Moderna's mRNA flu vaccine is more effective than the standard shot in a late-stage trial

An mRNA-based flu shot could make a huge difference in flu prevention, allowing scientists to pick a better strain match.

The efficacy of flu shots is not always the same and it’s not always optimal. Some years, they can reduce the risk of illness by as little as 20% to 30%.

Messenger RNA technology, or mRNA, is widely seen as a promising way to improve the effectiveness of flu shots, partly because it can be updated more quickly to match circulating strains.

New results published Wednesday in the New England Journal of Medicine found Moderna’s mRNA flu vaccine gave more protection against illness than the standard flu shot in a Phase 3 clinical trial.

The results — which showed the mRNA shot performed about 27% better — could help bolster the vaccine’s chances of approval after the Food and Drug Administration rejected Moderna’s original submission earlier this year.

No mRNA-based flu vaccine has been approved anywhere in the world. Moderna’s flu and Covid shots share the same mRNA technology.

“These are strong results, and would likely make it hard for the FDA to refuse in a way that withstands arbitrary and capricious review,” said Dorit Reiss, a vaccine policy expert at the University of California Law San Francisco.

The trial, funded by Moderna, included more than 40,000 adults ages 50 and up who were randomly assigned to get the mRNA vaccine or one of four standard flu shots during the 2024–2025 flu season. With the exception of very young children, older adults are generally at greater risk of severe complications from the flu than younger groups. The trial involved 301 sites across 11 countries, including the U.S.

The results found that fewer people got sick in the mRNA flu vaccine group — about 2%, compared with 2.8% in the standard flu shot group.

Side effects such as fatigue, headache and arm pain were more common in the mRNA group, but were mild and short-lived. People often have similar reactions after getting a traditional flu shot.

An mRNA flu shot could make a huge difference in flu prevention. Because it takes months to make a traditional flu shot, global health officials pick the strains up to 12 months before peak flu season. That time lag may result in mismatched strains. For example, last summer a strain called H3N2 subclade K emerged, making changes on the surface protein of the virus, raising concerns about the effectiveness of the flu shot, which was targeted to H1N1 and H3N2 (flu type A) and a Victoria virus (flu type B).

Developing an mRNA shot is typically faster, which could allow officials to make decisions later in the year — and give drugmakers more flexibility to pivot if the circulating strain changes.

“The ability to make vaccine in shorter time periods may help better match new vaccines to emerging influenza viruses,” said Dr. Jesse Goodman, an infectious disease specialist at Georgetown University Medical Center and former FDA chief scientist.

In February, the FDA said it denied Moderna’s application because the company failed to test its vaccine against the best available treatment for adults 65 and older. Instead of using a higher-dose flu shot typically recommended for that age group, Moderna tested its vaccine against a standard flu shot — a move, one FDA official said at the time, that could make the drugmaker’s vaccine appear more effective. (In response, Moderna said it ran the trial the way regulators had discussed and agreed to.)

According to trial results, the mRNA shot performed similarly in adults 65 and up: about 1.9% got sick, compared with 2.6% for the standard shot.

Following public backlash, the agency allowed Moderna to amend its application, splitting its filing by age — standard approval for adults 50 to 64, and accelerated approval for those 65 and up, with a promise to run another trial for that age group after approval.

Goodman said that although the mRNA vaccine was not compared to a high-dose flu shot in people 65 and up, “the degree of superiority to standard flu vaccines suggests at least a similar advantage.”

“The data should be very supportive of FDA licensure of the vaccine,” he said.

The FDA is expected to decide on the mRNA flu shot by Aug. 5, according to Moderna. The drugmaker declined a request to discuss the Phase 3 trial results.

Under anti-vaccine activist Robert F. Kennedy’s leadership, the Department of Health and Human Services has taken a harder line on vaccines, especially those that use mRNA technology.

Health Secretary Kennedy has singled out vaccines made with mRNA as particularly dangerous, calling the mRNA Covid vaccine “the deadliest vaccine ever made.”

In August, HHS canceled nearly $500 million in funding for mRNA vaccine research.

Last May, Moderna withdrew its application seeking approval for its combination flu and Covid mRNA shot after the FDA asked for more data.

Health experts say they hope the administration gives Moderna’s mRNA flu vaccine a fair review.

“With emerging pathogens and infections, it’s difficult to predict which technology will rise to the top to make the best vaccine,” said Dr. Peter Hotez, dean of the National School of Tropical Medicine at Baylor College of Medicine in Texas and co-director of the Texas Children’s Hospital Center for Vaccine Development.

“For Ebola in 2019 it was the VSV technology, for Covid in 2020 it was mRNA,” Hotez said. “The lesson learned is that we need to keep as many technologies in play as possible and to cut one of them out for ideological reasons limits our ability to protect the American people.”