Highlights
- High-dose inactivated influenza vaccine (HD-IIV) consistently outperforms standard-dose vaccine (SD-IIV) in reducing hospitalizations among adults aged 65 and older.
- The benefit of HD-IIV is comparable between individuals with and without diabetes for cardiorespiratory, cardiovascular, and influenza-specific hospitalizations.
- Participants with a diabetes duration of more than five years may derive a significantly greater relative benefit from high-dose vaccination regarding cardiorespiratory outcomes.
- These findings support the preferential use of HD-IIV in older populations with metabolic comorbidities to mitigate severe systemic complications of influenza.
Background
Influenza is not merely a respiratory ailment; in older adults, it acts as a significant trigger for acute cardiovascular events and severe respiratory failure. This vulnerability is particularly pronounced in individuals with diabetes mellitus, a population characterized by chronic low-grade inflammation and impaired immune responses. While the high-dose inactivated influenza vaccine (HD-IIV) is known to elicit stronger antibody responses and reduce laboratory-confirmed influenza compared to standard-dose vaccines (SD-IIV), its specific impact on preventing severe downstream clinical outcomes—such as cardiovascular hospitalizations—in the diabetic subset of the elderly has remained insufficiently characterized. The DANFLU-2 trial was designed to bridge this evidence gap using a pragmatic, randomized approach within a nationwide health system.
Key Content
The DANFLU-2 Trial Design and Population
The DANFLU-2 study was a pragmatic, open-label, individually randomized clinical trial conducted across several influenza seasons in Denmark. The study leveraged Denmark’s comprehensive nationwide health registries to track clinical outcomes with high precision. In this prespecified secondary analysis, researchers evaluated 332,438 participants with a mean age of 73.7 years. Within this cohort, 43,881 (13.2%) were identified as having diabetes. Participants were randomized 1:1 to receive either the HD-IIV (containing 60 µg of hemagglutinin per strain) or the SD-IIV (containing 15 µg per strain).
Relative Vaccine Effectiveness (rVE) and Primary Outcomes
The analysis demonstrated that HD-IIV was associated with a reduction in the risk of several critical hospitalization categories regardless of diabetes status:
- Influenza Hospitalization: The rVE for participants with diabetes was 41.6% (95% CI, 5.0%-64.7%), which was nearly identical to the 44.3% rVE observed in those without diabetes (Interaction P = .87).
- Cardiorespiratory Hospitalization: A consistent benefit was observed (rVE 7.4% for diabetes vs. 5.3% for no diabetes; Interaction P = .69).
- Cardiovascular Hospitalization: HD-IIV showed a trend toward superior protection in both groups (rVE 12.0% for diabetes vs. 6.0% for no diabetes; Interaction P = .38).
The Impact of Diabetes Duration
A pivotal finding of this secondary analysis was the modification of vaccine effect based on the duration of diabetes. In participants who had been diagnosed with diabetes for more than five years, HD-IIV showed a substantial benefit for cardiorespiratory hospitalizations, with an rVE of 20.4% (95% CI, 5.3%-33.1%). Conversely, in those with a shorter disease duration (less than five years), the relative benefit was negligible (rVE -0.4%; Interaction P = .03). This suggests that as the physiological burden of diabetes accumulates over time, the enhanced protection provided by a higher antigen dose becomes increasingly critical.
Expert Commentary
From a clinical perspective, the DANFLU-2 secondary analysis reinforces the “high-dose is better” paradigm for the elderly, specifically validating its efficacy in a high-risk metabolic subgroup. The mechanistic rationale for the superior performance of HD-IIV in patients with long-standing diabetes likely stems from the phenomenon of immunosenescence, which is accelerated by chronic hyperglycemia. Prolonged diabetes leads to advanced glycation end-products and oxidative stress that further impair T-cell and B-cell function.
The finding that diabetes duration modifies the vaccine’s effect is particularly salient for health policy. It suggests that older adults with more advanced disease states may have a higher “number needed to treat” with standard vaccines to achieve protection, making the high-dose alternative more cost-effective and clinically imperative in this specific cohort. While the study is limited by its open-label design, the use of objective registry-based hospitalization data minimizes bias and provides robust real-world evidence.
Conclusion
The secondary analysis of the DANFLU-2 trial provides strong evidence that HD-IIV is more effective than SD-IIV in preventing severe influenza-related complications in older adults, including those with diabetes. The consistent relative vaccine effectiveness across diabetic and non-diabetic populations—and the potentially enhanced benefit for those with long-standing disease—supports clinical guidelines that prioritize high-dose vaccines for the elderly. Future research should continue to explore whether specific glycemic control levels (HbA1c) further influence these outcomes and how the high-dose vaccine performs against emerging influenza variants in metabolic populations.
References
- Nielsen AB, Johansen ND, Modin D, et al. High-Dose vs Standard-Dose Influenza Vaccine in Older Adults With Diabetes: A Secondary Analysis of the DANFLU-2 Randomized Clinical Trial. JAMA Intern Med. 2026;186(3):311-320. PMID: 41525066.
- DiazGranados CA, Dunning AJ, Kimmel M, et al. Efficacy of high-dose versus standard-dose influenza vaccine in older adults. N Engl J Med. 2014;371(7):635-645. PMID: 25119609.
- Gravenstein S, Davidson HE, Taljaard M, et al. Comparative effectiveness of high-dose versus standard-dose influenza vaccination on inflammatory and cardiovascular hospitalizations and mortality in nursing home residents: a cluster-randomized clinical trial. Lancet Respir Med. 2017;5(9):738-746. PMID: 28736045.
