Highlights
- The DANFLU-2 trial, a large-scale pragmatic study in Denmark, compared high-dose versus standard-dose inactivated influenza vaccines in 332,438 older adults.
- The high-dose vaccine did not significantly reduce the primary endpoint of hospitalization for influenza or pneumonia (relative vaccine effectiveness [rVE], 5.9%; P=0.14).
- A significant reduction was observed in influenza-specific hospitalizations (rVE, 43.6%) and cardiorespiratory hospitalizations (rVE, 5.7%).
- Serious adverse events were comparable between the high-dose and standard-dose groups.
Introduction: The Challenge of Influenza in the Aging Population
The burden of influenza remains disproportionately high among older adults, a population characterized by immunosenescence—a gradual decline in immune function that reduces both the response to infection and the efficacy of standard vaccinations. To address this, high-dose inactivated influenza vaccines (HD-IIV) were developed, containing four times the antigen content of standard-dose vaccines (SD-IIV). While previous efficacy trials have demonstrated that HD-IIV provides superior protection against laboratory-confirmed influenza, evidence regarding its effectiveness in preventing severe clinical outcomes like hospitalization in large, real-world populations has remained less definitive.
The DANFLU-2 Trial: Study Design and Methodology
The DANFLU-2 trial was a pragmatic, open-label, randomized controlled trial conducted across three influenza seasons (2022–2025) in Denmark. The study leveraged the country’s robust nationwide administrative health registries, allowing for a massive sample size and comprehensive follow-up.
Population and Intervention
The study enrolled 332,438 participants aged 65 and older. Participants were randomized in a 1:1 ratio to receive either the high-dose quadrivalent inactivated influenza vaccine or the standard-dose quadrivalent inactivated influenza vaccine. The mean age of the cohort was 73.7 years, with a balanced gender distribution (48.6% women).
Endpoints
The primary endpoint was the first occurrence of hospitalization for influenza or pneumonia between 14 days post-vaccination and May 31 of the following year. Secondary endpoints included influenza-specific hospitalization, pneumonia-specific hospitalization, cardiorespiratory-related hospitalization, all-cause hospitalization, and all-cause mortality.
Key Findings: A Granular Look at Clinical Outcomes
The results of the DANFLU-2 trial provide a nuanced view of vaccine performance. While the high-dose vaccine showed clear benefits in specific areas, it failed to meet the threshold for statistical significance for its primary composite goal.
Primary Endpoint: Influenza or Pneumonia Hospitalization
A total of 1,138 participants (0.68%) in the high-dose group and 1,210 (0.73%) in the standard-dose group were hospitalized for influenza or pneumonia. The resulting relative vaccine effectiveness (rVE) was 5.9% (95.2% CI, -2.1 to 13.4), with a P-value of 0.14. Because the confidence interval crossed zero, the study could not conclude that the high-dose vaccine was superior for this combined metric.
Secondary Endpoint: Influenza-Specific Hospitalization
In contrast to the primary endpoint, the vaccine’s performance against influenza-specific hospitalization was robust. The incidence was 0.06% in the high-dose group versus 0.11% in the standard-dose group, representing an rVE of 43.6% (95.2% CI, 27.5 to 56.3). This significant finding confirms that the higher antigen load successfully translates into better protection against severe influenza-related illness.
Pneumonia and Cardiorespiratory Outcomes
Hospitalization for pneumonia alone showed virtually no difference between groups (rVE, 0.5%; 95.2% CI, -8.6 to 8.8). However, the high-dose vaccine did provide a statistically significant reduction in hospitalizations for cardiorespiratory diseases, with an rVE of 5.7% (95.2% CI, 1.4 to 9.9). This suggests that preventing influenza may have a downstream effect on preventing the exacerbation of chronic heart or lung conditions.
All-Cause Mortality and Safety
There was no significant difference in all-cause mortality between the two groups (rVE, -2.5%). Safety profiles were reassuringly similar, with no significant increase in serious adverse events in the high-dose group despite the higher antigen concentration.
Expert Commentary: Why the Primary Endpoint Missed Significance
The divergence between the primary endpoint (influenza or pneumonia) and the secondary endpoint (influenza-specific) is the most critical aspect of the DANFLU-2 trial for clinicians to understand.
The Dilution Effect of Pneumonia
Pneumonia is a syndrome with diverse etiologies, including bacterial pathogens (like Streptococcus pneumoniae), other respiratory viruses (like RSV), and non-infectious causes. Because an influenza vaccine is only designed to prevent influenza-related pneumonia, its effect is naturally ‘diluted’ when combined with pneumonia from all other causes. In this trial, pneumonia hospitalizations (0.63%) far outnumbered influenza hospitalizations (0.06% to 0.11%). This suggests that while the vaccine was highly effective against its specific target, the background rate of non-influenza pneumonia was too high for the HD-IIV to shift the needle on the combined total.
Pragmatic Trial Strengths and Weaknesses
The use of administrative registries is a double-edged sword. It allows for a massive, representative population but relies on ICD-10 coding by various clinicians across a national health system. Adjudication of ‘influenza’ versus ‘pneumonia’ in a busy clinical setting may lack the precision of laboratory-confirmed research protocols, potentially introducing noise into the data.
Public Health Implications and Clinical Practice
Despite the non-significant primary result, the DANFLU-2 data support the continued use of high-dose vaccines in the elderly. The 43.6% reduction in influenza-specific hospitalizations is clinically meaningful, particularly during severe flu seasons. Furthermore, the reduction in cardiorespiratory hospitalizations reinforces the ‘indirect’ benefits of influenza vaccination—preventing the viral trigger that often leads to myocardial infarction or heart failure exacerbation in vulnerable seniors.Health policy experts must weigh the higher cost of HD-IIV against these benefits. While the reduction in all-cause hospitalization was modest (2.1%) and not statistically significant, the specific protection against influenza and cardiorespiratory events remains a strong argument for high-dose regimens in high-risk geriatric populations.
Conclusion
The DANFLU-2 trial underscores the complexity of measuring vaccine effectiveness against broad clinical syndromes like pneumonia. While the high-dose inactivated influenza vaccine did not significantly lower the combined risk of influenza and pneumonia hospitalizations, it demonstrated superior protection against influenza-specific hospitalizations and cardiorespiratory events compared to the standard dose. For clinicians, the trial reaffirms that HD-IIV is a safe and effective tool for reducing the most direct consequences of influenza infection in older adults.
Funding and Clinical Trial Information
This trial was funded by Sanofi. DANFLU-2 is registered with ClinicalTrials.gov (NCT05517174) and the EU Clinical Trials Register (2022-500657-17-00).
References
Johansen ND, Modin D, Loiacono MM, et al. High-Dose Influenza Vaccine Effectiveness against Hospitalization in Older Adults. N Engl J Med. 2025 Dec 11;393(23):2291-2302. doi: 10.1056/NEJMoa2509907. Epub 2025 Aug 30. PMID: 40888720.
