Universal flu vaccine may be more challenging than expected
Many flu strains may be capable of mutating to escape universal-vaccine antibodies

Date:
June 23, 2020
Source:
Scripps Research Institute
Summary:
Some common strains of influenza have the potential to mutate
to evade broad-acting antibodies that could be elicited by a
universal flu vaccine, according to a new study. The findings
highlight the challenges involved in designing such a vaccine,
and should be useful in guiding its development.



FULL STORY ==========================================================================
Some common strains of influenza have the potential to mutate to evade
broad- acting antibodies that could be elicited by a universal flu
vaccine, according to a study led by scientists at Scripps Research.


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The findings highlight the challenges involved in designing such a
vaccine, and should be useful in guiding its development.

In the study, published in Science, the researchers found evidence
that one of the most common flu subtypes, H3N2, can mutate relatively
easily to escape two antibodies that were thought to block nearly all flu strains. Yet they found that it is much more difficult for another common subtype, H1N1, to escape from the same broadly neutralizing antibodies.

One of the main goals of current influenza research is to develop a
universal vaccine that induces broadly neutralizing antibodies, also
known as "bnAbs," to give people long-term protection from the flu.

"These results show that in designing a universal flu vaccine or a
universal flu treatment using bnAbs, we need to figure out how to make
it more difficult for the virus to escape via resistance mutations,"
says the study's senior author Ian Wilson, DPhil, Hansen Professor of Structural Biology and Chair of the Department of Integrative Structural
and Computational Biology at Scripps Research.

The promise of a universal vaccine Influenza causes millions of cases
of illness around the world every year and at least several hundred
thousand fatalities. Flu viruses have long posed a challenge for vaccine designers because they can mutate rapidly and vary considerably from
strain to strain.



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The mix of strains circulating in the population tends to change every
flu season, and existing flu vaccines can induce immunity against only
a narrow range of recently circulating strains. Thus, current vaccines
provide only partial and temporary, season-by-season protection.

Nevertheless, scientists have been working toward developing a universal
flu vaccine that could provide long-term protection by inducing an
immune response that includes bnAbs. Over the past decade, several
research groups, including Wilson's, have discovered these multi-strain neutralizing antibodies in recovering flu patients, and have analyzed
their properties. But to what extent circulating flu viruses can simply
mutate to escape these bnAbs has not been fully explored.

In the study, first-authored by postdoctoral research associate Nicholas
Wu, PhD, and staff scientist Andrew Thompson, PhD, the team examined
whether an H3N2 flu virus could escape neutralization by two of the more promising flu bnAbs that have been discovered so far.

Known as CR9114 and FI6v3, these antibodies bind to a critical region on
the virus structure called the hemagglutinin stem, which doesn't vary much
from strain to strain. Because of their broad activity against different
flu strains, they've been envisioned as antibodies that a universal flu
vaccine should be designed to elicit, and also as ingredients in a future therapy to treat serious flu infections.

Using genetic mutations to methodically alter one amino acid
building-block of the protein after another at the stem site where the
bnAbs bind, Wu and colleagues found many single and double mutations that
can allow H3N2 flu to escape the antibodies' infection-blocking effect.



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The team also found a few instances of these "resistance mutations" in a database of gene sequences from circulating flu strains, suggesting that
the mutations already happen occasionally in a small subset of ordinary
flu viruses.

Escape skills vary by flu strain Although experiments and analyses
suggested that H3N2 viruses are broadly capable of developing resistance mutations, the same was not true for H1N1 viruses. The researchers tested several H1N1 viruses and found that none seemed able to mutate and escape, except for rare mutations with weak escape effects.

The H3N2 and H1N1 subtypes account for most of the flu strains circulating
in humans.

The researchers used structural biology techniques to show how differences
in the hemagglutinin stem structure allow H3N2 flu viruses to develop resistance mutations to the two stem-binding antibodies more easily than
H1N1 viruses.

"If it's relatively easy for H3N2 to escape those bnAbs, which are the prototype antibodies that a universal flu vaccine should induce, then we probably need to think more carefully and rigorously about the design
of that universal flu vaccine against certain influenza subtypes,"
Wu says. "The good news is that a universal flu vaccine should at
least work well against the H1N1 subtype." The researchers now plan to
conduct similar studies with other flu subtypes and bnAbs. They say that
in principle, a vaccine eliciting multiple bnAbs that attack different
sites on flu viruses or are more accommodating to changes in the virus
could help mitigate the problem of resistance mutations.


========================================================================== Story Source: Materials provided by Scripps_Research_Institute. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Nicholas C. Wu, Andrew J. Thompson, Juhye M. Lee, Wen Su, Britni M.

Arlian, Jia Xie, Richard A. Lerner, Hui-Ling Yen, Jesse D. Bloom,
Ian A.

Wilson. Different genetic barriers for resistance to HA stem
antibodies in influenza H3 and H1 viruses. Science, 2020; 368
(6497): 1335 DOI: 10.1126/science.aaz5143 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/06/200623145350.htm

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