A major bump in the road to building broader, more durable vaccines may not be as much of a hurdle as scientists once thought, new research suggests.
In a study published Dec. 21 in PLOS Biology, a research team from the University of Pittsburgh announced they had discovered that when some people receive a trivalent flu vaccine, they produce a type of antibody that overcomes a major viral hurdle to stave off both of the two dominant subtypes of the seasonal bug. By reverse engineering their immune responses, the researchers hope to develop broader, more durable flu vaccines.
“Our immune system actually evolved to combat viruses,” study lead Kevin McCarthy, Ph.D., told Fierce Biotech Research in an interview. “If we understand how it evolved in those individuals who had very strong responses, then maybe we can help guide the evolution of everybody’s immune system to make similar responses.”
Flu vaccines currently target four subtypes of influenza—two different flu A viruses known as H1 and H3, and two flu B viruses, which include a Yamagata lineage virus and a Victoria lineage virus. The specific strains from each type that the vaccine will protect against are selected based on predictions made with surveillance data from influenza centers around the world. While some years’ vaccines may carry over protection from the prior year, they generally need to be reformulated annually.
The vaccines work by prompting immune cells called B cells to generate antibodies against the selected strains. These antibodies bind to a protein on the surface of the virus called hemagglutinin, which normally helps the virus infect cells. Blocking hemagglutinin prevents the virus from getting inside. Hemagglutinin evolves over time, resulting in new flu strains.
Researchers have been trying for years to figure out how to target multiple strains—specifically, strains of both subtypes H1 and H3—with a single antibody. While some antibodies with the H3 mutation can indeed target H1, there’s a major problem: If the H1 antibodies have a mutation in their hemagglutinin called the 133a insertion, the H3 antibodies won’t recognize them.
But as it turns out, humans can produce antibodies that circumvent the 133a insertion and protect against H3 and H1 strains, as McCarthy’s lab found in their new study. Using blood taken from donors before and after they received a flu vaccine, the researchers collaborated with scientists from Johns Hopkins University to examine individual B cells and the antibodies they produced, then profile the antibodies in a “high-throughput fashion,” McCarthy explained.
The results contained an exciting discovery: Two of the donors produced antibodies to H3 and H1 with or without the 133a insertion. Intriguingly, they were also around the same age, with similar histories of exposure to the flu: Both were children in the early 1990s, and both had antibodies that bound strongly to H3 strains from the decade. Their antibodies also contained an adaptation that allows the flu virus to grow better in chicken eggs, one of the flu vaccine manufacturing processes.
Their history may have led to a "jackpot event," as McCarthy described it.
“It’s really tempting to speculate that these people were infected as kids before childhood vaccination with the flu was really a thing, and then the vaccines came in with this adaptation and elicited a very strong response,” McCarthy explained. “I think what it shows is that the proper series of events are capable of eliciting similar antibodies quite strongly, and so that gives us a clue for how one can figure out ways to improve vaccines.”
Notably, the finding is not a step toward a universal flu vaccine, a goal of many researchers and biotechs. In fact, it may be evidence that targeting hemagglutinin alone is unlikely to be enough to create a vaccine against all strains of the flu, McCarthy said.
“An important point of this is that probably no single antibody or one single site on the flu hemagglutinin protein is going to be sufficient to have a universal vaccine,” he said. “So what we found here expands the repertoire of possibilities of antibodies that can engage different subtypes of influenza.”
Next, the researchers plan to take what they’ve learned from the donors and use it to trace the events that resulted in the development of these antibodies.
“We’re trying to also characterize broad antibody responses…which we can then use to rationally design vaccines that will elicit very strong responses simultaneously to multiple sites across the molecule,” McCarthy said.