Highlights
- DANFLU-2, a large pragmatic randomized trial, provides robust evidence on high-dose vs standard-dose influenza vaccine (HD-IIV vs SD-IIV) in adults ≥65 years, including subgroups with chronic kidney disease (CKD) and atherosclerotic cardiovascular disease (ASCVD).
- HD-IIV significantly reduced hospitalizations for influenza or pneumonia in CKD patients, with marked relative effectiveness compared to SD-IIV, while benefit in non-CKD individuals was negligible.
- In participants with and without pre-existing ASCVD, relative vaccine effectiveness against influenza-related and cardiovascular outcomes was consistent, with HD-IIV associated with reduced hospitalizations for cardiorespiratory disease and heart failure.
- The findings support preferential use of HD-IIV in elderly with CKD to mitigate severe influenza outcomes and suggest cardiovascular benefits beyond infection prevention in this population.
Background
Influenza infection in older adults frequently results in severe complications, especially among those with chronic comorbidities such as chronic kidney disease (CKD) and cardiovascular disease (CVD). CKD patients have compromised immune responses, predisposing them to higher risks of influenza-related hospitalization and mortality. Cardiovascular disease, including atherosclerotic cardiovascular disease (ASCVD), further amplifies risks related to influenza infection. Conventional standard-dose inactivated influenza vaccines (SD-IIV) provide suboptimal protection in these vulnerable populations.
High-dose inactivated influenza vaccines (HD-IIV) contain increased hemagglutinin antigen levels and are designed to enhance immunogenicity and clinical protection, yet limited data exist assessing their effectiveness specifically in CKD and cardiovascular subgroups. The DANFLU-2 trial, conducted over three influenza seasons (2022-2025) in Denmark, evaluated HD-IIV versus SD-IIV in a large elderly population and offers key insights into subgroup effects in CKD and ASCVD individuals.
Key Content
Study Design and Population
DANFLU-2 was a pragmatic, open-label, individually randomized controlled trial enrolling 332,438 adults aged ≥65 years in Denmark over three consecutive influenza seasons. Participants were randomized 1:1 to receive HD-IIV or SD-IIV each season, with public health registry linkage enabling comprehensive outcome ascertainment.
Subgroup analyses focused on participants with pre-existing CKD (14.1%) and ASCVD (14.1% for ASCVD—46,825/332,438 individuals), defined by ICD-10 codes and laboratory data up to 10 years prior to vaccination.
Outcomes and Measures
Primary outcomes included hospitalization for influenza or pneumonia, with secondary and exploratory cardiovascular (CV) outcomes such as hospitalization for major adverse cardiovascular events (MACE), cardiovascular disease (CVD), heart failure, and laboratory-confirmed influenza.
Relative vaccine effectiveness (rVE) of HD-IIV compared to SD-IIV was estimated for the overall cohort and subgroups with CKD and ASCVD, with attention to heterogeneity via interaction tests.
Effectiveness in Chronic Kidney Disease
Among CKD participants (n=46,788), the rVE of HD-IIV vs SD-IIV against hospitalization for influenza or pneumonia was 16.9% (95% CI: 3.4%-28.5%), indicating a statistically significant benefit favoring HD-IIV. Conversely, those without CKD showed a near-null rVE (0.6%, 95% CI: -9.6% to 9.9%; P interaction=0.046).
Absolute risk reductions translated to 0.29% fewer hospitalizations in the HD-IIV group within CKD, corresponding to a number needed to treat (NNT) of 359 to prevent one hospitalization.
Hospitalization specifically due to influenza showed even greater benefit: rVE 68.6% (95% CI: 46.7%-82.3%) in CKD vs 30.6% (95% CI: 7.2%-48.2%) in non-CKD (P interaction=0.0079), with NNTs of 561 and 3,953 respectively.
Notably, reductions in hospitalization for cardiorespiratory diseases, cardiovascular disease, heart failure, and laboratory-confirmed influenza were consistent regardless of CKD status (no significant interaction), indicating broad cardiopulmonary benefits of HD-IIV in elderly individuals.
Effectiveness in Atherosclerotic Cardiovascular Disease
The rVE of HD-IIV against hospitalization for influenza or pneumonia was similar among those with and without ASCVD (4.7% vs 6.9%; P interaction=0.80), with wide confidence intervals overlapping the null, indicating no clear differential effect.
