New target for universal influenza vaccine
From:
Scripps Research Institute
December 23, 2021 -- A new antibody
discovered in the blood of some people vaccinated against or infected with
influenza can recognize a broad variety of flu viruses.
Scientists at Scripps Research,
University of Chicago and Icahn School of Medicine at Mount Sinai have identified
a new Achilles' heel of influenza virus, making progress in the quest for a
universal flu vaccine. Antibodies against a long-ignored section of the virus,
which the team dubbed the anchor, have the potential to recognize a broad
variety of flu strains, even as the virus mutates from year to year, they
reported Dec. 23, 2021 in the journal Nature.
"It's always very exciting to
discover a new site of vulnerability on a virus because it paves the way for
rational vaccine design," says co-senior author Andrew Ward, PhD,
professor of Integrative Structural and Computational Biology at Scripps
Research. "It also demonstrates that despite all the years and effort of
influenza vaccine research there are still new things to discover."
"By identifying sites of vulnerability
to antibodies that are shared by large numbers of variant influenza strains we
can design vaccines that are less affected by viral mutations," says study
co-senior author Patrick Wilson, MD, who was previously at the University of
Chicago and recently recruited to Weill Cornell Medicine as a professor of
pediatrics and a scientist in the institution's Gale and Ira Drukier Institute
for Children's Health. "The anchor antibodies we describe bind to such a
site. The antibodies themselves can also be developed as drugs with broad
therapeutic applications."
In a typical year, influenza affects
more than 20 million people in the United States and leads to more than 20,000
deaths. Vaccines against influenza typically coax the immune system to generate
antibodies that recognize the head of hemagglutinin (HA), a protein that
extends outward from the surface of the flu virus. The head is the most
accessible regions of HA, making it a good target for the immune system;
unfortunately, it is also one of the most variable. From year to year, the head
of HA often mutates, necessitating new vaccines.
Researchers have designed experimental
influenza vaccines to be more universal, spurring the body to create antibodies
against the less-variable stalk region of HA, which extends like a stem between
the influenza virion and the HA head. Some of these universal flu vaccines are
currently in early clinical trials.
In the new study, a collaborative team
of scientists characterized 358 different antibodies present in the blood of
people who had either been given a seasonal influenza vaccine, were in a phase
I trial for an experimental, universal influenza vaccine, or had been naturally
infected with influenza.
Many of the antibodies present in the
blood of participants were antibodies already known to recognize either the HA
head or stalk. But a collection of new antibodies stood out; the antibodies
bound to the very bottom of the stalk, near where each HA molecule is attached
to the membrane of the flu virion.
The co-first authors of the manuscript
-- Julianna Han, a staff scientist in the Ward lab, and Jenna Guthmiller, a
postdoctoral fellow at the University of Chicago -- named this section of HA
the anchor, and began studying it further. In all, the scientists identified 50
different antibodies to the HA anchor, from a total of 21 individuals. The
antibodies, they discovered, recognized a variety of H1 influenza viruses,
which account for many seasonal flu strains. Some of the antibodies were also
able to recognize pandemic H2 and H5 strains of influenza in lab tests. And in
mice, the antibodies successfully protected against infection by three
different H1 influenza viruses.
"In order to increase our
protection to these highly mutating viruses, we need to have as many tools as
we can," says Han. "This discovery adds one more highly potent target
to our repertoire." Importantly, these antibodies appear to be fairly
common in people, and belong to a class of antibodies that any person's body
can produce -- an important consideration in designing a vaccine to spur their
development.
"The human immune system already
has the ability to make antibodies to this epitope, so it's just a matter of
applying modern protein engineering methods to make a vaccine that can induce
those antibodies in sufficient numbers," adds Guthmiller.
The researchers say that future,
improved iterations of a universal vaccine could more purposefully aim to
generate anchor antibodies. Until now, scientists designing universal vaccines
hadn't paid attention to whether the anchor region of the stem was included as
a target. Ideally, a universal influenza vaccine will lead to antibodies
against multiple sections of the virus -- such as both the HA anchor and the
stalk -- to increase protection to evolving viruses.
The researchers are planning future
studies on how to design a vaccine that most directly targets the HA anchor of
different influenza strains.
In addition to Han and Ward, authors of
the study, "Broadly neutralizing antibodies target a hemagglutinin anchor
epitope," include Sara Richey and Alba Torrents de la Pena of Scripps;
Jenna Guthmiller, Henry Utset, Lei Li, Linda Yu-Ling Lan, Carole Henry,
Christopher Stamper, Olivia Stovicek, Haley Dugan, Nai-Ying Zheng, Micah
Tepora, Dalia Bitar, Siriruk Changrob, Min Huang and Patrick Wilson of
University of Chicago; Meagan McMahon, George O'Dell, Alec Freyn, Fatima
Amanat, Victoria Rosado, Shirin Strohmeier, Adolfo Garcia-Sastre, Raffael
Nachbagauer, Peter Palese and Florian Krammer of Icahn School of Medicine at
Mount Sinai; Monica Fernandez-Quintero and Klaus Liedl of University of
Innsbruck, Lauren Gentles and Jesse Bloom of Fred Hutchinson Cancer Research
Center; and Lynda Coughlan of University of Maryland School of Medicine
https://www.sciencedaily.com/releases/2021/12/211223113049.htm
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