by Delthia Ricks , Medical Xpress

Cryo-EM Details of c115.131 and c968.180 Fab with H10 HA trimer. Credit: Science Translational Medicine (2025). DOI: 10.1126/scitranslmed.adr8373

Not long after the first flu shot was introduced in 1945 by University of Michigan virologist Thomas Francis and his co-researcher, Jonas Salk (who would later garner worldwide fame as developer of the first polio vaccine), scientists were on a decades-long quest to produce a better flu shot.

Globally, morbidity and mortality from seasonal flu are staggering. An estimated 1 billion people are stricken each year with the flu, which causes anywhere from 290,000 to 640,000 deaths. In the U.S. alone, this flu season is being characterized as the worst since 2009. An estimated 650,000 people have been hospitalized since October, according to the Centers for Disease Control and Prevention, and more than 16,000 have died. Those statistics are expected to increase before flu season ends in May.

Vaccinologists have long pushed for a universal flu vaccine that is effective against seasonal and pandemic strains.

Now, in an elegant series of experiments conducted at the Vaccine Research Center of the U.S. National Institute of Allergy and Infectious Diseases, scientists are reporting their work on what’s ultimately hoped to be a more robust flu shot.

That means one that prompts a potent immune response and doesn’t require seasonal updating. The center’s scientists have zeroed in on three candidate vaccines based on a subtype of a highly conserved flu protein. The team’s research is the first to test the promise of these subtypes and arrives amid uncertain times for biomedical research in general—and vaccine research in particular—in the United States.

“A major hurdle in the development of a universal influenza vaccine is the diversity of influenza viruses,” writes Dr. Grace E. Mantus, lead author of the flu virus research published in Science Translational Medicine. The research paper was authored by a government research team.

“Recurrent spillover of avian influenza virus into mammalian species, including several isolated cases of human H5 infection in the Americas in recent years, highlights the potential risk of an influenza pandemic,” Mantus added.

Flu A and B viruses cause human infection, but influenza A viruses additionally infect multiple animal species. Indeed, wild birds are the natural reservoir for most influenza A viruses, including H5N1, and other strains of bird flu. Choosing potential vaccine strains whose conserved regions are linked with potent antibody assaults may lead to better protection against seasonal and pandemic flu, the team contends.

Their research zeroes in on an infinitesimal protein that stipples the surface of the flu virus: hemagglutinin, which isn’t new to universal flu vaccine research. In fact, it is the protein that dozens of experimental universal and pandemic vaccines have been based on. What’s different now is the team’s focus on subtypes of hemagglutinin that have garnered scant analysis in the past.

Hemagglutinin is one of two critical flu virus surface proteins. And it isn’t even the entire protein that interests flu scientists, but the protein’s “stem” region, which has long been a key target. The stem is genetically stable across influenza viral strains.

Picture hemagglutinin’s shape as a submicroscopic mushroom, a stem with a broad head on top. The heads of countless hemagglutinin proteins are arrayed on the surface portion of the virus along with another mushroom-shaped influenza protein: neuraminidase.

During the process of infection, hemagglutinin is responsible for attaching the virus to the host’s cells. Neuraminidase, an enzyme, cuts the sugar sialic acid from an already-infected cell, allowing newly made flu viruses to escape from the cell to spread and infect others.

Vaccinologists worldwide, who have been racing to develop a universal flu vaccine, have turned to hemagglutinin as the protein to base vaccines. These researchers have lumped hemagglutinin subtypes into two broad categories, known simply as group 1 and group 2.

There are 12 hemagglutinin subtypes isolated from a number of different influenza viruses that are in group 1: H1, H2, H5, H6, H8, H9, H11, H12, H13, H16, H17, and H18. Group 2 includes 6: H3, H4, H7, H10, H14, and H15.

“The conserved influenza hemagglutinin stem, which is a target of cross-neutralizing antibodies, is now used in vaccine strategies focused on protecting against influenza pandemics,” Mantus asserted.

“Antibody responses to group 1 stem have been extensively characterized, but little is known about group 2,” added Mantus, whose work with her colleagues involved group 2.

Despite the stem’s Lilliputian size, it possesses specific regions along its length that elicit powerful antibody responses. Mantus and colleagues analyzed three vaccines based on three group 2 hemagglutinin subtypes.

Their aim was twofold: to determine how effectively these vaccines prompted an antibody response and to map precisely where on the stem that aggregations of flu-fighting antibodies could be found. These sites are known as epitopes, and they essentially serve as specific addresses along the length of the tiny stem. Pinpointing epitopes can enhance vaccine design, Mantus and her team said.

“We characterized the stem-specific repertoire from individuals vaccinated with one of three group 2 influenza subtypes: H3, H7, and H10,” Mantus explained.

She and colleagues examined antibodies in samples from people who were vaccinated against the three hemagglutinin subtypes. To the team’s surprise, they found two major “supersites” of epitopes on the group 2 hemagglutinin stems: a central site and a lower site.

People vaccinated against H7 produced more antibodies against the central site, while those vaccinated against H3 and H10 produced a more balanced antibody response against both sites.

“Our findings suggest that vaccine strategies targeting both group 2 stem epitopes would be complementary, eliciting broader and more potent protection against both seasonal and pandemic influenza strains,” Mantus explained.

When the scientists treated lab mice with antibodies that target both the central and lower hemagglutinin stem sites, the animals were protected from infection following exposure to H3N2 seasonal flu virus.

The reason Mantus and her team—and essentially all others chasing the possibility of a universal flu vaccine—focus on hemagglutinin’s stem is its genetic stability. Researchers avoid basing universal vaccines on hemagglutinin’s “head” to steer clear of a viral region associated with seasonal change.

Within the genetic machinery of both types of surface-facing proteins—hemagglutinin and neuraminidase—are seasonal gene shuffles, a process known as antigenic drift. Tiny genetic changes—mutations—alter the character of flu viruses annually.

These mutations are transcribed into new, slightly altered amino acid sequences that allow the virus to evade the human immune system year after year. It is these changes that force the current strategy of producing a different annual flu vaccine formulation.

“Antibodies targeting the influenza head can have extremely high affinity,” Mantus explained, referring to antibodies’ capacity to bind to the virus and neutralize it, “but they tend to have limited breadth and thus limited functionality in protecting against evolving endemic and potential pandemic influenza strains.”

Mantus and colleagues see group 2 hemagglutinin proteins as an untapped resource for fighting an annual worldwide threat. “The lower epitope should be considered in both stem immunogen design and therapeutic antibodies against both seasonal drifting H3 and novel animal-origin pandemic H3 and H10 viral strains,” Mantus concluded.

More information: Grace E. Mantus et al, Vaccination with different group 2 influenza subtypes alters epitope targeting and breadth of hemagglutinin stem–specific human B cells, Science Translational Medicine (2025). DOI: 10.1126/scitranslmed.adr8373

Journal information:Science Translational Medicine

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