A pair of large-scale trials reveal that a stronger influenza vaccine offers far greater protection than the standard version—not just against the flu itself, but also against hospitalizations linked to pneumonia and heart–lung complications.

Experts say the findings could reshape vaccination strategies for older adults, positioning flu shots as a key pillar in cardiovascular disease prevention worldwide.

Two major real-world clinical trials have now provided compelling evidence that a high-dose influenza vaccine significantly outperforms the standard-dose regimen. The studies, DANFLU-2 in Denmark and GALFLU in Spain, both showed that administering a higher antigen dose not only improved defense against influenza infections but also led to substantial reductions in flu-related hospitalizations. Results from both trials were published in the New England Journal of Medicine and presented at the 2025 European Society of Cardiology (ESC) Congress in Madrid.

Researchers stressed that these results go beyond traditional flu protection. The data suggest that enhanced vaccination could help prevent broader health risks, including pneumonia, cardiopulmonary complications, and even all-cause hospital admissions—making vaccination a preventive tool with far-reaching implications.

The Danish Experience: DANFLU-2

The DANFLU-2 trial enrolled over 330,000 adults aged 65 and older across three flu seasons (2022–2025). Participants were randomly assigned to receive either a high-dose vaccine—containing 60 µg of antigen per strain—or the standard 15 µg formulation.

Although the trial’s primary outcome, hospitalization for influenza or pneumonia, showed only a modest relative risk reduction of about 6% (and was not statistically significant), several secondary findings stood out. Notably, hospitalizations for influenza alone dropped by 43.6%, cardiorespiratory-related hospitalizations fell by 5.7%, and hospitalizations for any cause declined by 2.1%.

Lead investigator Dr. Tor Biering-Sørensen of the University of Copenhagen remarked with candor: “We designed the trial with the wrong primary outcome. If influenza hospitalizations had been our sole endpoint, the results would have shown a much stronger benefit.”

Spanish Findings: GALFLU

Meanwhile, the GALFLU trial, which included more than 103,000 adults aged 65–79 in Galicia during the 2023–2025 flu seasons, faced its own hurdles. A lower-than-expected incidence of flu limited the ability to achieve full statistical power. Despite this, the results still demonstrated a clear benefit of the high-dose vaccine.

The trial reported a 23.7% lower risk of hospitalization for influenza or pneumonia, a striking 31.8% reduction in influenza hospitalizations, and an 8.4% drop in cardiopulmonary-related hospitalizations compared with the standard-dose group.

“Even though the trial was underpowered relative to its initial assumptions, the consistency of the findings and their clinical significance remain undeniable,” said Dr. Federico Martinón-Torres, who led the study. He emphasized that the large sample size, robust data collection, and alignment with prior research strengthen confidence in the outcomes.

Pooled Power: The FLUNITY-HD Analysis

What truly solidified the evidence was the pooled analysis of both trials, known as the FLUNITY-HD study. By combining data from more than 466,000 older adults across two countries, researchers were able to overcome the statistical challenges that hampered individual trials.

The pooled results revealed substantial and statistically significant reductions in hospitalizations for influenza or pneumonia, laboratory-confirmed flu infections, cardiorespiratory conditions, and even all-cause hospitalizations. These findings are set to be published in The Lancet.

Beyond Influenza: RSV Protection

Complementary findings from another Danish trial, DAN-RSV, further highlighted the broader potential of vaccination in protecting older adults. In this study, vaccination against respiratory syncytial virus (RSV) sharply reduced the risk of RSV-related respiratory tract disease, including lower respiratory tract infections, and cut hospitalizations from both RSV-specific and all-cause respiratory illnesses.

Vaccines as Cardiovascular Medicine

The growing body of evidence is prompting cardiology experts to advocate for vaccines as an essential part of cardiovascular prevention. The European Society of Cardiology recently issued a consensus statement urging that routine vaccination be considered the “fourth pillar” of cardiovascular prevention, alongside blood pressure control, lipid-lowering therapy, and diabetes management. The American College of Cardiology echoed this guidance, recommending that adults with heart disease receive vaccination against influenza, COVID-19, RSV, and other relevant pathogens.

Dr. Biering-Sørensen summarized the significance: “These results help us better understand how respiratory infections drive cardiovascular outcomes—and, importantly, how improved vaccines can help us prevent those outcomes in the future.”