Universal Influenza Vaccine Candidate Produces Strong Responses in Animal Models

The search continues for a universal influenza vaccine that can fill in the gaps of the currently available seasonal vaccines, which typically do not protect well against various strains of influenza and do not provide significant protection against emerging pandemic strains.

Now, a team from the Perelman School of Medicine at the University of Pennsylvania has reported that immunization with an candidate vaccine elicited strong antibody responses to the hemagglutinin (HA) stalk, a structure on the surface of flu viruses, offering protection against multiple flu strains. These responses persisted through 30 weeks of the experiment. At the end of the study period, the anti-stalk responses were even stronger than they had been 4 weeks after immunization.

“This vaccine was able to do something that 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 at the University of Pennsylvania School of Medicine, in a recent statement. "It was able to elicit protective responses against a conserved region that offers broad protection."

In the new study, published in Nature Communications, the investigators set out to explore if a vaccine with mRNA molecules that encode HA proteins could elicit an antibody response in animal models. The mRNA molecules used in the vaccine are modified to not be recognized as foreign RNA by cells, which would inhibit the effectiveness of the vaccine. The modified mRNAs are also enclosed in nanoparticles which help them travel to target cells after being injected.

This approach is unique from most that focus on directing antibody responses towards a particular region of the HA protein referred to as the head, which tends to mutate quickly. Additionally, with seasonal influenza vaccines, prevalent strains in a particular flu season are replaced by different strains with different HA head structures in the next flu season, providing incomplete and temporary protection against the virus.

For the study, mice were immunized twice with 3, 10, or 30 µg of A/California/07/2009 (H1N1) HA-encoding mRNA-LNPs intradermally or 10, 30, or 90 µg of A/California/07/2009 HA mRNA-LNPs intramuscularly. The immunizations were delivered 4 weeks apart and assessed by the investigators. In a control population, mice were vaccinated with 30 µg intradermally or 90 µg intramuscularly with poly(C) RNA-LNPs.

“A single immunization with 3 µg of A/California/07/2009 HA mRNA LNPs resulted in ≥1:120 A/California/07/2009 hemagglutination inhibition assays (HAI) titers at 4 weeks post-immunization in mice,” the authors write.

Further, the investigators observed that higher vaccine doses produced higher HAI titers between the intradermally and intramuscularly immunized mice. A second dose induced HAI values that fell between the range of 1280 to 20,480 depending on dose and manner of administration.

The authors also wrote that a critical finding of this report is that a single immunization of A/California/07/2009 HA mRNA-LNPs resulted in protection against the homologous A/California/07/2009 and the heterologous A/Puerto Rico/8/1934 virus challenge in mice. However, 2 immunizations, induced protection against H5N1 influenza virus infection.

In a rabbit and ferret study, a single immunization of A/California/07/2009 HA mRNA-LNP elicited HA stalk-reactive antibodies, demonstrating that the findings yielded from the mouse model were also applicable in other, larger animal populations.

The investigators indicate that next steps is to test this approach in non-human primates and humans. The team hopes to launch clinical trials by 2020, according to a recent news release.

"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 at the University of Pennsylvania School of Medicine, in a statement.