



University of Pennsylvania (UPenn) researchers hope to start clinical trials of a universal mRNA flu vaccine within the next two years, on the back of promising results from tests in multiple animal models. Unlike traditional vaccines that need to be reformulated every year to match mutated viral proteins and different viral strains, the new lipid nanoparticle (LNP)-encapsulated mRNA vaccine triggers strong antibody responses to a part of the viral hemagglutinin (HA) protein that doesn’t mutate, and is conserved across viral strains. Experiments showed that the mRNA-LNP vaccine protected mice against deadly doses of three different flu strains. The overall results suggest that it may be feasible to generate mRNA vaccines against flu that only need one or two repeat administrations over a lifetime, rather than the current yearly shot.

“This vaccine was able to do something that most other candidate flu vaccines have not been able to do,” claims Drew Weissman, M.D., Ph.D., a professor of infectious diseases at UPenn’s department of medicine, and co-senior author of the team’s published paper, released in Nature Genetics. “It was able to elicit protective responses against a conserved region that offers broad protection.”

“If it works in humans even half as well as it does in mice, then the sky's the limit – it could be something that everyone uses in the future to protect themselves from the flu,” adds co-senior author Scott Hensley, Ph.D., an associate professor of microbiology at the UPenn Perelmen School of Medicine. The researchers report their results in a paper titled, “Nucleoside-modified mRNA immunization elicits influenza virus hemagglutinin stalk-specific antibodies.”

Current seasonal flu vaccines use viral proteins to elicit an antibody response that protects against future exposure to the virus. However, most flu virus vaccines trigger antibody responses against the ever-changing globular head region of the viral HA protein. This HA domain readily mutates within any one virus strain, while different flu strains that might be predominant from one flu season to the next will have different HA head structures. It means that flu vaccines have to be reformulated every year, based on predictions of the most likely strains that will be prevalent in the coming season.

“Currently available seasonal influenza virus vaccines do not protect well against antigenically drifted viral strains and they likely provide very little protection against emerging pandemic strains,” the authors comment. “There is a need to develop 'universal' influenza virus vaccines that induce potent immune responses against conserved viral epitopes and offer protection from heterologous and heterosubtypic strains.”

As an alternative approach to current vaccines, the UPenn team has developed an mRNA vaccine that encodes the HA proteins. Following injection, the recipient’s immune system dendritic cells take up the mRNAs and translate them into copies of the HA protein, which act as a much better foil for a flu infection, and trigger a much stronger protective antibody response. It’s a relatively new vaccine approach, but one that has previously been used to generate a one-shot vaccine that provides strong protection against Zika virus in mice and monkeys, the authors note. However, the potential effectiveness of mRNA vaccines against different strains of flu hasn't yet been well understood, they add. “Although, several recent studies indicate that mRNA-based vaccines can provide protection against influenza virus infection, none of these reports determined if mRNA-based influenza virus vaccines elicited broadly reactive antibodies capable of neutralizing antigenically distinct influenza virus strains after a single immunization.”

Initial tests in mice showed that just a single injection of the UPenn team’s candidate mRNA-LNP vaccine elicited strong antibody responses against both the readily mutated HA head, but also against the conserved stalk region of the HA protein, which doesn't readily mutate, and which is little altered between strains. Anti-HA responses in the immunized mice in addition continued to increase over the 30 week period of monitoring. “When we first started testing this vaccine, we were blown away by the magnitude of the antibody response,” Dr. Hensley states. The vaccine elicited similary high levels of HA stalk-reactive antibodies when tested in rabbits and ferrets.

Encouragingly, the vaccine protected mice against subsequent infection with different flu virus strains. Animals given just one injection of an mRNA vaccine encoding H1 virus subtype proteins survived otherwise lethal doses of the same H1 flu virus and a more distantly related H1 strain, while two doses were protective against an unrelated, H5N1 flu strain. “The next step is to test this in nonhuman primates and humans,” Dr. Hensley states. It should also be possible to generate even more potent vaccines based on combinations of HA antigens. “If we were to combine our vaccine approach with newly developed HA stalk antigens, it would probably lead to a really good universal vaccine,” Dr. Weissman adds.

The researchers suggest that as well as being safe, the mRNA vaccines should be cost-effective to manufacture. “The mRNA-LNP vaccine platform has additional beneficial features over other vaccines, including a favorable safety profile and highly scalable and potentially inexpensive manufacture.” New mRNA vaccines could also feasibly be produced very quickly in the event of flu pandemics.

“Production of conventional, FDA-approved vaccines against new pandemic viruses could take at least six months, leaving the population unprotected during this period,” the team writes. “On the contrary, once the genetic sequence of the target HA antigen is known, mRNA-LNP vaccines can potentially be produced within weeks.”



























