An international team of researchers has developed a new mRNA-based flu vaccine — the same technique used for the two main COVID-19 vaccines — that targets four proteins that differ little from virus strain to virus strain. This vaccine, successfully tested in mice, can be reused every year and remains effective regardless of circulating influenza strains.
Every winter in France between 2 and 6 million people become infected with the influenza virus. This condition can be very serious in the most vulnerable people, such as the elderly or people with chronic conditions. Since the main circulating viral strains, A and B, change from year to year, and the duration of vaccine protection may decrease after several months, it is recommended to vaccinate every year, after about two weeks. before the start of the epidemic.
The composition of the vaccine is updated annually in accordance with the recommendations of the World Health Organization and takes into account the most likely circulating viruses. But the flu virus remains unpredictable, and the effectiveness of the vaccine fluctuates: the closer the selected strains are to circulating strains, the more effective it is. The effectiveness of the 2021-2022 flu vaccine is estimated at 42%. Thus, this approach is not only expensive (due to the need to develop a new vaccine every year), but also risky, because sometimes an unexpected variant arises and the vaccine cannot fight it. Researchers are trying to find the best solution.
mRNA vaccine targeting four viral proteins
The influenza vaccination campaign started on 18 October. This season is 2022-2023. Four influenza vaccines are available in France: Vaxigrip Tetra®, Influvac Tetra®, Fluarix Tetra® and Efluelda®, the latter being for people over 65 years of age. These are inactivated vaccines (thus containing no live infectious agent) cultured on eggs; they contain only fragments of different viral strains.
The two main vaccines developed against COVID-19 are messenger RNA (mRNA) vaccines: they contain the genetic code encoding the SARS-CoV-2 spike protein; The cells of the body then begin to produce this protein, and the immune system learns to recognize them by producing immune memory cells that will attack viral particles carrying the same protein. The advantage of this approach is, in essence, the ease of obtaining mRNA (which also avoids the culture of potentially dangerous pathogens).
Researchers at the University of Pennsylvania, the Icahn School of Medicine at Mount Sinai in New York, and other institutions took inspiration from this method to develop a similar flu vaccine: They used several pieces of the viral genetic code to make the body produce antigens.
Hemagglutinin is an antigenic glycoprotein present on the surface of influenza A viruses; it roughly consists of two main parts: the “stem” and the “head”. “Existing seasonal vaccines that use three or four inactivated influenza viruses mainly target the head region, while the virus can show several mutations at this level to avoid immunity,” explains Invers Norbert Pardy, Associate Professor of Microbiology at School them. Medicine at the University of Pennsylvania and study co-author.
The mRNA segments used by the team encode the haemagglutinin stem, the M2 protein, the nucleoprotein and neuraminidase, all of which are present on the surface of influenza viruses. These proteins tend to remain nearly identical from one virus strain to another, making them ideal immune targets.
Increased levels of antibodies and killer T cells
The team tested their vaccine on mice, none of which had ever been infected with the influenza virus. A total of 20 mice were injected with different formulations of the new vaccine: some received a monovalent vaccine containing only one of the four mRNA segments, while others received a quadrivalent vaccine containing all four segments. Some mice were also given two doses of the vaccine, with a booster administered four weeks after the first injection.
The mice were then infected with a set of different strains of influenza virus that infect both humans and other animals such as dogs. Blood tests showed that all mice had some degree of increased antibody production, but only mice that received the quadrivalent vaccine were completely protected, with one exception: mice that received the monovalent vaccine containing only the mRNA encoding the nucleoprotein.
Antibodies produced by B cells are not our only defense against pathogens: cytotoxic T cells also play an important role in the adaptive immune response by destroying target cells presenting specific antigens. Previous studies have shown that they play an important role in fighting influenza infections in both mice and humans. The researchers found that a monovalent vaccine containing nucleoprotein mRNA promotes the production of these cytotoxic T cells, which explains the effectiveness of this formula.
However, according to the group, a “cocktail” of mRNA remains preferable to a monovalent vaccine. “When we mix them all together, we get the broadest immune response. You get T-cell interaction against the nucleoprotein, you get antibodies and a pretty strong neuraminidase response,” said Florian Krammer, a virologist at the Icahn School of Medicine at Mount Sinai and co-author of the study.
However, it is not certain that these encouraging results observed in mice are replicated in humans: our pre-existing immunity against influenza could affect the quality of the antibody response to a potential vaccine. Future clinical trials will shed light on this question.