Coupling HA Molecules from Various Flu Strains Could Make Vaccines More Effective

Seasonal influenza (flu) vaccines, which contain hemagglutinin (HA) molecules from various viral strains, have limited efficacy because most vaccinated people produce antibodies against only one of the vaccine strains. This “subtype bias” occurs either because prior exposure to a particular flu strain primes the immune system to respond to that strain later or variation in people’s genes for key immune system components affects the vaccine response. But now, results from a recent study suggest coupling HA molecules from various flu strains could make flu vaccines more effective.

The researchers, who examined the relative contributions of these mechanisms to flu vaccine responses, aimed to use this information to develop a vaccine that could limit the biased response. They began by measuring flu vaccine responses in 39 pairs of identical twins. In most cases, the immune systems of both twins showed the same subtype bias to a seasonal vaccine. Yet they also showed signs of having been exposed to different flu strains in the past.

The researchers also studied the response to seasonal flu vaccine in 15 infants, aged 6 to 12 months, who had never been infected with flu before. Most of the infants still developed a subtype-specific antibody response. Together, these findings suggest that individual genetic variation might exert a larger role than prior virus exposure in driving subtype bias, although initial virus exposure also contributes to such bias.

B cells and T helper (TH) cells coordinate to produce antibodies against a virus. When a B cell finds a molecule, like HA, that it recognizes, it engulfs it and chops it up into fragments called peptides, which are displayed on its surface to activate TH cell support. The peptides are anchored to the cell surface by molecules called MHC-II. Variations in the genes for MHC-II molecules can affect which peptides are displayed. HA from one flu strain may have more peptides that can be displayed on a B cell than other strains, which could lead some B cells to get more TH cell support than others, and hence bias antibody production toward that strain.  

To reduce bias in TH activation, the researchers linked together HA molecules from up to four different subtypes before vaccination so a B cell that recognized any one of the individual HAs would engulf all of them. Then, they reasoned, the different B cells would be able to display the same set of peptides and activate TH cell support equally well.

As expected, mice vaccinated with a mixture of unlinked antigens developed a clear subtype bias. But mice vaccinated with the linked HAs produced equal amounts of antibodies against all the subtypes tested. Similar results were obtained in organoids grown from human tonsil tissue — a laboratory model that generates an immune response.

The researchers also tried coupling an avian flu HA with the seasonal flu HA. This construct elicited a stronger immune response in the tonsil organoids than the avian flu HA did on its own.

“Overcoming subtype bias this way can lead to a much more effective influenza vaccine, extending even to strains responsible for bird flu,” said Mark Davis, PhD, at Stanford University School of Medicine who led the research. “The bird flu could very likely generate our next viral pandemic.”