Flu shots reduce hospitalizations and deaths for the roughly one billion people worldwide that get the flu each year. But they are less effective when the vaccine strains don’t closely match the viruses circulating in the community. 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%. 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.

Now, an investigational mRNA influenza vaccine, developed by Moderna, helps the immune system recognize a wider range of influenza viruses than today’s standard flu shot, offering stronger and potentially longer-lasting protection. The vaccine is currently under review by the U.S. Food and Drug Administration and, if approved, would be the first mRNA vaccine against influenza.

The findings are published in Nature Immunology in the paper, “mRNA-based influenza vaccine expands the breadth of the B cell response in humans.”

“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, professor in the department of pathology and immunology at WashU Medicine. “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.”

In a separate Phase III 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 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 (mRNA-1010). The other half got Fluarix, an approved flu shot containing inactivated influenza viruses. 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.

“Influenza is constantly evolving to evade our immune system,” said 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 germinal centers—where B cells improve their ability to recognize the virus and generate slightly different versions of themselves—in a subset of participants. It had not been previously understood if mRNA-based influenza virus vaccines can induce a superior germinal center (GC) response.

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, 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.

These findings, the authors note, reveal a key role for persistent GC responses in broadening the repertoire of vaccine-induced antibodies. “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.”

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