Contribution To Literature:
The FLUNITY-HD trial demonstrates that the high-dose inactivated influenza vaccine provides superior protection compared with the standard-dose vaccine in preventing hospitalization for severe respiratory infections among older adults.
Study Design:
This study is a prespecified, pooled analysis that combines data from the DANFLU-2 and GALFLU trials, conducted during the 2022-2025 influenza seasons in Denmark and the 2023-2025 seasons in Spain, respectively. Both trial designs were open-label, active comparator, individually randomized, and registry-based comparisons of the relative vaccine effectiveness of the high-dose inactivated influenza vaccine (HD-IIV; 60 mg hemagglutinin antigen/strain) vs. the standard-dose inactivated influenza vaccine (SD-IIV; 15 mg hemagglutinin antigen/strain). In both studies, participants attended a single, in-person trial visit for randomization and vaccine administration, with subsequent outcomes ascertained passively from administrative health care databases.
Total number of enrollees: 466,320 older adults (332,438 from DANFLU-2 and 133,882 from GALFLU)
Duration of follow-up: from 14 days after vaccination to May 31 of the following year
Mean patient age: 73.3 years
Demographics: 48.0% female, 48.9% with at least one chronic disease, 96.2% with COVID-19 vaccination during the same season, 23.1% with cardiovascular disease, 13.9% with diabetes, 10.4% with chronic kidney disease
Inclusion Criteria:
Participants were enrolled regardless of the presence of comorbidities
DANFLU-2: Any adult aged 65 years and older
GALFLU: Community-dwelling adults aged 65-79 years
No additional exclusion criteria
Principal Findings:
Primary outcome:
The relative vaccine effectiveness (rVE) for hospitalization due to influenza or pneumonia (defined as one minus the relative risk of the outcome) was 8.8% (95% CI 1.7-15.5%, p=0.0082) for the HD-IIV as compared to the SD-IIV. The incidence of hospitalization due to influenza or pneumonia was 0.56% vs. 0.62% in HD-IIV vs. SD-IIV recipients, respectively, reflecting an estimated number needed to vaccinate of 1,839 to prevent a single hospitalization due to influenza or pneumonia.
Secondary outcomes:
For recipients of the HD-IIV vs. the SD-IIV, there was also a lower incidence of secondary outcomes including hospitalization for any cardiorespiratory disease (2.02% vs. 2.16%, rVE 6.8%, p=0.0006), lab-confirmed influenza hospitalization (0.11% vs. 0.16%, rVE 31.9%, p<0.0001), and all-cause hospitalization (8.54% vs. 8.73%, rVE 2.2%, p=0.012). The number needed to vaccinate with the HD-IIV vs. the SD-IIV to prevent a single all-cause hospitalization was 515 (95% CI 278-3929). There was no difference in all-cause mortality between the groups.
Safety outcomes were not analyzed in aggregate, and are presented in previous individual trial publications, but were reported as similar between the HD-IIV and SD-IIV groups. There was between-trial heterogeneity of effects for the primary outcome of hospitalization for influenza or pneumonia (rVE 5.9%, 95% CI -2.1 to 13.3 in DANFLU-2; rVE 23.7%, 6.6 to 37.7 in GALFLU; p for interaction = 0.055), though sensitivity analyses yielded consistent results overall.
Interpretation:
The FLUNITY-HD study, a pooled analysis of two large, international, randomized trials, demonstrated that high dose inactivated influence vaccine (HD-IIV) provides superior protection compared with the standard-dose vaccine (SD-IIV) in older adults, significantly reducing hospitalizations due to influenza or pneumonia, cardiorespiratory illnesses, laboratory-confirmed influenza, and all-causes. The study’s design enhances the generalizability of its findings to higher-risk populations by including older adults and individuals with comorbidities including cardiovascular disease, diabetes and chronic kidney disease.
Although the absolute effect sizes are modest, these findings should be interpreted in the context of the large vaccine-eligible population and the established benefits of the standard-dose inactivated influenza vaccine as the active comparator. Broad implementation of the high-dose inactivated influenza vaccine among older adults could meaningfully reduce the global burden of acute cardiorespiratory illnesses each year.
References
Presented by Dr. Manan Pareek at the American Heart Association Scientific Sessions (AHA 2025), New Orleans, LA, Nov. 10, 2025.
Keywords:
AHA Annual Scientific Sessions, AHA25