Her findings on immunity and the body’s response to flu virus proteins could lead to changes in the composition of future flu vaccines.

The flu may never go away, but new research from the University of Georgia’s Center for Vaccines and Immunology (CVI) foretells the possible end of influenza B, a type of influenza that causes respiratory illness and disproportionately affects children and elderly populations. The findings of this research, featured in the latest issue of the journal Science Advances, has broader implications of improving next generation influenza vaccines.

The paper summarizing the research, “Neuraminidase-Specific Antibodies Drive Differential Cross-Protection Between Contemporary FLUBV Lineages,” describes new insights into the disappearance of one of two lineages of influenza B from human circulation.

Influenza A and B viruses circulate globally, causing up to 710,000 hospitalizations and 52,000 deaths each year in the U.S. alone. Influenza A viruses are the most frequent causes of illness and may cause flu pandemics because they infect both humans and animals. This gives the viruses a multitude of opportunities to evolve and outpace the preventative efforts of vaccine development.

Mark Tompkins, Director of the Center for Vaccines and Immunology

Influenza B, however, only infects humans. Without animal reservoirs, flu B can’t cause pandemics, but it does account for up to 25 percent of influenza related infections and hospitalizations each year. Yamagata, one of the two flu B lineages, disappeared from human circulation after the COVID-19 pandemic. CVI Director Mark Tompkins said his lab set out to learn why. They found that infection with the Victoria lineage of flu B offers immunity to both lineages of influenza B, but Yamagata only protects against Yamagata.

Caroline K. Page, who recently defended her Ph.D. in the College of Veterinary Medicine and is the lead author of the paper, explained that CVI researchers speculate that, among susceptible populations, immunity to Yamagata had become high enough to prevent new infections. This, combined with the dominance of Victoria circulation leading up to the COVID-19 pandemic as well as the public health restrictions brought on during the COVID-19 pandemic led to Yamagata’s disappearance due to a lack of susceptible hosts.

“Influenza viruses, A and B, have two surface proteins, hemagglutinin (HA) and neuraminidase (NA), which drive the majority of the immune response to the virus,” she explained. Addressing immunity to both surface proteins on the flu virus may be the key to fully eliminating flu B and “simplifying” the flu season for vaccine researchers, Page said.

Lead author of the paper, Caroline Page

Most vaccines focus on HA because it is the more immunodominant of the two proteins. In other words, most of the antibodies a person produces in response to the flu target the HA protein. However, this protein changes rapidly, which is why a new flu vaccine is needed every year.

“It’s good at preventing infection if you can match that HA, but it changes so frequently that it’s not the most reliable target,” Page said. “If you could also generate immunity to the NA protein, you might achieve broader protection that may last a bit longer.”

Page’s research found that the neuraminidase protein was responsible for the broad immunity provided by the Victoria strain of flu B, which could protect against both Victoria and Yamagata infections. “While other studies have demonstrated the potential to elicit broad immunity using NA as a vaccine, Caroline’s work describes a mechanism for broad, cross-lineage protection elicited by infection, which may have contributed to the disappearance of an entire flu B lineage,” Tompkins said.

Vaccine development has focused on the HA protein in the past because it can prevent infection, rather than just reduce viral replication like NA, and HA is naturally at higher levels in inactivated vaccines. Vaccines designed to elicit immunity to both proteins could potentially be more effective, Page said, because the NA component could provide broader protection, even if the vaccine strain is mismatched due to the evolution of the HA protein.

“If we’re being realistic, influenza is probably never going to go away. As an RNA virus, it replicates very quickly, making numerous mutations and constantly changing,” Page said. “The situation is even more complicated for influenza A because animals are also involved. Animals can get infected with one strain, while humans are infected with another, and when these strains mix, it can lead to the emergence of pandemic viruses.

“Flu B viruses don’t have that problem, so I strongly believe there is a real opportunity to eliminate flu B from humans. I think the disappearance of Yamagata supports this, as one of the lineages is potentially gone, leaving only one remaining.”