Creative new strategy for a universal, long-lasting flu shot| MEDICUS 2024 Issue 3

Creative new strategy could lead to universal, long-lasting flu shot
By Karl Leif Bates, Executive director of research communications at Duke University

Assoc Prof Nicholas Heaton discussing the study’s finding with his team member // Credit: Duke University

Sometimes, it’s better not to attack a difficult problem head-on. Yet vaccines used against influenza tend to do just that by targeting one of two proteins extending from the surface of the virus, proteins whose initials also make up the names of particular influenza strains, like H5N1 for example.

“So then our idea was, ‘What if we can come up with a vaccine that gives us both? What if we can get good head antibodies and at the same time also get stalk antibodies in case the vaccine selection was wrong, or if there’s a pandemic?’”
Assoc Prof Nicholas Heaton

The H (sometimes HA), refers to haemagglutinin, a lollipop-shaped protein that binds to a receptor on a human cell, the first step toward getting the virus inside the cell. The N is neuraminidase, a second protein that enables a newly made virus to break out of its host cell and go on to infect other cells.

Every flu season, people are encouraged to go for a new flu shot not because their immune system is forgetful, but because the virus is constantly remodelling these two crucial attachment points targeted by vaccines. Even with new vaccines each year, influenza still kills about half a million people around the world.

Duke Human Vaccine Institute researcher Nicholas Heaton, who has been wondering if there’s a better way for years, has come up with one way to potentially outmaneuver the virus.

In a study published in Science Translational Medicine, he and his colleagues describe a five-year effort to develop a longer-lasting universal flu vaccine that would be able to foil all versions of the virus.

It would do so by taking a less-direct approach, targeting the stalk holding up haemagglutinin, rather than the ever-changing protein itself.

“A number of groups have gone through and experimentally mutagenised the whole haemagglutinin and asked ‘which areas can change and still allow the haemagglutinin to function?’” explained Heaton. “And the answer is, you can’t really change the stalk and expect it to continue to function.”

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An illustration showing the haemagglutinin proteins on an influenza virus and the antibodies targeting the stem // Credit: Duke University

So the Duke team sought to design proteins that elicit an immune response more focused on the stalk than the head of haemagglutinin. “The virus has evolved to have the immune system recognise these (features on the head region). But these are the shapes the virus can change. That is an insidious strategy,” said Heaton.

Using gene-editing, Heaton and his postdoctoral associate Dr Luo Zhaochen created more than 80,000 variations of the haemagglutinin protein, where each carried some differences to the top of their bulb-like head domain, and then tested a vaccine filled with a mixture of these variations on mice and ferrets.

In lab tests, this experimental vaccine caused the immune system to respond more strongly to stalk regions because they stayed consistent. This, in turn, boosted the immune response to the vaccine overall, and in some cases, even improved antibody responses to the head region of the haemagglutinin protein as well.

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It worked because of the broad variety of head conformations being presented to the immune system and the relative consistency of the stalks. The experimental vaccine also produced more antibodies to the stalk portion of the haemagglutinin.

“The opportunity for the immune system to see that (head portion) over and over and over, like it needs to, is compromised because there’s diversity there,” said Heaton, who is also an associate professor of molecular genetics and microbiology at Duke School of Medicine.

The stalk portion, however, provided the immune system with a more consistent target.

“Antibodies against the stalk work differently,” said Heaton. “Their mechanism of protection is not necessarily to block the first step of infection. So then our idea was, ‘What if we can come up with a vaccine that gives us both? What if we can get good head antibodies and at the same time also get stalk antibodies in case the vaccine selection was wrong, or if there’s a pandemic?’”

“Essentially, the paper says, ‘Yes, we can accomplish that’,” said Heaton, who developed the methods to create large antigen libraries for the study with Luo.

Their approach worked well in preclinical experiments. After a shot of the experimental vaccine was administered, 100 per cent of the animals avoided illness or death from what should have been a lethal dose of flu viruses.

The methods developed by Heaton and Luo to create large antigen libraries have been patented and the next steps of the research will attempt to understand whether the same level of immunity can be achieved by presenting fewer than 80,000 haemagglutinin variants.