Antibodies have been identified 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.
The new findings, from a study conducted by an international team of scientists, indicate that 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. The key will be to identify the targets of the “broadly neutralizing” antibodies on the spike protein.
“By focusing on antibodies that target these highly conserved sites on the spike protein, there is a way to overcome the virus’ continual evolution,” said David Veesler, PhD, one of the study’s leaders. Vessler is an investigator with the Howard Hughes Medical Institute and associate professor of biochemistry at the University of Washington School of Medicine in Seattle. The study’s other leaders are Gyorgy Snell, PhD, director of structural biology at Vir Biotechnology, and Davide Corti, PhD, senior vice president of antibody research at Humabs Biomed, a subsidiary of Vir Biotechnology.
The study’s findings were published in the journal Nature, in an article titled, “Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift.” The article, which was peer-reviewed, was posted before it could be copy-edited and finalized, according to an “Advance Article Preview” notice that referred to the expedited presentation“as a response to the exceptional public-health crisis.”
“Most receptor-binding motif (RBM)-directed monoclonal antibodies (mAbs) lost in vitro neutralizing activity against Omicron, with only 3 out of 29 mAbs retaining unaltered potency, including the ACE2-mimicking S2K146 mAb,” the article’s authors wrote. “Furthermore, a fraction of broadly neutralizing sarbecovirus mAbs neutralized Omicron through recognition of antigenic sites outside the RBM, including sotrovimab, S2X259, and S2H97.”
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.
According to Veesler, the scientists performing the study were interested in determining how the constellation of mutations in the Omicron variant’s spike protein affected the variant’s ability to bind to cells and to evade the immune system’s antibody responses. The scientists also wondered how the Omicron variant accumulated so many mutations. One possibility, they speculated, is that the mutations accumulated during a prolonged infection in someone with a weakened immune system. Another possibility is that the virus jumped from humans to an animal species and back again.
To assess the effect of the spike protein’s 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 the angiotensin converting enzyme-2 (ACE2) receptor, the cell surface protein that the virus uses to latch onto and enter the cell. They found the Omicron variant spike protein was able to bind 2.4 times better than the 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.”
The researchers 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 fourfold reduction in neutralizing activity. “This shows that a third dose is really, really helpful against omicron,” Veesler insisted.
When the scientists tested a larger panel of antibodies that had been generated against earlier versions of the virus, they 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.
