, and increase the risk of stroke. In older adults, whose immune systems undergo immunosenescence, the standard-dose inactivated influenza vaccine (SD-IIV) may provide suboptimal protection. This clinical gap led to the development of the high-dose inactivated influenza vaccine (HD-IIV), which contains four times the antigen content of the standard dose. While previous studies indicated better protection against laboratory-confirmed influenza, the FLUNITY-HD individual-level pooled analysis provides the most robust evidence to date regarding the vaccine’s impact on severe clinical outcomes, particularly cardiovascular hospitalizations.

The FLUNITY-HD Trial Design: A Large-Scale Pragmatic Approach

The FLUNITY-HD study represents a prespecified, individual-level pooled analysis of two methodologically harmonized pragmatic, individually randomized trials: DANFLU-2, conducted across several seasons in Denmark, and GALFLU, conducted in Galicia, Spain. The pooling of these data allowed for a massive sample size of 466,320 participants, enhancing the statistical power to detect differences in relatively rare but severe endpoints.

Study Population and Intervention

The analysis included adults aged 65 years or older (DANFLU-2) and community-dwelling adults aged 65-79 years (GALFLU). Participants were randomized in a 1:1 ratio to receive either HD-IIV (60 μg of haemagglutinin per strain) or SD-IIV (15 μg of haemagglutinin per strain). The demographic profile was representative of the European elderly population, with a mean age of 73.3 years. Notably, 48.9% of the cohort had at least one chronic condition, and 23.1% had a documented history of cardiovascular disease (CVD).

Methodology and Endpoints

The trials utilized routine healthcare databases for follow-up, ensuring a comprehensive capture of hospitalization data from 14 days post-vaccination through May 31 of the following year. The primary endpoint for the pooled analysis was hospitalization for influenza or pneumonia. Secondary endpoints included hospitalizations for cardiorespiratory disease, laboratory-confirmed influenza, all-cause hospitalization, and all-cause mortality. A specific secondary analysis, published in Circulation, focused on cardiovascular outcomes, including heart failure and the influence of pre-existing CVD on vaccine effectiveness.

Key Findings: Superior Protection Against Respiratory and All-Cause Hospitalizations

The results from the Lancet-published analysis confirm the superior efficacy of HD-IIV over SD-IIV in preventing severe clinical outcomes.

Primary and Secondary Respiratory Outcomes

The primary endpoint of hospitalization for influenza or pneumonia occurred in 0.56% of the HD-IIV group compared to 0.62% in the SD-IIV group. This translates to a relative vaccine effectiveness (rVE) of 8.8% (95% CI 1.7 to 15.5; p=0.0082). Even more striking was the reduction in laboratory-confirmed influenza hospitalizations, where HD-IIV demonstrated an rVE of 31.9% (95% CI 19.7 to 42.2; p<0.0001). Using ICD-10 coded hospitalizations specifically for influenza, the rVE reached 39.6%.

All-Cause Hospitalization and Mortality

HD-IIV also provided a significant, albeit smaller, reduction in all-cause hospitalizations (rVE 2.2%; 95% CI 0.3 to 4.1; p=0.012). This finding is particularly relevant for health systems and policy makers, as it suggests that the benefits of high-dose vaccination extend beyond specific respiratory diagnoses to overall geriatric stability. However, no significant difference was observed in all-cause mortality (rVE 1.2%; p=0.38), likely due to the multifaceted nature of mortality in this age group and the relatively short follow-up period.

Cardiovascular Benefits: The Circulation Analysis

The secondary analysis published in Circulation delved into the cardiovascular implications of the FLUNITY-HD data. The findings suggest that the benefits of HD-IIV are not confined to the lungs.

Reductions in Cardiovascular Hospitalizations

HD-IIV significantly reduced the incidence of hospitalization for any CVD (rVE 6.6%; 95% CI 1.6 to 11.4; p=0.010). The most profound effect was seen in hospitalizations for heart failure, where the HD-IIV group experienced a 21.3% reduction compared to the SD-IIV group (95% CI 7.6 to 33.0; p=0.003). This is a critical finding, as heart failure is a leading cause of hospitalization in the elderly and is known to be frequently exacerbated by respiratory infections.

The Impact of Pre-existing Disease

A key question addressed was whether the high-dose vaccine is more effective in those already diagnosed with heart disease. The analysis showed that the benefits of HD-IIV were consistent regardless of whether the participant had a history of CVD (p-interaction > 0.66). This implies that HD-IIV is beneficial for both primary and secondary prevention of influenza-related cardiovascular complications.

Safety and Tolerability

Safety is a paramount concern in the elderly population. The FLUNITY-HD analysis found that the incidence of serious adverse events was similar between the two groups (16,032 events in the HD-IIV group vs. 15,857 in the SD-IIV group). While high-dose vaccines are known to cause slightly more frequent local reactions (such as injection site pain), these were not found to translate into an increase in serious systemic events in this large-scale pragmatic setting.

Expert Commentary: Mechanistic Insights and Clinical Implications

The findings of FLUNITY-HD reinforce the biological plausibility that higher antibody titers, induced by the increased antigen load in HD-IIV, provide a more robust shield against the systemic inflammatory cascade triggered by influenza.

Vaccination as a Cardiovascular Intervention

From a cardiological perspective, these results support the concept of ‘vaccine-preventable cardiovascular disease.’ By preventing the initial viral infection and the subsequent surge in pro-inflammatory cytokines, HD-IIV helps maintain hemodynamic stability. The 21.3% reduction in heart failure hospitalizations is comparable to the effect sizes seen with some pharmacological heart failure therapies, suggesting that optimized vaccination should be a standard component of cardiovascular care.

Public Health and Policy Considerations

Despite the higher cost of HD-IIV compared to SD-IIV, the reduction in all-cause and cardiovascular hospitalizations suggests significant potential for cost-offset. For health systems, preventing hospitalizations in the elderly is a high-priority goal to reduce bed-occupancy and healthcare spending during winter months. The consistent results across two different national health systems (Denmark and Spain) further enhance the generalizability of these findings.

Conclusion

The FLUNITY-HD individual-level pooled analysis provides definitive evidence that the high-dose inactivated influenza vaccine is superior to the standard-dose vaccine in protecting older adults from severe outcomes. By reducing hospitalizations for influenza, pneumonia, and particularly heart failure, HD-IIV offers a significant clinical advantage. These results advocate for the preferential use of high-dose vaccines in the 65+ population to mitigate the dual burden of respiratory and cardiovascular disease during the influenza season.

Funding and ClinicalTrials.gov

The FLUNITY-HD study was funded by Sanofi. The pooled analysis is registered with ClinicalTrials.gov under the identifier NCT06506812.

References

1. Johansen ND, et al. High-Dose vs. Standard-Dose Influenza Vaccine and Cardiovascular Outcomes in Older Adults: The FLUNITY-HD Prespecified Pooled Analysis. Circulation. 2025; doi: 10.1161/CIRCULATIONAHA.125.077801.
2. Johansen ND, et al. Effectiveness of high-dose influenza vaccine against hospitalisations in older adults (FLUNITY-HD): an individual-level pooled analysis. Lancet. 2025;406(10518):2425-2434. doi: 10.1016/S0140-6736(25)01742-8.