Combined results from two large real-world trials of a high-dose influenza vaccine have found not only does the higher dose provide superior protection against influenza than the standard regimen, it also is better at preventing hospitalizations. 

The results of the DANFLU-2 and GALFLU trials were published today in the New England Journal of Medicine and presented at the 2025 congress of the European Society of Cardiology in Madrid.

The data reinforce recent calls for vaccination against influenza and other respiratory infections to be part of regular cardiovascular prevention strategies for older adults.

“Wrong Primary Outcome”

DANFLU-2 involved more than 330,000 adults aged 65 years and older in Denmark during the 2022-23, 2023-24, and 2024-25 flu seasons. The individuals were randomly assigned to receive either a high-dose (60 µg of antigen per strain) or standard-dose vaccine (15 µg of antigen per strain). 

Fewer people in the high-dose group experienced the primary endpoint of hospitalization for influenza or pneumonia, with a relative risk reduction of around 6%, but the result was not statistically significant. 

The researchers also observed differences in rates of hospitalization for influenza alone (relative risk reduction [RRR], 43.6%), cardiorespiratory disease (RRR, 5.7%), and hospitalization for any cause (RRR, 2.1%).

“We designed the trial with the wrong primary outcome,” Tor Biering-Sørensen, MD, MPH, PhD, a cardiologist at the University of Copenhagen, who led the trial, said wryly. “The results would have been different if we had chosen influenza hospitalizations alone.”

Investigators on the GALFLU trial, which involved more than 103,000 adults aged 65-79 in Galicia, Spain, during the 2023-24 and 2024-25 flu seasons, experienced similar statistical difficulties. 

The researchers observed fewer cases of flu than expected during the study, so the number needed for formal statistical testing was not reached. But Federico Martinón-Torres, MD, PhD, director of Translational Pediatrics and Infectious Diseases at the Hospital Clínico Universitario de Santiago, Santiago, Spain, who led the study, said the higher dose was associated with a 23.7% lower risk for hospitalization due to influenza or pneumonia, a 31.8% reduction in influenza hospitalizations, and 8.4% fewer cardiopulmonary hospitalizations.

“Despite being underpowered relative to its initial assumptions, the study still detected significant and clinically relevant differences, not only for the primary outcome but also for other prespecified endpoints,” he said. “The large sample size, high data completeness, and consistency with prior evidence reinforce the robustness of our findings.”

Combined Results Are Positive

The statistical problems were largely overcome by the fact that the two trials were designed using the same DANFLU-2 protocol so that their results could be combined in a pooled analysis, the FLUNITY-HD study, which Biering-Sørensen also led and presented at ESC. The FLUNITY-HD data will be published in an upcoming issue of The Lancet.

The combined results, encompassing more than 466,000 adults, showed significant reductions in the primary endpoint of influenza or pneumonia hospitalizations, as well as cardiorespiratory hospitalizations, laboratory-confirmed influenza hospitalizations, and hospitalizations from any cause.

In a related study, DAN-RSV, the Danish group also found vaccination against respiratory syncytial virus (RSV) significantly reduced the incidence of hospitalization for RSV-related respiratory tract disease in adults 60 years and older, as well as hospitalizations for RSV-related lower respiratory tract disease and for all-cause respiratory tract disease, compared with unvaccinated people. The findings were published in NEJM and presented at ESC by Biering-Sørensen.

Vaccines for the Heart

The importance of vaccination as a cardioprotective effort has been highlighted recently by the European Society of Cardiology, which issued a consensus statement in June calling for routine vaccination to become the fourth major pillar of cardiovascular prevention alongside antihypertensives, lipid-lowering drugs, and medications that treat diabetes. That was followed this month by a recommendation from the American College of Cardiology that adults with heart disease should get vaccinated against a range of respiratory viruses, including influenza, COVID, and RSV, and other diseases where vaccination is shown to offer cardiovascular protective benefits.

The results of the flu and RSV trials provide more evidence to support those recommendations. “The combined information that we received from these clinical trials provides some insights into the pathophysiology of how these infections can lead to cardiovascular outcomes, and which outcomes we potentially could prevent by providing our patients with an improved vaccine,” Biering-Sørensen said.

DANFLU-2 and GALFLU were funded by Sanofi. The DAN-RSV trial was funded by Pfizer. Sørensen and Martinón-Torres have disclosed financial relationships with several companies. See full study for details.

Brian Owens is a freelance writer in New Brunswick, Canada.