Highlight
– Two of the largest individually randomized trials, DANFLU-2 and GALFLU, demonstrate that high-dose influenza vaccines provide superior protection against influenza and substantially reduce hospitalization rates compared to standard-dose vaccines in adults aged 65 years and older.
– Pooled analysis (FLUNITY-HD) of over 466,000 older adults reveals significant reductions in hospitalizations for influenza or pneumonia, cardiorespiratory diseases, and all-cause hospitalizations with the high-dose vaccine.
– Complementary data from the DAN-RSV trial indicate that respiratory syncytial virus (RSV) vaccination also reduces hospitalization in older adults, supporting incorporation of vaccines as a core pillar of cardiovascular disease prevention.
Study Background and Disease Burden
Seasonal influenza poses a significant health risk for older adults, who experience disproportionately higher rates of severe disease, complications, and hospitalizations. Influenza infections are known triggers for acute cardiovascular events, exacerbating morbidity and mortality in this high-risk group. Despite vaccination recommendations, standard-dose flu vaccines often confer suboptimal protection in elderly populations due to immunosenescence.
Efforts to enhance vaccine efficacy have focused on high-dose formulations that provide increased antigen content, aiming to elicit stronger immune responses. Previous smaller trials indicated improved immunogenicity and influenza prevention with high-dose vaccines, but robust real-world evidence assessing clinical outcomes, especially hospitalizations and cardiovascular benefits, remained limited.
Emerging data linking respiratory infections to cardiovascular complications has prompted clinical specialty bodies, including the European Society of Cardiology (ESC) and American College of Cardiology (ACC), to advocate for routine respiratory vaccination as an integral component of cardiovascular disease prevention strategies in older adults.
Study Design
The DANFLU-2 trial enrolled over 330,000 Danish adults aged 65 years and older during three consecutive influenza seasons (2022-23 through 2024-25). Participants were individually randomized to receive either a high-dose influenza vaccine containing 60 µg of antigen per strain or a standard-dose vaccine with 15 µg per strain. The primary endpoint was hospitalization for influenza or pneumonia.
Concurrently, the GALFLU trial randomized more than 103,000 adults aged 65-79 years in Galicia, Spain, during the 2023-24 and 2024-25 flu seasons using the same protocol. Both trials utilized extensive real-world data sources and electronic health records to ascertain outcomes.
Endpoints included hospitalization for laboratory-confirmed influenza, pneumonia, cardiorespiratory diseases, and hospitalizations from any cause. Secondary analyses addressed vaccine safety and cardiopulmonary hospitalization rates.
Additionally, the pooled analysis termed FLUNITY-HD combined datasets from both trials to achieve greater statistical power and assess combined endpoints. A related Danish study, DAN-RSV, examined the impact of RSV vaccination on respiratory and all-cause hospitalizations in adults aged 60 and older.
Key Findings
In DANFLU-2, although the predefined primary outcome—hospitalization for influenza or pneumonia—showed only a 6% relative risk reduction (RRR) with high-dose vaccine without reaching statistical significance, substantial benefits were observed in secondary outcomes. Hospitalizations due to influenza alone were reduced by 43.6%, cardiorespiratory disease hospitalizations by 5.7%, and all-cause hospitalizations by 2.1% relative to the standard dose. Trial investigators acknowledged that the choice of composite primary endpoint diluted the measurable effect.
Similarly, GALFLU faced limitations due to fewer-than-anticipated influenza cases reducing statistical power. Despite this, the high-dose vaccine was associated with a 23.7% lower risk of hospitalization for influenza or pneumonia and a 31.8% reduction specifically for influenza hospitalizations. Cardiopulmonary hospitalizations were reduced by 8.4%. The robustness of findings was supported by large sample size, complete data capture, and consistency with prior evidence.
The pooled FLUNITY-HD analysis encompassing over 466,000 older adults demonstrated statistically significant and clinically meaningful reductions in the primary composite endpoint, laboratory-confirmed influenza hospitalizations, cardiorespiratory hospitalizations, and all-cause hospitalizations with high-dose vaccines compared to standard-dose.
