Introduction: The Dual Threat of Influenza and Diabetes in the Aging Population
Influenza remains a formidable public health challenge, particularly for the geriatric population. For individuals aged 65 years and older, the intersection of immunosenescence—the gradual decline of the immune system with age—and chronic comorbidities creates a landscape of high vulnerability. Among these comorbidities, diabetes mellitus stands out as a significant risk factor for severe influenza-related outcomes. Patients with diabetes are not only at a higher risk of contracting the virus but are also more likely to experience severe complications, including pneumonia, cardiovascular events, and prolonged hospitalizations.
While the high-dose inactivated influenza vaccine (HD-IIV) has been shown to provide superior protection compared to the standard-dose inactivated influenza vaccine (SD-IIV) in the general elderly population, its specific efficacy within the diabetic subgroup has remained a subject of clinical inquiry. The DANFLU-2 trial’s secondary analysis provides much-needed clarity on whether the increased antigen content of HD-IIV translates into tangible clinical benefits for this high-risk demographic.
The Rationale for High-Dose Vaccination in Diabetes
Individuals with diabetes often exhibit altered immune responses. Chronic hyperglycemia can impair neutrophil function, diminish cytokine production, and alter T-cell activity. When coupled with the natural decline in immune vigor seen in older adults, the ‘standard’ vaccine dose may not elicit an antibody response robust enough to prevent severe disease. HD-IIV contains four times the amount of hemagglutinin antigen (60 µg per strain vs. 15 µg in SD-IIV), aiming to overcome this suboptimal immune response.
Prior studies have established the efficacy of HD-IIV in preventing laboratory-confirmed influenza, but the DANFLU-2 secondary analysis shifts the focus toward ‘hard’ clinical endpoints: hospitalizations due to cardiorespiratory and cardiovascular events. This is particularly relevant given the known link between influenza infection and acute myocardial infarction or exacerbations of heart failure, risks that are already elevated in diabetic patients.
Study Design: A Pragmatic Approach via DANFLU-2
The DANFLU-2 trial was a large-scale, pragmatic, open-label, individually randomized clinical trial conducted in Denmark. Pragmatic trials are designed to evaluate the effectiveness of interventions in real-life routine practice settings, making the results highly generalizable to clinical practice. The study spanned multiple influenza seasons (2022/2023 to 2024/2025) and utilized Denmark’s robust nationwide health registries to track participant outcomes.
Participants included 332,438 adults aged 65 years or older. They were randomized in a 1:1 ratio to receive either the HD-IIV or the SD-IIV. Out of the total cohort, 43,881 participants (13.2%) had a diagnosis of diabetes. The study’s primary objective in this secondary analysis was to determine the relative vaccine effectiveness (rVE) of HD-IIV versus SD-IIV against severe outcomes, specifically looking at how diabetes status might modify these effects.
Key Findings: Consistent Protection Across the Board
The results of the analysis provide strong evidence for the use of HD-IIV in the elderly. Overall, the high-dose vaccine was associated with a significant reduction in cardiorespiratory, cardiovascular, and influenza-specific hospitalizations.
Cardiorespiratory Hospitalizations
For participants with diabetes, the rVE of HD-IIV against cardiorespiratory hospitalization was 7.4% (95% CI, -2.5% to 16.3%). For those without diabetes, the rVE was 5.3% (95% CI, 0.4% to 10.0%). Crucially, the interaction P-value was 0.69, indicating that the vaccine’s effectiveness did not significantly differ based on whether the patient had diabetes or not.
Cardiovascular Hospitalizations
Similar trends were observed for cardiovascular outcomes. The rVE for patients with diabetes was 12.0% (95% CI, -0.9% to 23.3%), while for those without diabetes, it was 6.0% (95% CI, -0.4% to 12.0%). Again, no significant interaction was found (P = 0.38), suggesting consistent benefit.
Influenza-Specific Hospitalizations
The most dramatic reductions were seen in influenza-specific hospitalizations. Participants with diabetes saw a 41.6% reduction (95% CI, 5.0% to 64.7%) when using the high-dose vaccine, compared to a 44.3% reduction (95% CI, 25.3% to 58.7%) in the non-diabetic group (Interaction P = 0.87).
The Impact of Diabetes Duration: A Critical Subgroup Insight
One of the most intriguing findings from this analysis was the potential modification of vaccine effect by the duration of diabetes. The researchers discovered that participants who had lived with diabetes for longer than five years appeared to derive a more pronounced benefit from the high-dose vaccine.
For those with a diabetes duration >5 years, the rVE for cardiorespiratory hospitalization was 20.4% (95% CI, 5.3% to 33.1%). In contrast, those with a shorter duration of the disease (<5 years) showed an rVE of -0.4% (95% CI, -13.8% to 11.5%). This interaction was statistically significant (P = 0.03). This suggests that as the duration of metabolic disease increases—likely correlating with greater cumulative physiological stress and potentially more profound immune impairment—the added value of a higher antigen dose becomes even more critical.
Expert Commentary: Mechanistic Insights and Clinical Utility
From a clinical perspective, these findings reinforce the current shift toward preferential recommendation of enhanced influenza vaccines for the elderly. The data suggests that the protective effect of HD-IIV is robust and extends to the prevention of severe secondary complications like heart failure exacerbations or pneumonia, which are major drivers of mortality in the diabetic population.
The biological plausibility for the greater benefit in long-term diabetes may lie in the concept of ‘inflammaging.’ Long-standing diabetes accelerates the aging of the immune system. By providing a higher dose of antigen, the HD-IIV may successfully trigger a threshold of B-cell activation and antibody production that the standard dose simply cannot reach in an exhausted immune environment.
Study Strengths and Limitations
A major strength of this study is its scale and the use of high-quality registry data, which minimizes loss to follow-up and provides a comprehensive view of hospitalization trends across an entire national population. The randomized design also reduces the risk of healthy-user bias, which often plagues observational studies of vaccine effectiveness.
However, limitations must be noted. As a secondary analysis, the study might have limited statistical power for some specific subgroups. Additionally, the pragmatic nature means that while hospitalizations were tracked accurately, laboratory confirmation of influenza for every cardiorespiratory event was not always possible, though the influenza-specific hospitalization endpoint helps mitigate this concern.
Conclusion: Moving Toward Precision Vaccination
The DANFLU-2 secondary analysis confirms that high-dose influenza vaccination is a superior strategy for reducing hospitalizations in older adults, irrespective of their diabetes status. The evidence is particularly compelling for those with long-standing diabetes, a group that represents one of the most vulnerable segments of our healthcare system.
For clinicians and health policy experts, these results support the routine use of HD-IIV in the elderly. As we move toward more personalized medicine, understanding how specific comorbidities and their duration affect vaccine response will be essential in optimizing preventative care and reducing the global burden of seasonal influenza.
Funding and Clinical Trial Information
The DANFLU-2 trial was supported by various health research foundations and conducted through the Danish nationwide health infrastructure. ClinicalTrials.gov Identifier: NCT05517174.
