TOPLINE:

Among adults aged 65 years or older, the high-dose inactivated influenza vaccine (HD-IIV) was associated with fewer cardiorespiratory, cardiovascular, and influenza hospitalisations than the standard-dose inactivated influenza vaccine (SD-IIV), regardless of diabetes status.

METHODOLOGY:

• This secondary analysis of the DANFLU-2 trial conducted across 2022/2023 to 2024/2025 influenza seasons assessed whether HD‑IIV vs SD‑IIV reduces severe respiratory and cardiovascular outcomes in older adults and whether effectiveness differed by diabetes status and diabetes subgroups.
• Overall, 332,438 older adults (mean age, 73.7 years; 48.6% women) were randomly allocated to receive either quadrivalent HD-IIV containing 60 μg of haemagglutinin antigen per strain (n = 166,218) or quadrivalent SD-IIV containing 15 μg per strain (n = 166,220).
• The analysis included 43,881 participants with diabetes, identified using diagnostic codes from the past 10 years or A1c levels ≥ 6.5% within 5 years before randomisation.
• The follow-up period extended from 14 days post-vaccination through May 31 of the following year.
• Prespecified endpoints included hospitalisation for any cardiorespiratory disease, any cardiovascular disease, influenza, and laboratory-confirmed influenza.

TAKEAWAY:

• Overall, compared with SD-IIV, HD-IIV was associated with reduced hospitalisations for any cardiorespiratory disease, any cardiovascular disease, influenza, and laboratory-confirmed influenza.
• The benefit of HD-IIV vs SD-IIV for hospitalisation for any cardiorespiratory disease was similar between participants with and without diabetes (diabetes: relative vaccine effectiveness [rVE], 7.4%; 95% CI, -2.5% to 16.3%; no diabetes: rVE, 5.3%; 95% CI, 0.4%-10.0%; P for interaction = .69).
• Similarly, benefits of HD-IIV vs SD-IIV were observed for hospitalisation for any cardiovascular disease, influenza, and laboratory-confirmed influenza, regardless of diabetes status.
• Among participants with diabetes, those with a diabetes duration longer than 5 years derived a greater benefit from HD-IIV in reducing hospitalisation for any cardiorespiratory disease than those with a shorter diabetes duration.

IN PRACTICE:

"[The study] findings, while exploratory, underscore the importance of influenza vaccination and suggest potential benefit of HD-IIV compared with SD-IIV in individuals with diabetes," the authors wrote.

SOURCE:

This study was led by Anne Bjerg Nielsen, MD, Copenhagen University Hospital-Herlev and Gentofte, Copenhagen, Denmark. It was published online on January 12, 2026, in JAMA Internal Medicine.

LIMITATIONS:

The DANFLU-2 trial was not powered for subgroup analyses; therefore, the findings were exploratory and hypothesis generating. The results should be interpreted in the context of the neutral primary outcome of hospitalisation for influenza or pneumonia. The duration of diabetes may have been underestimated because some participants could have been diagnosed earlier than the time windows used.

DISCLOSURES:

This study was funded by Sanofi. Three authors reported being employees of the funder; one author reported holding shares in Sanofi and another reported having stock options in Sanofi. Several authors reported receiving personal fees, grants, and travel support from various pharmaceutical companies, including Sanofi.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.