Multivalent mRNA-based vaccine may serve as a preventive measure against future influenza pandemics

An experimental mRNA-based vaccine against all 20 known subtypes of flu viruses provided broad protection against otherwise deadly flu strains in initial tests and may therefore one day serve as a general preventive measure against future flu pandemics, according to Perelman School of Medicine researchers at the University of Pennsylvania.

The “multivalent” vaccine, which the researchers describe in a paper published today in Science, uses the same messenger ribonucleic acid (mRNA) technology used in the Pfizer and Moderna SARS-CoV-2 vaccines. This mRNA technology that made these COVID-19 vaccines possible was pioneered at Penn. Tests in animal models showed that the vaccine dramatically reduced signs of illness and protected against death, even when the animals were exposed to influenza strains different from those used to make the vaccine.

The idea here is to have a vaccine that will give people a base level of immune memory against different strains of flu, so there will be far less illness and death when the next flu pandemic occurs.”

Scott Hensley, PhD, study senior author, professor of microbiology, Perelman School of Medicine

Hensley and his lab collaborated on the study with the lab of mRNA vaccine pioneer Drew Weissman, MD, PhD, the Roberts Family Professor in Vaccine Research and director of Vaccine Research at Penn Medicine.

Influenza viruses periodically cause pandemics with huge death tolls. The best known of these was the “Spanish Flu” pandemic of 1918-19, which killed at least tens of thousands of people worldwide. Influenza viruses can circulate in birds, pigs and other animals, and pandemics can start when one of these strains jumps to humans and acquires mutations that adapt it better to spread among humans. Current influenza vaccines are merely “seasonal” vaccines that protect against newly circulating strains but are not expected to protect against new, pandemic strains.

The strategy used by the Penn Medicine researchers is to vaccinate using immunogens — a type of antigen that stimulates immune responses — from all known influenza subtypes to induce broad protection. The vaccine is not expected to provide “sterilizing” immunity that completely prevents viral infections. Instead, the new study shows that the vaccine induces a memory immune response that can be quickly recalled and adapted to new pandemic virus strains, significantly reducing severe illness and death from infections.

“It would be comparable to first-generation SARS-CoV-2 mRNA vaccines, which targeted the original Wuhan strain of the coronavirus,” Hensley said. “Against later variants such as Omicron, these original vaccines did not completely block viral infections, but they continue to provide lasting protection against serious illness and death.”

The experimental vaccine, when injected and taken up by recipients’ cells, begins to produce copies of a key influenza virus protein, the hemagglutinin protein, for all twenty influenza hemagglutinin subtypes—H1 through H18 for influenza A virus and two more for influenza. B virus.

“For a conventional vaccine, immunizing against all of these subtypes would be a big challenge, but with mRNA technology, it’s relatively easy,” Hensley said.

In mice, the mRNA vaccine elicited high levels of antibodies that remained elevated for at least four months and responded strongly to all 20 influenza subtypes. Furthermore, the vaccine appeared relatively unaffected by previous influenza virus exposures, which can skew immune responses to conventional influenza vaccines. The researchers observed that the antibody response in the mice was strong and broad, regardless of whether the animals had been exposed to influenza virus before or not.

Hensley and his colleagues are currently designing human clinical trials, he said. The researchers envision that if these trials are successful, the vaccine could be useful in inducing long-term immune memory against all influenza subtypes in people of all ages, including young children.

“We think this vaccine can significantly reduce the chances of ever getting a serious flu infection,” Hensley said.

In principle, he added, the same multivalent mRNA strategy could be used for other viruses with pandemic potential, including the coronavirus.

Support for the research was provided by the National Institute of Allergy and Infectious Diseases (75N93021C00015, 75N93019C00050, 1R01AI108686 and R56AI150677).


University of Pennsylvania School of Medicine

Multivalent mRNA-based vaccine may serve as a preventive measure against future influenza pandemics

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