A University of Nebraska–Lincoln research effort aims to strengthen defenses against future flu pandemics by advancing a vaccine designed to provide strong, durable immunity against multiple high-risk avian strains.
By targeting both mutating surface proteins and more stable viral components, the approach could create a universal vaccine capable of guarding against viruses with pandemic potential.
Backed by a new $4 million, five-year grant from the National Institutes of Health, Husker virologist Eric Weaver will build on his team’s prior research with the Epigraph vaccine strategy, which was shown to be superior to traditional flu vaccines in building broad cellular immunity and lasting — potentially decades long — protection.
Prior studies with the Epigraph approach demonstrated its ability to build broad immunity to swine flu viruses. Weaver is now turning his attention to applying the approach to a universal vaccine targeting avian influenza viruses H2, H5, H7 and H9.
“These are viruses that have either already been in the human population and caused a pandemic or have the potential to cause an epidemic or pandemic,” said Weaver, professor of biological sciences and director of the Nebraska Center for Virology. “We're going to tackle these one by one, creating vaccines for each of the subtypes, then combine them to see if we can protect against all these strains.
“The real primary goal is to make sure that we have vaccines in hand in case there is a pandemic or the indication of one.”
The World Health Organization and the Centers for Disease Control and Prevention predict that an avian-origin Influenza A is the most likely culprit for a future epidemic or pandemic. These predictions and virus surveillance are guiding Weaver’s selection of strains to test with this new vaccine approach. Weaver also pointed to the potential lethality of the viruses — with possible mortality rates between 30% and 50% — if humans become infected.
The proposed vaccine strategy will work in two ways — recognize changes in the virus’s outer structure and target genetic material that is more stable across multiple viruses.
Influenza viruses have a coat of armor comprised of proteins hemagglutinin and neuraminidase. Hemagglutinin can change its “color,” Weaver said, becoming harder for the immune system to see it, but the Epigraph approach recognizes these changes, giving a breadth of protection against different circulating strains. The Epigraph vaccine strategy was developed by computationally analyzing the genetic codes of more than 6,000 strains of influenza virus, from 1930 to 2021, targeting the most common epitopes — or “colors” — of the hemagglutinin that illicit an immune antibody response. The strategy increases the likelihood that the vaccine contains the right epitopes to trigger an immune response.
Inside the hemagglutinin protein’s stem is a more stable genetic material that is similar virus to virus, and the second function of the vaccine targets this material.
“This vaccine strategy combines the multivalent broadly protective aspect of an Epigraph design that is married to the stalk domains of the hemagglutinin that are conserved across the influenza viruses, providing a breadth of protection even through a virus’s evolution,” Weaver said.
In previous studies with swine flu viruses in pigs, the Epigraph approach was superior to the commercially available vaccine for pigs and a “wild type” vaccine based on naturally occurring strains with similar immunogens. In a six-month study in pigs in 2024, immunity was protected for the duration of the experiment. Computer analyses following the experiment predicted cellular immunity to swine flu viruses would be maintained for more than a decade.
Weaver expects to see similar results when translating the vaccine strategy to avian flu viruses.
“A lot of the work we do focuses on driving a T-cell response, which is about half of your immune system — known as cellular immunity,” Weaver said. “Most conventional vaccines, including the COVID-19 vaccines and standard commercial flu shots, primarily stimulate antibody responses, and don’t generate T-cell response. Ours does, and I think that is the key reason why it lasts a long time and is effective against different strains.”
