A large, pragmatic randomized trial conducted in Denmark over three influenza seasons (2022–2025) found that a high-dose inactivated influenza vaccine did not significantly reduce hospitalizations for influenza or pneumonia compared with the standard-dose vaccine in adults aged 65 years and older. The trial enrolled 332,438 participants, with a mean age of 73.7 years; nearly half (48.6%) were women. The scale of this trial and its reliance on real-world registry data mark an important contribution to influenza vaccine effectiveness research, which has often been limited to observational studies.
The primary endpoint, hospitalization for influenza or pneumonia from 14 days post-vaccination through May 31, occurred in .68% of participants in the high-dose group and .73% of those in the standard-dose group. This translated to a relative vaccine effectiveness of 5.9% (95% CI, –2.1 to 13.4; P=.14), a nonsignificant difference.
Hospitalizations specifically for influenza were lower in the high-dose group (.06% vs .11%; relative vaccine effectiveness, 43.6%; 95% CI, 27.5 to 56.3). No meaningful differences were observed for pneumonia hospitalizations (.63% vs .63%; relative effectiveness, .5%), cardiorespiratory hospitalizations (2.25% vs 2.38%; relative effectiveness, 5.7%), or all-cause hospitalizations and deaths. Serious adverse event rates were similar between the two vaccine groups.
The open-label, randomized trial leveraged nationwide Danish health registries, providing comprehensive follow-up and large-scale data capture. Investigators highlighted that using routine health data enhances generalizability but may also introduce misclassification or coding variability.
What You Need To Know
In a trial of 332,438 participants, hospitalization for influenza or pneumonia occurred in .68% of high-dose recipients and .73% of standard-dose recipients (relative vaccine effectiveness, 5.9%; 95% CI, –2.1 to 13.4).
High-dose vaccination was associated with lower rates of influenza-coded hospitalizations (.06% vs .11%), but not with pneumonia or cardiorespiratory outcomes.
Both vaccine groups had similar rates of serious adverse events, underscoring comparable safety profiles.
Previous meta-analyses had suggested that high-dose influenza vaccines reduced the risk of influenza- or pneumonia-related hospitalization by as much as 23.5% compared with standard-dose formulations. The present trial, however, did not confirm a statistically significant benefit for the composite primary outcome, though reductions in influenza-coded hospitalizations were observed.
“These results provide no evidence of significant effectiveness of the high-dose vaccine compared with the standard dose against hospitalization for influenza or pneumonia. Considering this nonsignificant finding, we conducted no hypothesis testing for the secondary end points, and, therefore, no conclusions can be drawn,” the authors wrote.
Limitations of the trial include its open-label design, which could have influenced healthcare-seeking behavior, though hospitalization outcomes are less subject to bias. Reliance on administrative health data may have introduced imprecision, and influenza testing was limited to a subgroup of about 12,000 participants, raising the possibility of misclassification. In addition, shifts in respiratory testing and coding practices during the COVID-19 pandemic may have affected pneumonia-related outcomes. Finally, because the trial was conducted in Denmark using quadrivalent vaccines, the findings may not be fully generalizable to other populations or vaccine formulations.
For clinicians, these findings suggest that high-dose influenza vaccination may lower influenza-coded hospitalizations but does not clearly reduce the broader composite outcome of influenza or pneumonia hospitalizations. Given that both formulations demonstrated comparable safety profiles, vaccine selection may ultimately depend on patient risk factors, vaccine availability, and evolving strain circulation patterns.
Reference
Johansen N.D, Modein D, Loiacono M.M, et al. High-Dose Influenza Vaccine Effectiveness against Hospitalization in Older Adults. N Engl J Med. 2025;392(9):857-869. doi:10.1056/NEJMoa2509907
