Conflicting Results Emerge from Large-Scale High-Dose Influenza Vaccine Studies in Older Adults
Key Insights
Two major studies examining high-dose influenza (search) vaccines in older adults produced contradictory results, with one showing significant benefits and another finding no meaningful difference compared to standard-dose vaccines.
The FLUNITY-HD study involving 466,320 participants demonstrated that Sanofi's high-dose vaccine reduced laboratory-confirmed influenza (search) hospitalizations by 31.9% and all-cause hospitalizations by 2.2% compared to standard-dose vaccines.
A separate Danish trial with 332,438 participants found no statistically significant reduction in the primary endpoint of influenza (search) or pneumonia (search) hospitalizations, with only 5.9% relative vaccine effectiveness.
Two major clinical studies examining high-dose influenza (search) vaccines in older adults have produced starkly different results, creating uncertainty about the superior effectiveness of these formulations compared to standard-dose vaccines. The conflicting findings from studies involving nearly 800,000 participants combined may reshape clinical guidelines and vaccination strategies for older adults.
FLUNITY-HD Study Shows Significant Benefits
The FLUNITY-HD study, published in The Lancet, demonstrated that Sanofi's Efluelda (search) (known as Fluzone High-Dose in North America) significantly reduced hospitalization risks in adults 65 years and older compared to standard-dose influenza (search) vaccines. This pre-specified pooled analysis involved 466,320 participants across two pragmatic individually randomized trials: DANFLU-2 in Denmark and GALFLU in Spain's Galicia region.
The study achieved its primary endpoint, showing 8.8% additional protection against pneumonia (search)/influenza (search) hospitalizations (95% CI, 1.7 to 15.5; one-sided p=0.008). Secondary endpoints revealed even more substantial benefits:
- 31.9% additional reduction in laboratory-confirmed influenza hospitalizations (95% CI, 19.7 to 42.2; p<0.001)
- 6.3% additional reduction in hospitalizations for cardio-respiratory events (95% CI, 2.5 to 10.0; p<0.001)
- 2.2% additional protection against all-cause hospitalizations (95% CI, 0.3 to 4.1; p=0.012)
"This first-of-its-kind study assessed the benefits of the high-dose influenza vaccine (search) against severe outcomes compared to standard-dose, including against cardio-respiratory hospitalizations, in a randomized setting," said Professor Tor Biering-Sørensen, Chief Investigator of the FLUNITY-HD study.
Danish Trial Finds No Significant Difference
In contrast, a separate large-scale Danish trial published in the New England Journal of Medicine found no statistically significant benefit for high-dose influenza (search) vaccination. This open-label, randomized trial conducted over three influenza seasons (2022-2025) enrolled 332,438 participants with a mean age of 73.7 years.
The primary endpoint of hospitalization for influenza (search) or pneumonia (search) occurred in 0.68% of participants in the high-dose group compared to 0.73% in the standard-dose group, translating to a relative vaccine effectiveness of only 5.9% (95% CI, -2.1 to 13.4; P=0.14), which was not statistically significant.
While hospitalizations specifically for influenza (search) were lower in the high-dose group (0.06% vs 0.11%; relative vaccine effectiveness, 43.6%; 95% CI, 27.5 to 56.3), no meaningful differences were observed for pneumonia (search) hospitalizations, cardiorespiratory hospitalizations, or all-cause hospitalizations and deaths.
"These results provide no evidence of significant effectiveness of the high-dose vaccine compared with the standard dose against hospitalization for influenza (search) or pneumonia (search)," the Danish study authors wrote.
Study Design and Population Differences
The contrasting results may stem from differences in study design, populations, and geographic factors. The FLUNITY-HD study combined data from Denmark and Spain across multiple seasons, while the Danish-only trial focused exclusively on the Danish population. Both studies leveraged nationwide health registries for comprehensive follow-up and large-scale data capture.
The Danish trial investigators noted that using routine health data enhances generalizability but may introduce misclassification or coding variability. Additionally, shifts in respiratory testing and coding practices during the COVID-19 pandemic may have affected pneumonia (search)-related outcomes.
Clinical Implications
The conflicting findings present a challenge for clinicians and public health officials. Dr. Bogdana Coudsy, Global Head of Medical at Sanofi Vaccines, emphasized the potential impact: "For every 515 older adults who receive our high-dose flu vaccine instead of standard-dose vaccines, one all-cause hospitalization is prevented."
However, the Danish trial's findings suggest that vaccine selection may ultimately depend on patient risk factors, vaccine availability, and evolving strain circulation patterns, given that both formulations demonstrated comparable safety profiles.
High-Dose Vaccine Technology
High-dose influenza (search) vaccines are specifically designed for older adults whose immune systems gradually decline with age. These vaccines contain four times the antigen compared to standard-dose vaccines to deliver a better immune response against influenza in this vulnerable population.
Adults 65 and older represent up to 70% of flu hospitalizations, making effective vaccination strategies crucial for this demographic. The high-dose formulation aims to address the reduced immune response typically seen in older adults following standard vaccination.
Future Research Directions
These conflicting results underscore the complexity of influenza (search) vaccine effectiveness research and highlight the need for continued investigation. Previous meta-analyses had suggested that high-dose influenza vaccines reduced the risk of influenza- or pneumonia (search)-related hospitalization by as much as 23.5% compared with standard-dose formulations, but real-world evidence continues to evolve.
The studies' different outcomes may influence future clinical guidelines and public health strategies, particularly as healthcare systems seek to optimize vaccination programs for older adults during influenza (search) seasons.