BARCELONA – A Danish feasibility study that tested a high-dose quadrivalent influenza vaccine versus a standard dose hinted at morbidity and mortality benefits, researchers reported.

In the DANFLU-1 study, there was a 48.9% reduction in the risk of all-cause mortality and a 64% reduction in the incidence of hospitalization for influenza or pneumonia for high-dose versus standard-dose vaccination. Also, hospitalization for cardiorespiratory complaints — a combination of any cardiovascular or respiratory illnesses — was reduced by 12% with the high-dose vaccine, according to Tor Biering-Sørensen, MD, PhD, MPH, of the University of Copenhagen.

Less than 1% of patients in both trial arms died in the 14 days after being vaccinated against influenza, and there were no significant differences in serious adverse events between the high-dose and standard-dose groups, he reported in a presentation at the European Society of Cardiology (ESC) meeting.

However, Biering-Sørensen emphasized that “this is just a hypothesis-generating finding because this was just a pilot trial that was not powered for outcomes.” The open-label DANFLU-1 enrolled about 12,000 patients (median age 71.7; 47.1% women), and a study with a larger patient population is needed to support the results, he added.

“That study is now being planned,” Biering-Sørensen told MedPage Today. “We know that to have a definitive result we will have to enroll 208,000 Danish citizens to have sufficient power to assess whether the high-dose vaccine will reduce outcomes for pneumonia or influenza, and also to see if the high dose will reduce the risk of cardiovascular outcomes.”

High-dose vaccines contain 60 μg of hemagglutinin antigen for each strain, while standard-dose vaccines contain 15 μg, and “high-dose vaccines are approved for adults aged 65 years and older in most countries, and for those 60 years and older in some countries,” he explained in an ESC press release. ” However, only a few countries offer older adults a high-dose vaccine by default. Thus, high-dose vaccines are not widely implemented despite accumulating evidence of additional protection against influenza infection and influenza-related morbidity compared with standard-dose vaccines.”

Biering-Sørensen noted that he would use the high dose for his patients now because “we already know that the high dose protects at least 25% greater than the standard dose against influenza. We know that the high dose can prevent against the influenza, but we cannot yet say that the high dose prevents hospitalization.”

Amit Khera, MD, a spokesperson for the American Heart Association, told MedPage Today that “in the United States, the high dose is generally recommended for the elderly because there is a better immune response.” Previous research has that the flu vaccine was tied to a lower risk of fatal and nonfatal cardiovascular events within a year. Khera is at the University of Texas Southwestern Medical School in Dallas.

He reiterated that the DANFLU-1 “was underpowered to show which dose prevented outcomes.” Also, patients in the trial were “all-comers” over age 65, “but not necessarily those with cardiovascular disease.”

Khera, who was not involved in the study, said that he offered high-dose influenza vaccine to his elderly patients, and that the current trial “does remind us that vaccine is feasible, it is safe, and whether the high dose or low dose is the right dose, it doesn’t take away the necessity to vaccinate our vulnerable patients.”

The trial was integrated into the Danish vaccination program, with only one study visit at the time of vaccination, and registry-based follow-up occurring after. Enrollment began in October 2021, and was completed within the next 2-3 weeks, with 11,463 patients enrolled in the first 15 days of the trial.

Biering-Sørensen explained at a ESC press conference that “conducting an innovative pragmatic randomized trial in Denmark using administrative health registries as the primary data source was feasible. Integrating an influenza vaccine trial into the official Danish vaccination program was also feasible. The next step is to conduct a fully powered trial of high-dose versus standard-dose quadrivalent influenza vaccine in older adults.”

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