A secondary analysis of a large, randomized clinical trial published this week in JAMA Internal Medicine suggests that high-dose influenza vaccination provides added protection against severe respiratory and cardiovascular outcomes in adults 65 years and older, including those with diabetes, a group at elevated risk for flu-related complications.
The analysis, led by a team from Copenhagen University Hospital, included more than 332,000 older adults in Denmark who were vaccinated across three flu seasons (2022–23 through 2024–25). Of all participants, approximately 44,000 (13%) had diabetes.
Participants were randomly assigned to receive either a high-dose inactivated influenza vaccine (HD-IIV), which contains four times the amount of antigen of standard-dose vaccines, or a standard-dose inactivated influenza vaccine (SD-IIV). The researchers then used nationwide health registries to track respiratory and cardiovascular hospitalizations.
Overall, receipt of HD-IIV was associated with reductions in hospitalization for cardiorespiratory disease (diabetes relative vaccine effectiveness (rVE), 7.4%; no diabetes rVE, 5.3%), cardiovascular disease (diabetes rVE, 12.0%; no diabetes rVE, 6.0%), and influenza (diabetes rVE, 41.6%; no diabetes rVE, 44.3%) compared with receipt of SD-IIV. The protective benefits of the high-dose vaccine were similar in people with and without diabetes.
‘Greater absolute benefit’ for people with diabetes
While the analysis suggests that HD-IIV offers protective benefits to adults with and without diabetes, it may confer “greater absolute benefit” to people with diabetes. That’s because people with diabetes are at higher risk for serious flu-related complications, so each vaccination in that population is more likely to prevent a serious illness, note the authors.
The analysis also suggests that HD-IIV offers greater protection to those who have had diabetes for five years or longer, as well as those with diabetes-related complications, compared with those with less severe cases.
“Although exploratory and requiring confirmation in future research, these findings could imply that for certain end points, the protective benefits of HD-IIV compared with SD-IIV may be more prominent in individuals with more advanced diabetes,” write the researchers. Individuals with greater disease burden may have a suboptimal immune response to SD-IIV, as well as increased susceptibility to flu-related complications, speculate the authors.
The DANFLU-2 trial is one of the largest individually randomized influenza vaccine trials conducted to date and the largest to include people with diabetes. The findings, the researchers said, “suggest that the effects of HD-IIV vs SD-IIV against severe respiratory and cardiovascular outcomes remain consistent regardless of diabetes status” and they “underscore the importance of influenza vaccination and suggest potential benefit of HD-IIV compared with SD-IIV in individuals with diabetes.”
