Evolution of the SARS-CoV-2 omicron variants BA.1 to BA.5: Implications for immune escape and transmission

Abstract

The first dominant SARS-CoV-2 Omicron variant BA.1 harbours 35 mutations in its Spike protein from the original SARS-CoV-2 variant that emerged late 2019. Soon after its discovery, BA.1 rapidly emerged to become the dominant variant worldwide and has since evolved into several variants. Omicron is of major public health concern owing to its high infectivity and antibody evasion. This review article examines the theories that have been proposed on the evolution of Omicron including zoonotic spillage, infection in immunocompromised individuals and cryptic spread in the community without being diagnosed. Added to the complexity of Omicron's evolution are the multiple reports of recombination events occurring between co-circulating variants of Omicron with Delta and other variants such as XE. Current literature suggests that the combination of the novel mutations in Omicron has resulted in the variant having higher infectivity than the original Wuhan-Hu-1 and Delta variant. However, severity is believed to be less owing to the reduced syncytia formation and lower multiplication in the human lung tissue. Perhaps most challenging is that several studies indicate that the efficacy of the available vaccines have been reduced against Omicron variant (8-127 times reduction) as compared to the Wuhan-Hu-1 variant. The administration of booster vaccine, however, compensates with the reduction and improves the efficacy by 12-35 fold. Concerningly though, the broadly neutralising monoclonal antibodies, including those approved by FDA for therapeutic use against previous SARS-CoV-2 variants, are mostly ineffective against Omicron with the exception of Sotrovimab and recent reports suggest that the Omicron BA.2 is also resistant to Sotrovimab. Currently two new Omicron variants BA.4 and BA.5 are emerging and are reported to be more transmissible and resistant to immunity generated by previous variants including Omicron BA.1 and most monoclonal antibodies. As new variants of SARS-CoV-2 will likely continue to emerge it is important that the evolution, and biological consequences of new mutations, in existing variants be well understood.

Keywords: SARS-COV-2; immune evasion; monoclonal antibodies; omicron.

FIGURE 1

A time‐scaled phylogenetic tree of a representative global subsample of 3110 SARS‐CoV‐2 genomes, with tips coloured according to Nextstrain clades that predominantly correspond to variants of concern. Samples corresponding to Omicron sublineages BA.1, BA.2, BA.4, and BA.5 are labelled. BA.3 is not included since it does not yet satisfy the Nextstrain clade definition criteria; however, BA.3 falls under the overall Omicron clade 21M. Figure modified from the Nextstrain ‘omicron‐recombinant’ build (2022‐04‐08), using data available from the GISAID initiative (accession and author details available in Supplementary Table1).

FIGURE 2

Amino acid substitutions within the Omicron variant lineage. Black colour represents shared mutations, red Omicron BA.1, blue BA.2, orange BA.3 and Green BA.4/BA.5. BA.4 and BA.5 share a similar spike profile as BA.2, except for additional mutations: 69‐70del, L452R, F486V (Green) and reversion to wild type: Q493 (Q493R in BA.1, BA.2 and BA.3). BA.4 and BA.5 differ from each other by 3 amino acid mutations outside Spike. BA.4 additional mutations: ORF7b:L11F, N:P151S. BA.5 additional mutations: M:D3N. Figure drawn using Microsoft Office PowerPoint.

FIGURE 3

(a) Ribbon representation of Spike protein substitution in Delta variant (PDB ID 7W92), red spheres indicate amino acid substitution (b) Ribbon representation of Spike protein substitution in Omicron variant (PDB ID 7TGW), red spheres indicate amino acid substitution. Figure drawn by using Pymol; residues obtained from PDB (www.rcsb.com) using following PDB ID 7W92, 7TGW).