A new way, that could lead to universal, long-lasting flu shot

This novel vaccination strategy is part of a five-year-old endeavour to create a more durable, universal flu vaccine that can thwart all viral strains

By developing a vaccine that stimulates the immune system to focus on a less changeable area of the viral surface, Duke researchers have opened a new front in the fight against influenza viruses.

Their strategy was effective in trials involving mice and ferrets, and it might result in influenza vaccinations that are more widely protective and less dependent on a yearly dose that is specific to the virus strains of that particular year. Influenza kills over 500,000 people worldwide each year, even with vaccinations.

This novel vaccination strategy is part of a five-year-old endeavour to create a more durable, universal flu vaccine that can thwart all viral strains, as detailed in an article in the journal Science Translational Medicine.

Influenza strains are identified by a shorthand code, such as H5N1, which indicates the flavours of two specific surface proteins that they carry. The H, or occasionally HA, stands for hemagglutinin, a protein with a lollipop-like form that attaches to a receptor on a human cell to initiate the virus’s entry into the cell. The N stands for neuraminidase, a second protein that helps a virus break off from its host cell and spread to neighbouring cells.

On the virus particle, there’s five to 10 times more hemagglutinin than neuraminidase,

If we took your blood to see if are you likely to be protected from a strain of flu, we’d be measuring what your antibodies do to hemagglutinin as the best metric of what’s likely to happen to you. The strongest correlates of protection have to do with hemagglutinin-directed immunity.

Nicholas Heaton, PhD

Immunisations prepare the body to fight against portions of the virus that are unique to the strains of influenza that are predicted to pose the greatest hazard during the upcoming flu season. The influenza virus continuously modifies the surface proteins that vaccines target, which is why we require a fresh dose every autumn rather than because the vaccination fades out.

Rather than the stalk, the bulb-like “head” of hemagglutinin is often the focus of flu vaccines and immune systems. But the intricacies of that head area are also ever-changing, so much so that viruses and vaccine designers are engaged in an arms race. In contrast, the stalk varies somewhat less.

A number of groups have gone through and experimentally mutagenized the whole hemagglutinin and asked ‘which areas can change and still allow the hemagglutinin to function?,

And the answer is, you can’t really change the stalk and expect it to continue to function.

The virus has evolved to have the immune system recognize these (features on the head region). But these are the shapes the virus can change. That is an insidious strategy

Nicholas Heaton

They tested a vaccination containing a combination of these variants on mice and ferrets after using gene editing to produce over 80,000 variants of the hemagglutinin protein with alterations in one area directly on the top of the head domain.

These vaccinations elicited a greater response in terms of antibodies to the stalk part of hemagglutinin due to the wide range of head conformations exposed to the immune system and the relative consistency of the stalks.

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.

Nicholas Heaton

Because stalk areas remained stable, the experimental vaccination induced a stronger immune response in both lab testing and animals. This enhanced the body’s overall immunological response to the vaccination and, in certain situations, even enhanced the body’s antibody reaction to the protein’s head region.

Antibodies against the stalk work differently,

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.

Nicholas Heaton

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In certain trials, 100% of the mice who received an injection of the highly variable vaccination were able to prevent contracting a sickness or dying from what would have been a fatal dosage of flu viruses.

Subsequent studies will aim to investigate if presenting less than 80,000 hemagglutinin variants may provide the same degree of protection.

Source: Duke University – Duke Today

Journal Reference: Luo, Zhaochen, et al. “Vaccination with Antigenically Complex Hemagglutinin Mixtures Confers Broad Protection from Influenza Disease.” Science Translational Medicine, 2024, https://doi.org/adj4685.

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