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Researchers help shed light on why the Omicron variant of SARS-CoV-2 can evade immunity, to some extent. T. Narayan/Bloomberg via Getty Images
  • Omicron is currently the dominant variant of SARS-CoV-2 globally.
  • It is able to evade previous immunity from infection and vaccination, which has triggered large booster vaccination programs in many countries.
  • Its ability to evade immunity is due to mutations occurring on its spike protein, which interrupts antibody binding.

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Ever since the development of vaccines for SARS-CoV-2, the virus that causes COVID-19, there have been concerns that the virus would mutate in a way that would evade immunity.

Of course, with the discovery of the Omicron variant in late November 2021, some of those fears have become a reality. While there is evidence that three doses of mRNA vaccines can provide immunity, its enhanced ability to evade immunity from vaccination and previous infection compared with other variants has surprised many researchers.

The discovery that it could evade immunity led to a rush to sequence the variant’s genome to pinpoint exactly how it could do this.

One team of researchers from the University of Missouri, Columbia, and the University of Nebraska was able to sequence Omicron. They recently published their findings in the Journal of Autoimmunity.

“We know that viruses evolve over time and acquire mutations, so when we first heard of the new Omicron variant, we wanted to identify the mutations specific to this variant,” said co-author Dr. Kamlendra Singh, assistant director of the Missouri University Molecular Interactions Core.

Using Omicron genome sequences made available by November 26, 2021, the team processed them to identify mutations. They selected mutations that occurred on over 50% of the sequences they analyzed and found 46 high prevalence mutations unique to the Omicron variant.

Of these, 23 were localized to the spike protein, which researchers have identified as crucial to SARS-CoV-2 infectiousness, and mRNA vaccines were designed to create antibodies that target it.

Using existing models of the spike protein, they modeled its interaction with antibodies to investigate how the mutations might help Omicron evade immunity.

These showed that the positioning of the mutations interfered with the binding of and interactions with antibodies. “Many mutations are at the places in the receptor-binding domain of spike protein, where antibodies are supposed to bind,” Dr. Singh told MNT in an interview.

“If there is a mutation, obviously, one would think that the antibodies will not be effectively bound to the spike protein, and that can reduce the efficacy of vaccination and prior infection.”

Interested in determining how the Omicron variant had evolved in the first place, the researchers used phylogenetic analysis to map the sequences of each of the variants Alpha, Beta, Gamma, Delta, Mu, and Omicron.

The paper concludes that Omicron is most closely related to the Gamma variant of SARS-CoV-2.

Spyros Lytras, an evolutionary virologist and doctoral candidate from the University of Glasgow, who was not involved in the research, described Omicron as the biggest “evolutionary leap” of SARS-CoV-2 we’ve seen so far. He also explained that it is not a “sub-clade” of any previously known variant of concern.

He explained the findings of the Journal of Autoimmunity paper in an email to MNT: The paper “does not claim that Omicron evolved from the Gamma clade,” Lytras said.

“What they say is that the Omicron clade shared a more recent common ancestor with the Gamma clade compared to all other [variants of concern] clades. That Omicron/Gamma last common ancestor was neither Omicron nor Gamma at the time. This is not news, since the placement of the Omicron clade in the tree can be viewed at [Nextstrain], which is one of the best tools out there for exploring the SARS-CoV-2 tree.”

He revealed the findings of his own research, currently in the pre-print stage, which suggest the mutations that researchers found in Omicron seem to be only beneficial to the virus when they are all present together.

Lytras’ research showed, “Omicron has independently accumulated some immune evasion mutations we’ve seen before, but most of its unique changes are not predicted to evade immunity on their own,” the researcher said.

“However, the Omicron spike has many changes that have never been seen before in circulating SARS-CoV-2 or the bat viruses most closely related to SARS-CoV-2, as we show in our pre-print.”

“The predicted immune evasion effects […] are measured individually, so the mutations that, on their own, have a small antigenic effect, might additively increase the effect when present together (as in Omicron),” Lytras explained.

“The most likely explanation of all these unexpected changes showing up in a single variant is ‘positive epistasis,’ i.e., these changes are beneficial to the virus and make it evade immunity or transmit faster, only when they are all present at the same time.”

“Overall, [Omicron] has accumulated a large number of mutations that seem to be beneficial to the virus only when present together, and even though most changes do not seem to strongly increase immune evasion on their own, when present together, they certainly allow the virus to evade previously acquired immunity — of course to some extent — as it is clear from the Omicron wave the world is facing right now.”

– Spyros Lytras

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