High-dose inactivated influenza vaccine (HD-IIV) demonstrated significantly greater effectiveness in reducing severe outcomes and hospitalizations compared with standard-dose inactivated influenza vaccine (SD-IIV), based on findings from the FLUNITY-HD pooled analysis published in The Lancet.

The analysis, authored by Niklas Dyrby Johansen, MD, Daniel Modin, MD, et al., focuses on the results from two large-scale studies out of Denmark and Spain – DANFLU-2 and GALFLU. Both studies were released at ESC Congress 2025 and looked at the impact of HD-IIV vs. SD-IIV in preventing hospitalization for influenza or pneumonia in adults over the age of 65 years.

All told, the FLUNITY-HD analysis included 466,320 individually randomized participants from both trials and spanned two geographic areas and three different seasons. The incidence of hospitalization for influenza or pneumonia among this combined group was 0.56% in the HD-IIV group and 0.62% in the SD-IIV group (relative vaccine effectiveness (rVE) was 8.8%).

“Nearly 9% of hospitalisations for influenza or pneumonia were prevented with HD-IIV compared with SD-IIV,” said Johansen, et al. “Importantly, similar rVE estimates were observed in comorbid patients with higher baseline risk of the primary endpoint, suggesting that the number needed to vaccinate per case averted in these populations would be lower.”

Researchers also noted that patients in the HD-IIV group compared with those in the SD-IIV group had fewer incidences of all-cause hospitalizations, as well as hospitalizations for cardio-respiratory-related events and laboratory-confirmed influenza. “The 6.3% reduction in cardio-respiratory hospitalisations with HD-IIV versus SD-IIV represents a clinically meaningful finding with important implications for cardiovascular preventive care, warranting consideration in clinical practice guidelines,” they said.

In other findings, death from all causes and serious adverse events occurred with similar frequency in both groups. The effectiveness of HD-IIV and SD-IIV remained consistent across seasons and subgroups, researchers said. According to the authors, the FLUNITY-HD findings provide “critical and timely evidence” that can be used to help not only inform treatment discussions between clinicians and patients but assist with the development of public health and vaccination strategies globally.

“These findings provide the first definitive evidence of the superior protection of HD-IIV vs. SD-IIV against hospitalisation outcomes – severe outcomes of great importance to patients, clinicians, and decision makers,” write Johansen, Modin and colleagues. “…These findings confirm the full breadth of protection conferred by HD-IIV beyond influenza infection, from specific LCI hospitalisations to broader all-cause hospitalisations, consistently across seasons. With a number-needed-to vaccinate of 515 older adults to prevent one all-cause hospitalisation, a simple switch from SD-IIV to HD-IIV could substantially reduce burden on health systems.”

In a related editorial comment published in JACC, Paul A. Heidenreich, MD, MS, FACC, highlights the value of “giga-trials” like FLUNITY-HD, which involve more than 100,000 patients. “Such a large number of participants allows the detection of very small be benefits of treatment,” he writes. “At a population level, any benefit is important if it can be provided at a reasonable cost.” Heidenreich also notes that FLUNITY-HD demonstrates “the importance of combining data to inform clinical practice.” Previously thought impossible, these trials are proving to be feasible, he says, provided they are “incorporated into the flow of clinical care and use easily extracted health system data for outcomes.”