Protecting against future flu pandemics with the 20-subtype mRNA flu vaccine

Penn scientists develop experimental mRNA flu vaccine to protect against all 20 known subtypes of influenza virus

In initial tests, the 20-subtype mRNA flu vaccine provides broad protection from lethal flu strains. Thus, researchers from the Perelman School of Medicine at the University of Pennsylvania hope it might one day serve as a general preventative measure against future flu pandemics.

The “multivalent” vaccine, which the researchers describe in a paper published today in Science, uses the same messenger ribonucleic acid (mRNA) technology employed in the Pfizer and Moderna SARS-CoV-2 vaccines. The mRNA technology has been pioneered at Penn.

Tests in animal models showed that the vaccine dramatically reduced signs of illness and protected from death, even when the animals were exposed to flu strains different from those used in the vaccine.

Far less disease and death when the next flu pandemic occurs

“The idea here is to have a vaccine that will give people a baseline level of immune memory to diverse flu strains so that there will be far less disease and death when the next flu pandemic occurs,” explained study senior author Scott Hensley, PhD, a professor in of Microbiology at in the Perelman School of Medicine.

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

The 1918-19 “Spanish flu” pandemic killed millions

Influenza viruses periodically cause pandemics with horrific death tolls. The best known of these was the 1918-19 “Spanish flu” pandemic, which killed at least tens of millions of people worldwide.

Flu 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 for spreading among humans. Current flu vaccines are merely “seasonal” vaccines that protect against recently circulating strains but would not be expected to protect against new pandemic strains.

The strategy employed by the Penn Medicine researchers is to vaccinate using immunogens—a type of antigen that stimulates immune responses—from all known influenza subtypes to elicit broad protection.

The vaccine is not expected to provide “sterilizing” immunity that completely prevents viral infections. Alternatively, the new study shows that the vaccine elicits a memory immune response that can be quickly recalled and adapted to new pandemic viral strains, significantly reducing severe illness and death from infections.

20-subtype mRNA flu vaccine comparable to first-generation SARS-CoV-2 mRNA vaccines

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

When injected and taken up by the recipients’ cells, the experimental mRNA flu vaccine starts producing copies of a key flu virus protein, the hemagglutinin protein, for all twenty influenza hemagglutinin subtypes—H1 through H18 for influenza A viruses and two more for influenza B viruses.

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

In mice, the mRNA vaccine elicited high levels of antibodies, which stayed elevated for at least four months, and reacted strongly to all 20 flu subtypes. Moreover, the vaccine seemed relatively unaffected by prior influenza virus exposures, which can change immune responses to conventional influenza vaccines. The Penn scientists observed that the antibody response in the mice was strong and broad whether or not the animals had been exposed to the flu virus before.

Hensley and his colleagues are currently designing human clinical trials. He explains that if those trials are successful, the researchers envision that the vaccine may be useful for eliciting long-term immune memory against all influenza subtypes in people of all age groups, including young children.

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

In principle, the same multivalent mRNA strategy can be used for other viruses with pandemic potential, including coronaviruses.