Possible Universal Flu Vaccine May Protect Against Multiple Strains in Preclinical Study

A modified-RNA vaccine elicits protective response in mice to a conserved region of the flu virus

PHILADELPHIA—A universal flu vaccine that protects people against most influenza strains is one step closer to reality, with a study from the Perelman School of Medicine at the University of Pennsylvania.
The candidate vaccine, described in “Nature Communications”, elicited a strong antibody response to a structure on the surface of flu viruses, called the hemagglutinin (HA) stalk. It protected mice from infection by various flu strains.
Despite the widespread use of seasonal vaccines, flu viruses in the United States annually cause millions of infections, hundreds of thousands of hospitalizations, and tens of thousands of deaths. The newly described vaccine has the potential to be a universal flu vaccine, which – unlike the current seasonal flu vaccines – could be given a few times over a lifetime to provide protection potentially similar to a tetanus vaccine.
“This vaccine was able to do something most other candidate flu vaccines have not been able to do,” said study co-senior author Drew Weissman, MD, PhD, a professor of Infectious Diseases, “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,” said co-senior author Scott Hensley, PhD, an associate professor of Microbiology.
Modern viral vaccines typically use lab-grown viral proteins to elicit an immune response that protects people against future exposures to a virus. On the whole, this approach hasn’t worked well against influenza viruses. Flu virus particles are studded with mushroom-like HA proteins, which seasonal flu vaccines use to elicit antibody responses.
The problem is the antibody responses are almost entirely directed against the outermost “head” region of the HA protein, which tends to mutate rapidly. Strains of flu that are prevalent in one flu season are often replaced by other strains with different HA head structures in the next flu season. As a result, seasonal flu vaccines provide incomplete and temporary protection against the flu.
The Penn vaccine does not use flu HA proteins—at least, not directly. Instead, it uses mRNA molecules that encode HA proteins to elicit an antibody response.
“When we first started testing this vaccine, we were blown away by the magnitude of the antibody response,” said Hensley.
The team observed that after immunization, these strong antibody responses to the vaccine persisted through the thirty weeks of the experiment. At the end of this period the responses were even stronger than four weeks after immunization.
Researchers successfully repeated the experiments in ferrets and rabbits, other species commonly used as vaccine-development animal models.
“The next step is to test this in non-human primates and humans,” Hensley said.
mRNA vaccine technology is relatively new but has already been demonstrated in other settings. In 2017, Weissman and colleagues reported in “Nature” protection against Zika virus in mice and monkeys with just a single injection of an mRNA vaccine.
The mRNA molecules used in these vaccines are modified so they cannot be recognized by cells as foreign RNAs, which otherwise would trigger an immune reaction that would hamper the vaccine’s effectiveness. The modified mRNAs are also encapsulated in tiny fat-like spheres called lipid nanoparticles, which helps them travel to target cells after being injected.
“If we were to combine our vaccine approach with newly developed HA stalk antigens, it would probably lead to a really good universal vaccine,” Weissman said. The team hopes to begin clinical trials within two years.

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