Dr Niklas Dyrby Johansen (Herlev and Gentofte Hospital, Denmark) pointed out that several previous studies have indicated that influenza infection is strongly associated with heart failure and myocardial infarction hospitalisations, coupled with evidence that influenza vaccination can prevent cardiovascular events1-3. The DANFLU-1 study (NCT05048589) aimed to address the unmet need that to date, no randomised trial has assessed the effects of high-dose, compared with standard-dose, quadrivalent influenza vaccines on severe clinical outcomes such as hospitalisations and mortality in a general population of older adults which would conclusively determine the potential public health value of high-dose vaccines4.
However, to achieve this goal, a very large sample size would be required. DANFLU-1 was therefore conducted as a feasibility trial, which integrated a pragmatic open-label randomised trial into the official Danish vaccination programme.
The primary endpoint was feasibility (e.g. number of participants included and randomised to each vaccine, agreement between randomisation assignment and actual received vaccine, the balance between groups in terms of number of subjects in each arm and baseline characteristics, and a comparison of baseline characteristics with the overall Danish general population aged 65 to 79 years). The secondary endpoint was to determine the relative vaccine effectiveness (rVE) of the high-dose compared with the standard-dose for cardiovascular and respiratory endpoints.
Participants aged 65 to 79 years were randomised 1:1 to either high-dose (n=6,245) or standard-dose (n=6,232) influenza vaccine. Baseline characteristics were comparable with the overall Danish population aged 65 to 79 years.
The primary endpoint for feasibility was met; registry-based data collection and complete follow-up information was available for >99.9% of participants. The initial efficacy results were promising: High-dose recipients had a lower incidence of hospitalisation for influenza or pneumonia (0.2%) compared with standard-dose recipients (0.4%) and a rVE of 64.4% (95% CI 24.4–84.6; P<0.001). High-dose recipients also had a lower incidence of all-cause mortality (0.3% vs 0.7%, respectively) and a rVE of 48.9% (95% CI 11.5–71.3; P<0.001). There were no significant differences in serious adverse events between the different doses.
The researchers concluded that integrating an influenza vaccine trial into the Danish vaccination programme was feasible, and estimate that a fully powered trial to establish superiority of high-dose influenza vaccines will require a sample size of approximately 200,000 participants.