An international team of scientists have identified antibodies that
neutralize omicron and other SARS-CoV-2 variants. These antibodies target
areas of the virus spike protein that remain essentially unchanged as the
viruses mutate.
By identifying the targets of these “broadly neutralizing” antibodies on the
spike protein, it might be possible to design vaccines and antibody
treatments that will be effective against not only the omicron variant but
other variants that may emerge in the future, said David Veesler,
investigator with the Howard Hughes Medical Institute and associate
professor of biochemistry at the University of Washington School of Medicine
in Seattle. “This finding tells us that by focusing on antibodies that
target these highly conserved sites on the spike protein, there is a way to
overcome the virus’ continual evolution,” Veesler said.
Veesler led the research project with Davide Corti of Humabs Biomed SA, Vir
Biotechnology, in Switzerland. The study’s findings were published on
December 23 in the journal Nature. The lead authors of the study were
Elisabetta Cameroni and Christian Saliba (Humabs), John E. Bowen (UW
Biochemistry) and Laura Rosen (Vir).
The omicron variant has 37 mutations in the spike protein, which it uses to
latch onto and invade cells. This is an unusually high number of mutations.
It is thought that these changes explain in part why the variant has been
able to spread so rapidly, to infect people who have been vaccinated and to
reinfect those who have previously been infected.
“The main questions we were trying to answer were: how has this
constellation of mutations in the spike protein of the omicron variant
affected its ability to bind to cells and to evade the immune system’s
antibody responses,” Veesler said.
Veesler and his colleagues speculate that omicron’s large number of
mutations might have accumulated during a prolonged infection in someone
with a weakened immune system or by the virus jumping from humans to an
animal species and back again.
To assess the effect of these mutations, the researchers engineered a
disabled, nonreplicating virus, called a pseudovirus, to produce spike
proteins on its surface, as coronaviruses do. They then created
pseudoviruses that had spike proteins with the omicron mutations and those
found on the earliest variants identified in the pandemic.
The researchers first looked to see how well the different versions of the
spike protein were able to bind to protein on the surface of cells, that the
virus uses to latch onto and enter the cell. This protein is called the
angiotensin converting enzyme-2 (ACE2) receptor.
They found the omicron variant spike protein was able to bind 2.4 times
better than spike protein found in the virus isolated at the very beginning
of the pandemic. “That’s not a huge increase,” Veesler noted, “but in
the SARS outbreak in 2002-2003, mutations in the spike protein that
increased affinity were associated with higher transmissibility and
infectivity.” They also found that the omicron version was able to bind to
mouse ACE2 receptors efficiently, suggesting omicron might be able to
“ping-pong” between humans and other mammals.
The researchers then looked at how well antibodies against earlier isolates
of the virus protected against the omicron variant. They did this by using
antibodies from patients who had previously been infected with earlier
versions of the virus, vaccinated against earlier strains of the virus, or
had been infected and then vaccinated.
They found that antibodies from people who had been infected by earlier
strains and from those who had received one of the six most-used vaccines
currently available all had reduced ability to block infection.
Antibodies from people who had previously been infected and those who had
received the Sputnik V or Sinopharm vaccines as well as a single dose of
Johnson & Johnson had little or no ability to block – or “neutralize” –
the omicron variant’s entry into cells. Antibodies from people who had
received two doses of the Moderna, Pfizer/BioNTech, and AstraZeneca vaccines
retained some neutralizing activity, albeit reduced by 20- to 40-fold, much
more than any other variants.
Antibodies from people who had been infected, recovered, and then had two
doses of vaccine also had reduced activity, but the reduction was less,
about fivefold, clearly demonstrating that vaccination after infection is
useful.
Antibodies from people, in this case a group of renal dialysis patients, who
had received a booster with a third dose of the mRNA vaccines produced by
Moderna and Pfizer/BioNTech showed only a 4-fold reduction in neutralizing
activity. “This shows that a third dose is really, really helpful against
omicron,” Veesler said.
All but one antibody treatments currently authorized or approved to be used
with patients exposed to the virus, had no or had markedly reduced activity
against omicron in the laboratory. The exception was an antibody called
sotrovimab, which had a two- to three-fold reduction of neutralizing
activity, the study finds.
But when they tested a larger panel of antibodies that have been generated
against earlier versions of the virus, the researchers identified four
classes of antibodies that retained their ability to neutralize omicron.
Members of each of these classes target one of four specific areas of the
spike protein present in not only SARS-CoV-2 variants but also a group of
related coronaviruses, called sarbecoviruses. These sites on the protein may
persist because they play an essential function that the protein would lose
if they mutated. Such areas are called “conserved.”
The finding that antibodies are able to neutralize via recognition of
conserved areas in so many different variants of the virus suggests that
designing vaccines and antibody treatments that target these regions could
be effective against a broad spectrum of variants that emerge through
mutation, Veesler said.
Reference:
Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift,
Nature.
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