mRNA flu vaccine offers immune protection against wide array of influenza virus strains

A new study led by researchers at Washington University School of Medicine in St. Louis has found that an investigational mRNA influenza vaccine helps the immune system recognize a wider range of influenza viruses than today’s standard flu shot, offering stronger and potentially longer-lasting protection.

About 1 billion people worldwide get the flu each year. Flu shots reduce hospitalizations and deaths, but they are less effective when the vaccine strains don’t closely match the viruses circulating in the community. A broader immune response could translate to a more effective vaccine even when the virus is changing faster than vaccine makers can update their shots.

The vaccine, developed by Moderna, is currently under review by the U.S. Food and Drug Administration and if approved would be the first against influenza using mRNA technology.

The findings are published June 15 in Nature Immunology.

“We are seeing that the mRNA flu vaccine doesn’t just boost the immune system’s response to what it has already seen, it can help expand and diversify the antibody response, covering a broader range of flu strains,” said Ali Ellebedy, PhD, the Leo Loeb Professor in the WashU Medicine Department of Pathology & Immunology and the study’s senior author. “If we can make flu immunity broader and more durable, that could mean fewer hospitalizations and deaths, which translates into a major impact on public health.”

Keeping up with flu

Influenza viruses change as they spread from person to person, picking up small genetic mutations over time. Such changes are driven by immune pressure, forcing the virus to mutate ever so slightly to escape the antibodies. Eventually, these tweaks alter the virus’ surface proteins enough that immune protection from past infections or vaccinations may no longer fully work against new strains. A vaccine that elicits broader antibodies could help limit this viral escape by making it harder for the virus to evade immunity with just a few mutations.

Meanwhile, today’s vaccines are made months in advance of the flu season due to a long manufacturing process. When projections are off, strain mismatch can reduce the efficacy of the flu vaccines from about 60% in a good year down to 19%. In addition to producing the broader immune response identified in this new study, the mRNA technology that helped change the course of the COVID-19 pandemic could allow vaccine manufacturers to quickly update and produce new vaccines, potentially enabling a faster response to emerging viral strains.

In a separate phase 3 clinical trial, Moderna found that its mRNA-based flu vaccine reduced the risk of illness by 26.6% more than the standard flu vaccine in older adults. Seeking to understand possible causes of this improved protection, the new study examined how immune responses to the mRNA-based flu vaccine differ from those of the standard vaccine.

The researchers, including co-corresponding author Jiwon Lee, PhD, an associate professor in the Department of Convergence Medicine at Korea University College of Medicine and an adjunct professor at Thayer School of Engineering at Dartmouth, followed 75 adults ages 20 to 50 over either the 2022-2023 flu season or the 2023-2024 flu season. About half received the investigational mRNA vaccine, known as mRNA-1010, which delivers genetic instructions that prompt the body to make proteins from four strains of influenza that trigger immune responses against intruding viruses. The other half got Fluarix, an approved flu shot containing inactivated pieces of four influenza viruses grown in eggs. Both vaccine platforms targeted the same strains recommended by the World Health Organization for the two flu seasons.

Analyzing blood samples, the researchers found a stronger immune response in participants who received the mRNA vaccine compared with participants who received the standard flu shot. Specifically, those given the mRNA vaccine produced more flu-specific antibodies and more flu-specific memory B cells, immune cells that remember past infections and can quickly generate antibodies against pathogens such as viruses.

“Influenza is constantly evolving to evade our immune system,” said first author Hanover Matz, PhD, a postdoctoral research associate working in Ellebedy’s laboratory. “But if we can develop vaccines that activate diverse B cells that target a broad portfolio of flu viruses, we have a better chance of avoiding strain mismatches and potentially even reducing the frequency with which the vaccine is needed.”

To investigate the vaccine’s ability to diversify B cells, the researchers studied in a subset of participants their germinal centers — the immune system’s training hub — where B cells improve their ability to recognize the virus and generate slightly different versions of themselves. These B cells produce antibodies that target different parts of the virus, creating a diverse pool that is more likely to recognize and fight new variants.

Among 13 people receiving the mRNA flu vaccine, five developed flu-specific germinal center responses in the lymph nodes that persisted for the 26 weeks of the study. In contrast, persistent immune responses were not seen in the 15 participants who received the traditional flu shot.

In addition, from four weeks after vaccination until the six-month mark, when the study ended, antibodies from mRNA vaccine recipients recognized and bound to many diverse flu strains across many decades of viral evolution, especially those known to cause the most widespread illness. Antibodies from standard vaccine recipients bound to fewer divergent virus strains. When antibodies bind to viruses, they block them from infecting cells while also tagging them for destruction by immune cells.

“We are seeing that the mRNA flu vaccine is driving strong, persistent germinal center responses,” said Ellebedy. “This can broaden the antibody response and better arm the immune system against an ever-changing virus.”

Matz HC, Yu T, Dixit K, Kikawa C, Zhou JQ, Pena Alzua G, Peyton L, Madsen A, Han F, Ghez Farrell A, Hoelzl R, Schmitz AJ, Horvath SC, Keplinger HK, Strnad BS, Hoegger MJ, Middleton WD, Klebert MK, Lin NH, Nachbagauer R, Krammer F, Paris R, Bloom JD, Turner JS, Presti RM, Lee J, Ellebedy AH. mRNA-based influenza vaccine expands the breadth of the B cell response in humans. June 15, 2026. Nature Immunology. DOI: 10.1038/s41590-026-02569-5

This work was supported by grants from the NIH National Institute of Allergy and Infectious Diseases (NIAID), grant numbers U01AI141990, U01AI144616 and R01AI165821, contract numbers 75N93021C00014, 75N93019C00051, 75N93021C00015 and 75N93019C00051; Moderna, Inc.; NIAID training grants T32AI007172, T32CA009547 and T32AI083203; National Institutes of Health, grant numbers P20GM113132 and P01AI089618; Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (RS-2024-00411420); Howard Hughes Medical Institute. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official view of NIH or NIAID.

Competing interests: The Ellebedy laboratory and Infectious Disease Clinical Research Unit received funding under sponsored research agreements from Moderna related to the data presented in the current study. The Ellebedy laboratory received funding from Emergent BioSolutions and AbbVie that are unrelated to the data presented in the current study. A.H.E. has received consulting and speaking fees from InBios International, Fimbrion Therapeutics, RGAX, Mubadala Investment Company, Moderna, Pfizer, GSK, Danaher, Third Rock Ventures, Goldman Sachs and Morgan Stanley and is the founder of ImmuneBio Consulting. A. J. S., J.S.T., and A.H.E. are recipients of a licensing agreement with Abbvie that is unrelated to the data presented in the current study. N.H.L., R.N., and R.P. are employees of and shareholders in Moderna, Inc. The Icahn School of Medicine at Mount Sinai has filed patent applications regarding influenza virus vaccines on which F.K. is listed as inventor and F.K. has received royalty payments from some of these patents. F.K. is co-founder and scientific advisory board member of Castlevax. F.K. has consulted for Merck, GSK, Sanofi, Curevac, Gritstone, Seqirus and Pfizer and is currently consulting for 3rd Rock Ventures and Avimex. The Krammer laboratory is also collaborating with Dynavax on influenza vaccine development and with VIR on influenza virus therapeutics. J.D.B is on the scientific advisory boards of Apriori Bio, Invivyd, Aerium Therapeutics, and the Vaccine Company. J.D.B consults for GlaxoSmithKline and Pfizer. J.D.B receives royalty payments as inventors on Fred Hutch licensed patents related to incorporating barcodes into the influenza genome and viral deep mutational scanning.