The DAN-RSV trial, conducted in parallel, found RSV vaccination in adults over 60 years significantly lowered hospitalizations related to RSV respiratory tract infections, RSV lower respiratory tract disease, and all-cause respiratory illnesses—a novel finding that strengthens the cardiopulmonary protective role of vaccines.
Regarding safety, no unexpected adverse events or safety signals emerged, aligning with the established safety profile of high-dose formulations.
Expert Commentary
The large-scale, individually randomized trials DANFLU-2 and GALFLU are landmark studies that provide compelling real-world evidence supporting enhanced influenza vaccination strategies for older adults. Despite design challenges related to endpoint selection and lower-than-expected flu incidence, the aggregate data convincingly favor high-dose vaccines for reducing clinically relevant hospitalizations.
Tor Biering-Sørensen, MD, MPH, PhD, principal investigator of DANFLU-2, reflected on trial design lessons noting that had influenza hospitalizations alone been chosen as the primary endpoint, the results would have demonstrated even stronger significance. This underscores the critical need for endpoint precision in vaccine effectiveness trials.
Federico Martinón-Torres, MD, PhD, lead investigator of GALFLU, emphasized that the study’s large cohort and data completeness reinforce the clinical relevance of the findings, despite underpowering relative to initial assumptions.
These findings align with the recent ESC consensus recommending vaccination as the fourth pillar of cardiovascular prevention, alongside pharmacotherapies for hypertension, lipid management, and diabetes. Moreover, ACC guidelines now advocate respiratory vaccinations—including influenza, COVID-19, and RSV vaccines—for adults with cardiovascular disease to mitigate infection-triggered cardiac events.
Pathophysiologically, influenza and RSV infections trigger systemic inflammatory responses, endothelial dysfunction, and prothrombotic states that elevate risks for myocardial infarction, arrhythmias, and decompensated heart failure. Effective vaccination thus represents a strategic intervention to prevent these downstream cardiac complications.
Limitations include the trials’ reliance on real-world data with potential misclassification biases and lack of mechanistic biomarkers. Nonetheless, the large sample sizes and consistency across multiple outcomes increase confidence in generalizability to older populations in diverse settings.
Conclusion
The DANFLU-2 and GALFLU trials, augmented by pooled FLUNITY-HD analyses, establish that high-dose influenza vaccination significantly reduces hospitalizations due to influenza, pneumonia, cardiorespiratory, and all causes in adults aged 65 and older. Complementary evidence for RSV vaccine further expands the protective scope against respiratory illnesses linked to cardiovascular complications.
These data substantiate recent guideline endorsements integrating vaccination into cardiovascular prevention frameworks, especially for vulnerable elderly patients. Clinicians should consider preferential use of high-dose influenza vaccines in older adults to optimize outcomes.
Future research should refine endpoint definitions, explore vaccine efficacy across varied viral strains, and elucidate immunologic mechanisms linking respiratory infections with cardiovascular pathology. The integration of vaccination into routine cardioprotective regimens promises a paradigm shift improving both infectious and cardiovascular health outcomes in aging populations.
References
1. Biering-Sørensen T, et al. High-Dose Influenza Vaccine to Reduce Hospitalizations. N Engl J Med. 2025; DOI:10.1056/NEJMoa2509834.
2. Martinón-Torres F, et al. Largest-Ever Individually Randomized Trials Show High-Dose Flu Vaccines Reduce Hospitalizations. N Engl J Med. 2025; DOI:10.1056/NEJMoa2508157.
3. European Society of Cardiology. ESC Guidance on Vaccination and Cardiovascular Disease Prevention. 2025.
4. American College of Cardiology. Vaccination Recommendations for Adults with Cardiovascular Disease. 2025.
5. Biering-Sørensen T, et al. Prevention of RSV-Related Hospitalizations in Older Adults via Vaccination. N Engl J Med. 2025; DOI:10.1056/NEJMoa250… (Published forthcoming)
