Findings from the DANFLU-2 and GALFLU trials on high-dose influenza vaccines and the DAN-RSV trial evaluating a bivalent respiratory syncytial virus (RSV) prefusion F protein–based vaccine add to the growing body of evidence surrounding the benefits of influenza and RSV vaccinations in preventing hospitalizations. All three were presented at ESC Congress 2025.

In DANFLU-2 out of Denmark, 332,438 older adult patients over the age of 65 years (48.6% women) were randomized to receive either a high dose of the influenza vaccine or a standard dose. Conducted during the 2022-2023, 2023-2024 and 2024-2025 flu seasons, the primary endpoint was hospitalization for influenza or pneumonia that occurred from 14 days post-vaccination through May 31 of the following year.

Overall findings from the trial, simultaneously published in NEJM, found that the high-dose inactivated influenza vaccine did not result in a significantly lower incidence of hospitalization for influenza or pneumonia compared with a standard dose among older adults (0.68% vs. 0.73%, respectively). However, Niklas Dyrby Johansen, MD, PhD, et al., note that secondary endpoint results "are consistent with possible benefits of the high-dose vaccine over the standard-dose vaccine for prevention of hospitalization for influenza and cardiorespiratory disease."

Among the secondary findings, an analysis published in JAMA Cardiology, found reduced incidence of cardiorespiratory hospitalization among DANFLU-2 participants who received the high-dose influenza vaccine vs. the standard dose. This was driven by a lower incidence of cardiovascular-related hospitalizations, and particularly heart failure (HF) hospitalizations. "These differences should be interpreted as exploratory findings in the setting of a large RCT with a neutral primary outcome," said Johansen, et al.

In a related editorial, Robert M. Califf, MD, MACC, writes: "DANFLU-2 trial clarifies the small differences in clinical outcomes between two doses of influenza vaccine. More importantly, though, it highlights what we need to do to understand the most effective interventions. Better health outcomes would ensue if health systems, insurance companies, and federal agencies worked together to build a learning health system for better patient outcomes, vs. the current obsession with financialization of every transaction. We now have the technology and methods to clarify the road ahead on the health care highway—let's use them."

Like DANFLU-2, GALFLU, also simultaneously published in NEJM, also compared high-dose influenza vaccination with standard dose in older adults over 65 years to gauge impact on hospitalizations for influenza and pneumonia. Conducted in Galicia, Spain, the trial randomized a total of 103,169 participants over the course of the 2023-2024 and 2024-2025 influenza seasons.

Results showed fewer hospitalizations for influenza or pneumonia among those assigned to the high-dose influenza vaccine compared with the standard dose. "Because of a lower-than-expected incidence of influenza, the number of cases needed to perform formal statistical testing was not reached," said said lead author Jacobo Pardo‑Seco, PhD, et al. "However, the observed incidence of hospitalization for influenza or pneumonia seemed to be lower among those who received the high-dose vaccine than among those who received the standard-dose vaccine. At the population level, such differences could translate into a meaningful effect on the health care system."

Moving from influenza to RSV, the DAN-RSV trial, simultaneously published in JAMA, found the bivalent RSVpreF prevented cardiorespiratory hospitalizations in older adults. In the randomized trial of more than 130,000 adults over the age of 60 years, the incidence of all-cause cardiorespiratory hospitalization was significantly lower in the RSVpreF group compared with the control group (26.3 vs. 29.2 events per 1,000 participant-years).

Study investigators, including Mats C. Højbjerg Lassen, MD, noted similar effects for participants with and without preexisting cardiovascular disease. "For isolated cardiovascular events, no statistically significant between-group differences were observed," said Lassen, et al. "The findings suggest potential downstream cardiorespiratory benefits of RSV immunization."

In a related prespecified analysis of DAN-RSV published in JACC, Kristoffer Grundtvig Skaarup, MD, et al., found that RSVpreF vaccination was associated with reduced risks of RSV-related, respiratory and cardio-respiratory hospitalizations. There were no appreciable differences between individuals with and without HF and across HF subgroups.

Similarly in JAMA, findings from the IVY Network study investigating respiratory viruses in the acutely ill showed one dose of RSV vaccine prevented RSV-associated hospitalization during two RSV seasons.

"Findings in this multicenter, test-negative, case-control study of 6,958 adults with RSV, estimated RSV vaccine effectiveness against RSV-associated hospitalization during two seasons was 58%," said Diya Surie, MD, et al. "Vaccine effectiveness was 69% when vaccination occurred in the same season before illness onset and 48% when vaccination occurred in the prior season; these estimates were not statistically significantly different."

In a related editorial, Helen Y. Chu, MD, MPH, and Alastair F. Murray, MD, write: "Vaccines remain one of the greatest public health achievements, and large-scale evaluations such as this one have the power to reveal benefits that extend beyond prevention of the target infection. Recognizing these broader impacts underscores that vaccination is not simply a tool for infection prevention but an intervention that is also capable of shaping outcomes in cardiovascular health."