Omicron SARS-CoV-2 variant: Unique features and their impact on pre-existing antibodies
Highlights
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Phylogenetically SARS-CoV-2 Omicron variant is closely related to the Gamma variant.
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There are a total of 46 high prevalent mutations throughout the SARS-CoV-2 Omicron variant.
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Twenty three of the 46 mutations, which is more than any previously emerged variant belong to the S protein.
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Twenty-three of the 46 mutations are a markedly high number of mutations than has been previously reported for the S protein of other emerging variants.
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A significant number of mutations are at the antibody binding surface of S protein.
Abstract
Severe Acute Respiratory Coronavirus (SARS-CoV-2) has been emerging in the form of different variants since its first emergence in early December 2019. A new Variant of Concern (VOC) named the Omicron variant (B.1.1.529) was reported recently. This variant has a large number of mutations in the S protein. To date, there exists a limited information on the Omicron variant. Here we present the analyses of mutation distribution, the evolutionary relationship of Omicron with previous variants, and probable structural impact of mutations on antibody binding. Our analyses show the presence of 46 high prevalence mutations specific to Omicron. Twenty-three of these are localized within the spike (S) protein and the rest localized to the other 3 structural proteins of the virus, the envelope (E), membrane (M), and nucleocapsid (N). Phylogenetic analysis showed that the Omicron is closely related to the Gamma (P.1) variant. The structural analyses showed that several mutations are localized to the region of the S protein that is the major target of antibodies, suggesting that the mutations in the Omicron variant may affect the binding affinities of antibodies to the S protein.
We also analyzed the cryo-EM structure of an NTD-directed neutralizing antibody in complex with prefusion SARS-CoV-2 spike glycoprotein (PDB entry 7L2D) [15]. We selected this structure because the RMSD between Cα atoms of the antibody binding domain of this structure and corresponding Cα atoms of the S protein encoded by currently used Pfizer vaccine BNT162b2 (PDB entry 7L7K) [16] was 1.8 Å. It is important to note that the BNT162b2-encoded S protein structure does not include the bound antibody. As shown in Fig. 2C, Y145 forms hydrophobic interactions with antibody residues A97 and V98. A deletion mutation (Y145del), as seen in the Omicron variant, will result in the loss of these interactions and thereby reduce the binding affinity of the appropriate antibodies. Notably, Y145del is in close vicinity of positions where some signature mutations in Delta and Delta Plus have been reported [4].
In summary, in this report, we show that the Omicron variant has many mutations in the S protein. These mutations co-evolved with the mutations throughout the viral genome at a very high prevalence and the Omicron variant is closely related to the Gamma variant. The structural analyses suggest that the uniquely positioned mutations in the Omicron variant may reduce the binding of antibodies present in an individual induced by either prior infection or following vaccination against the SARS-CoV-2 virus. However, our structural analyses were restricted to monoclonal antibodies and their impact on polyclonal antibodies remains to be analyzed.
