In a phase 3 randomized controlled clinical trial published yesterday in the New England Journal of Medicine, Moderna’s investigational mRNA-based seasonal flu vaccine provided significantly better protection against influenza illness than standard-dose flu shots in adults 50 years and older.
The findings arrive after a swirl of regulatory uncertainty surrounding the trivalent (three-strain) vaccine, mRNA-1010. Earlier this year, the US Food and Drug Administration (FDA) unexpectedly declined to review Moderna’s application for the vaccine after previously indicating support for the company’s phase 3 trial.
The move raised concerns about shifting regulatory standards under the leadership of Health and Human Services Secretary Robert F. Kennedy Jr., who has been openly critical of mRNA vaccines. A week later, however, the FDA reversed course and agreed to review the application.
mRNA vaccine ‘superior’ to standard dose
The trial enrolled 40,703 adults at 301 sites in 11 countries during the 2024-25 Northern Hemisphere flu season. A team led by researchers from Ghent University and Moderna randomly assigned participants to receive either 50 micrograms of mRNA-1010 or a standard-dose flu vaccine. The median follow-up was about six months.
In total, 2.0% of 20,179 participants who received mRNA-1010 contracted flu, compared with 2.8% of 20,124 standard-dose recipients. That translated to a relative vaccine efficacy (rVE) of 26.6%, which met “the criteria for noninferiority, superiority, and higher-level superiority.”
The team also found that rVE for mRNA-1010 was generally consistent across three different circulating flu strains—29.6% against influenza A/H1N1; 22.2% against A/H3N2; and 29.1% against B/Victoria. The vaccine also appeared to perform consistently among higher-risk groups. Among the 19,260 participants 65 years or older, the rVE was 27.4%.
There were also fewer flu-related healthcare visits among mRNA-1010 recipients. Eighty mRNA-1010 vaccinees sought care for flu-related symptoms, compared with 120 recipients of standard-dose vaccine. That translates to an rVE of 33.7%.
Closer strain match possible with mRNA
The authors acknowledge that enhanced vaccines such as high-dose, adjuvanted, or recombinant-based formulations, generally protect older adults better than standard-dose vaccines. But their effectiveness can vary from year to year, depending on how well the vaccine matches the flu strains circulating that season.
Because mRNA-1010 uses mRNA technology instead of traditional egg-based methods, it could be updated more quickly to match circulating flu strains.
Because mRNA-1010 uses mRNA technology instead of traditional egg-based methods, it could be updated more quickly to match circulating flu strains. Egg-based production can also introduce mutations, making the vaccine match the season’s circulating strain less closely.
Similar rate of serious side effects
Side effects were more common with the mRNA vaccine, though most were mild to moderate and short-lived. Injection-site pain was reported in 65.8% of mRNA-1010 recipients, compared with 29.8% of standard-dose recipients. Fatigue, headache, and muscle aches were also more frequent among mRNA vaccine recipients. Serious adverse events were uncommon and occurred at similar rates in both groups—2.2% in the mRNA group and 1.9% in the standard-dose group.
The flu is estimated to cause as many as 5 million severe illnesses and up to 650,000 deaths each year, according to the World Health Organization, and it carries a higher risk of complications for older adults. “Improved vaccine efficacy in adults 50 years of age or older is needed, given the increased morbidity and mortality in this population,” the authors write. “These findings support the role of mRNA-1010 in improving influenza prevention.”