For influenza hospitalizations, rVE was robust and comparable: 45.7% (95% CI,16.7%-65.2%) with ASCVD vs 42.9% (95% CI, 22.1%-58.4%) without ASCVD (P interaction=0.84).
Similarly, major adverse cardiovascular events (MACE) outcomes did not differ significantly by ASCVD status.
Overall Cardiovascular Outcomes
The broader analysis of cardiovascular outcomes in the DANFLU-2 trial highlighted reduced incidence of hospitalization for cardiorespiratory disease and heart failure among HD-IIV recipients. Relative vaccine effectiveness for any cardiovascular hospitalization was 7.5% (95% CI: 1.5%-12.5%). Heart failure hospitalization risk reduction was particularly notable (rVE 19.5%; 95% CI: 3.3%-33.1%).
These benefits were independent of pre-existing cardiovascular disease history, implying an overall cardioprotective effect of HD-IIV beyond influenza prevention alone.
Methodological Considerations
The trial’s pragmatic design, large sample size, and registry-based outcome ascertainment notably strengthen the validity and generalizability of the findings.
Noteworthy is the open-label design, although outcomes were objectively measured in nationwide registries and adjudicated, minimizing bias. The multiple influenza seasons enhance robustness across variable viral epidemiology.
The prespecified subgroup analyses and statistical testing for interaction afford confidence in observed heterogeneity by CKD status for influenza/pneumonia hospitalizations.
Expert Commentary
The DANFLU-2 trial addresses critical knowledge gaps regarding influenza vaccine efficacy in frail older adults with CKD and cardiovascular disease. CKD-associated immune dysregulation and increased infection susceptibility render enhanced vaccine immunogenicity imperative. The demonstrated substantial relative and absolute benefit of HD-IIV in the CKD subgroup markedly advances clinical evidence supporting preferential high-dose vaccine use in these patients.
The lack of differential benefit by ASCVD status suggests that vaccine dose escalation confers equal protection across cardiovascular risk strata, reinforcing current vaccination strategies in secondary prevention paradigms.
Cardiovascular outcome improvements observed, especially in heart failure hospitalization reduction, align with evidence linking influenza infection to acute CV events possibly through systemic inflammation and endothelial dysfunction. Preventing influenza may thus indirectly mitigate CV morbidity.
Limitations include the neutral primary outcome in the main trial on influenza/pneumonia hospitalizations overall, tempering headline interpretation of secondary cardiovascular benefits. Nevertheless, the trial size and consistent subgroup effects underscore the clinical relevance.
Contemporary guidelines might consider integrating these findings to recommend HD-IIV preferentially for elderly CKD patients and reinforce the role of influenza vaccination in cardiovascular risk mitigation.
Future research should explore immunological correlates underpinning enhanced HD-IIV efficacy in CKD and assess cost-effectiveness in targeted populations.
Conclusion
The DANFLU-2 trial sub-analyses establish that high-dose influenza vaccine confers superior protection against influenza and pneumonia hospitalization in elderly patients with chronic kidney disease, with a significantly greater relative reduction than in non-CKD elders. Cardiovascular benefits of HD-IIV, including reduced hospitalizations for heart failure and cardiorespiratory diseases, were observed regardless of baseline cardiovascular disease status. These findings support prioritizing the HD-IIV formulation for older adults with CKD and reinforce influenza vaccination’s broader impact in cardiovascular health maintenance. Implementing these insights may enhance preventive care strategies and reduce seasonal influenza-associated morbidity in high-risk elderly populations.
References
- Bartholdy KV, et al. High-Dose vs Standard-Dose Influenza Vaccine in Chronic Kidney Disease: The DANFLU-2 Trial Subgroup Analysis. J Am Coll Cardiol. 2025;86(25):2636-2647. doi:10.1016/j.jacc.2025.10.005. PMID: 41295932.
- Pareek M, et al. High-dose vs. standard-dose inactivated influenza vaccine and cardiovascular outcomes in persons with or without pre-existing atherosclerotic cardiovascular disease: the DANFLU-2 trial. Eur Heart J. 2025;46(41):4282-4290. doi:10.1093/eurheartj/ehaf678. PMID: 40884413.
- Johansen ND, et al. High-Dose vs Standard-Dose Influenza Vaccine and Cardiovascular Outcomes in Older Adults: A Prespecified Secondary Analysis of the DANFLU-2 Randomized Clinical Trial. JAMA Cardiol. 2025;10(11):1186-1194. doi:10.1001/jamacardio.2025.3460. PMID: 40884442.