Summary Seasonal influenza vaccines offer little protection against pandemic influenza virus strains. It is difficult to create effective pre-pandemic vaccines because it is not clear which subtype of influenza virus will cause the next pandemic. In this work, we developed a nucleoside-modified messenger RNA (mRNA) lipid nanoparticle vaccine encoding hemagglutinin antigens from all 20 known influenza A virus subtypes and influenza B virus lineages. This multivalent vaccine elicited high levels of antibodies subtype-specific and cross-reactive in mice and ferrets that reacted to all 20 encoded antigens. Vaccination protected mice and ferrets challenged with matching and mismatched viral strains, and this protection was at least partially dependent on antibodies. Our studies indicate that mRNA vaccines can provide protection against antigenically variable viruses by simultaneously inducing antibodies against multiple antigens. |
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Penn scientists develop 20-subtype mRNA flu vaccine to protect against future flu pandemics.
Promising results in animal models help pave the way for clinical trials
An experimental mRNA-based vaccine against all 20 known influenza virus subtypes provided broad protection against lethal influenza strains in initial testing and could therefore one day serve as a general preventative measure against future influenza pandemics. , according to researchers at the Perelman School of Medicine at the University of Pennsylvania.
The "multivalent" vaccine, which 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 enabled those COVID-19 vaccines was 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 different flu strains than those used to make the vaccine.
"The idea here is to have a vaccine that gives people a baseline level of immune memory for various strains of flu, so that there will be much less illness and death when the next flu pandemic occurs," said the study’s lead author. , Scott Hensley, Ph.D. Professor of Microbiology at the 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 enormous numbers of deaths. The best known of these was the “Spanish flu” pandemic of 1918-19, which killed at least tens of millions of people around the world. Flu viruses can circulate in birds, pigs and other animals, and pandemics can begin when one of these strains jumps to humans and acquires mutations that make it better suited to spread among humans. Current flu vaccines are simply "seasonal" vaccines that protect against recently circulating strains, but are not expected to protect against new pandemic strains.
The strategy employed by Penn Medicine researchers is to vaccinate with immunogens, a type of antigen that stimulates immune responses, against all known influenza subtypes for broad protection. The vaccine is not expected to provide "sterilizing" immunity that completely prevents viral infections. Instead, the new study shows that the vaccine triggers a memory immune response that can quickly recover and adapt to new pandemic viral strains, significantly reducing severe illness and death from infections.
“It would be comparable to the first-generation SARS-CoV-2 mRNA vaccines, which targeted the original strain of the Wuhan coronavirus,” Hensley said. “Unlike later variants like Omicron, these original vaccines did not completely block viral infections, but continue to provide long-lasting protection against serious illness and death.”
The experimental vaccine, when injected and absorbed by recipients’ cells, begins to produce copies of a key influenza virus protein, the hemagglutinin protein, for all twenty influenza hemagglutinin subtypes: H1 to H18 for influenza A virus and two more for influenza B. viruses
“For a conventional vaccine, immunization against all of these subtypes would be very challenging, but with mRNA technology it is relatively easy,” Hensley said.
In mice, the mRNA vaccine elicited high levels of antibodies, which remained elevated for at least four months, and reacted strongly to all 20 flu subtypes. Additionally, the vaccine appeared relatively unaffected by prior exposures to the influenza virus, which can bias 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 the flu virus before or not.
Hensley and his colleagues are currently designing human clinical trials, he said. Researchers anticipate that if those trials are successful, the vaccine may be useful in obtaining long-term immunological memory against all influenza subtypes in people of all ages, including young children.
“We believe this vaccine could significantly reduce the chances of getting a serious flu infection,” Hensley said.
In principle, he added, the same multivalent mRNA strategy can be used for other viruses with pandemic potential, including coronaviruses.
Research support was provided by the National Institute of Allergy and Infectious Diseases (75N93021C00015, 75N93019C00050, 1R01AI108686, and R56AI150677).
