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An international team of scientists has identified antibodies that neutralize omicron & other variants of SARS-CoV-2. These antibodies target areas of the virus spike protein that remain essentially unchanged when viruses mutate.
By identifying the targets of these “largely neutralizing” antibodies on the spike protein, it might be possible to design vaccines & antibody treatments that will be effective not only against the omicron variant, but also against other variants that may emerge in future, said David Veesler, investigator with Howard Hughes Medical Institute & associate Professor of Biochemistry at the University of the Washington School of Medicine in seattle. “This discovery tells us that by focusing on the antibodies that target these highly conserved sites on the spike protein, there is a way to overcome virus continual-evolution,” said Veesler.
Veesler led research project with Davide Corti of Humabs Biomed SA, Vir Biotechnology, Switzerland. The results of the study were published on Dec 23 in the journal Nature. The main authors of the study were Elisabetta Cameroni & Christian Saliba (Humabs), John E. Bowen (UW Biochimica) & Laura Rosen (Vir).
The Omicron variant has 37 mutations of the SPIKE protein, which uses to latch onto & invade the cells. This is unusually high number of mutations. These changes have been thought to be explained in part because the variant has been able to spread so quickly, to infect-people who have been vaccinated & reinfect those who have already been infected.
“The main questions we were trying to answer were as follows: how has this constellation of mutations in spikke protein of omicron variant affect & to evade immune system antibody responses, “said Veesler.
Veesler & his colleagues speculate that the large number of mutations of Omicron could be accumulated during a prolonged infection in a person with an weakened immune system or by virus jumping from human to an animal species & back again.
To assess effect of these mutations, the researchers designed a disabled, non-reproducing virus called pseudoviruses to produce spike proteins on its surface, like coronaviruses do. They then created pseudoviruses that had spike proteins with omicron mutations & those found on the previous variants identified in the pandemic.
The researchers first sought to determine to how different versions of the spike protein were able to bind to proteins on the cell surface, which the virus uses to latch onto & enter the cell. This protein is called angiotensin converting enzyme-2 (ACE2). receptor.
They found that the omicron variant spike protein was able to bind 2.4 times better than the spike protein found in virus isolated at the start of the pandemic. “It’s not a huge increase,” Veesler noted, “but during the 2002-2003 SARS epidemic, mutations in the spike protein that increased affinity were associated with higher transmissibility & infectivity. They also found that the omicron version was able to efficiently bind to ACE2 receptors in mice, suggesting that omicron might be able to “ping-pong” between humans & other mammals.
The researchers then examined how well the antibodies against the previous virus isolates were protected against the omicron variant. They did this by using antibodies from patients who had previously been infected with previous versions of the virus, vaccinated against previous strains of the virus, or had been infected & then vaccinated.
They found that the antibodies of people who had been infected with previous strains and those who had received one of the 6 most widely used vaccines currently available all had a reduced ability to block infection.
Antibodies from people who had previously been infected and from those who had received Sputnik V or Sinopharm vaccines and a single dose of Johnson and Johnson had little or no ability to block or “neutralize” of the omicron variant into cells. The antibodies of the people who had received 2 doses of modern vaccines, Pfizer / Biontech & Astrazeneca vaccines maintained some neutralizing activities, even if they are reduced by 20 to 40 fold, much more than any other variant.
The antibodies of those infected, re-covered & then had 2 doses of the vaccine also had reduced activity, but reduction was less, about 5 times, clearly demonstrating that post-infection vaccination is beneficial.
Antibodies from people, in this case a group of kidney dialysis patients, who received a boosted with a 3rd dose of mRNA vaccines made by Moderna & Pfizer / BioNTech showed only a 4-fold reduction in neutralizing activity. “It shows that a 3rd dose is really, really helpful against omicron,” Veesler said.
All but 1 antibody therapy currently licensed or approved for use with patients exposed to the virus, had no or had significantly reduced laboratory activity against omicron. The exception was an antibody called sotrovimab, which showed a two to three-fold reduction in neutralizing activity, according to the study.
But when they tested a larger panel of antibodies that generated against previous versions of the virus, the researchers identified 4 classes of antibodies that retained their ability to neutralize the omicron. Members of each of these classes target one of four specific areas of the spike protein found not only in SARS-CoV-2 variants, but also in a group of related coronaviruses, called sarbecoviruses. These sites on the protein can persist because they perform an essential function that the protein should lose if mutated. These areas are said to be “conserved”.
The discovery that the antibodies are able to neutralize the recognition of conserved areas in so many different variants of the virus suggesting that design vaccines & anti-body treatments that target these regions could be effective against a wide range of variants that emerge through the mutation, said veesler.
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