Omicron has 37 spike protein mutations as “unprecedented.” This is an unusually high number of mutations. It is thought that these changes partly explain why the variant has been able to spread so rapidly, infect people who have been vaccinated, and reinfect those who have previously been infected.
However, it remains elusive how these mutations in the spike protein of the omicron variant affected its ability to bind to cells and evade the immune system’s antibody responses.
An international team of scientists recently identified antibodies that neutralize omicron and other SARS-CoV-2 variants. These antibodies target the infection spike protein that remains unaltered as the infections change.
David Veksler, an investigator with the Howard Hughes Medical Institute and associate professor of biochemistry at the University of Washington School of Medicine in Seattle, said, “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. 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.”
By engineering a disabled, nonreplicating virus called a pseudovirus, scientists assessed the effect of these mutations. They then created pseudoviruses that had spike proteins with the omicron mutations and those found on the earliest variants identified in the pandemic.
Scientists, at first, observed how well the different versions of the spike protein were able to bind to a 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 could bind 2.4 times better than the spike protein found in the virus isolated at the very beginning of the pandemic. They also found that the omicron version bind to mouse ACE2 receptors efficiently. It suggests that omicron might be able to “ping-pong” between humans and other mammals.
Veksler noted, “That’s not a huge increase, but in the SARS outbreak in 2002-2003, mutations in the spike protein that increased affinity were associated with higher transmissibility and infectivity.”
Later, scientists observed how well antibodies against earlier isolates protected against the omicron variant. This observation was made 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 whose earlier strains had infected and 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 the 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.
Veksler said, “This shows that a third dose is helpful against omicron.”
Scientists noted, “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.”
Scientists generated a larger panel of antibodies that have been generated against earlier versions of the virus. They tested the panel and identified four classes of antibodies that retained their ability to neutralize omicron.
Members from each of these classes target one of four explicit spaces of the spike protein present in SARS-CoV-2 variants, as well as 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.”
Veksler said, “The finding that antibodies can 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.”
- Elisabetta Cameroni, John E. Bowen et al. Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift. DOI: 10.1038/d41586-021-03825-4