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
Peer-Reviewed PublicationPHILADELPHIA – An experimental mRNA-based vaccine against all 20 known subtypes of influenza virus provided broad protection from otherwise lethal flu strains in initial tests, and thus might serve one day as a general preventative measure against future flu pandemics, according to researchers from the Perelman School of Medicine 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 employed 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 flu strains different from those used in making the vaccine.
“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,” said 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.
Influenza viruses periodically cause pandemics with enormous 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 in order to elicit broad protection. The vaccine is not expected to provide “sterilizing” immunity that completely prevents viral infections. Instead, 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.
“It would be comparable to first-generation SARS-CoV-2 mRNA vaccines, which were targeted to the original Wuhan strain of the coronavirus,” Hensley said. “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.”
The experimental vaccine, when injected and taken up by the cells of recipients, 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 skew immune responses to conventional influenza vaccines. The researchers observed that the antibody response in the mice was strong and broad whether or not the animals had been exposed to flu virus before.
Hensley and his colleagues currently are designing human clinical trials, he said. The researchers envision that, if those trials are successful, 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, he added, the same multivalent mRNA strategy can be used for other viruses with pandemic potential, including coronaviruses.
Support for the research was provided by the National Institute of Allergy and Infectious Diseases (75N93021C00015, 75N93019C00050, 1R01AI108686, and R56AI150677).
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Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $9.9 billion enterprise.
The Perelman School of Medicine has been ranked among the top medical schools in the United States for more than 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $546 million awarded in the 2021 fiscal year.
The University of Pennsylvania Health System’s patient care facilities include: the Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center—which are recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report—Chester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; and Pennsylvania Hospital, the nation’s first hospital, founded in 1751. Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Medicine at Home, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.
Penn Medicine is powered by a talented and dedicated workforce of more than 52,000 people. The organization also has alliances with top community health systems across both Southeastern Pennsylvania and Southern New Jersey, creating more options for patients no matter where they live.
Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2021, Penn Medicine provided more than $619 million to benefit our community.
JOURNAL
Science
METHOD OF RESEARCH
Randomized controlled/clinical trial
SUBJECT OF RESEARCH
Animals
ARTICLE PUBLICATION DATE
24-Nov-2022
Multivalent mRNA vaccine candidate another step closer to universal flu vaccine
Peer-Reviewed PublicationClaudia Arevalo and colleagues have developed a mRNA lipid nanoparticle vaccine that contains antigens from all 20 known subtypes of influenza A and B viruses, a strategy that may serve as the basis for universal flu vaccines. Their vaccine produced high levels of cross-reactive and subtype-specific antibodies in mice and ferrets and could protect animals against disease symptoms and death after infection with both antigenically matched and mismatched strains of influenza. Even with increased global surveillance, it is difficult to predict which flu strain will cause the next flu pandemic, making a universal vaccine important. The approach by Arevalo et al. differs from previous attempts to craft a universal flu vaccine by including antigens specific to each subtype, rather than just a smaller set of antigens shared among subtypes. Following on the success of mRNA vaccines against SARS-CoV-2, the researchers prepared 20 different nanoparticle encapsulated mRNAs, each encoding a different hemagglutinin antigen – a highly immunogenic flu protein that helps the virus enter cells. Antibody levels remained mostly stable four months after vaccination in the mice. Multivalent protein vaccines produced using more traditional methods elicited fewer antibodies and were less protective compared to the multivalent mRNA vaccine in the animals. In a related Perspective, Alyson Kelvin and Darryl Falzarano discuss the results, noting that “questions remain regarding the regulation and approval pathway of such a vaccine that targets viruses of pandemic potential but are not currently in human circulation.”
JOURNAL
Science
ARTICLE TITLE
A multivalent nucleoside-modified mRNA vaccine against all known influenza virus subtypes
ARTICLE PUBLICATION DATE
25-Nov-2022
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