The variant gambit: COVID-19's next move

Abstract

More than a year after its emergence, COVID-19, the disease caused by SARS-CoV-2, continues to plague the world and dominate our daily lives. Even with the development of effective vaccines, this coronavirus pandemic continues to cause a fervor with the identification of major new variants hailing from the United Kingdom, South Africa, Brazil, and California. Coupled with worries over a distinct mink strain that has caused human infections and potential for further mutations, SARS-CoV-2 variants bring concerns for increased spread and escape from both vaccine and natural infection immunity. Here, we outline factors driving SARS-CoV-2 variant evolution, explore the potential impact of specific mutations, examine the risk of further mutations, and consider the experimental studies needed to understand the threat these variants pose. In this review, Plante et al. examine SARS-CoV-2 variants including B.1.1.7 (UK), B.1.351 (RSA), P.1 (Brazil), and B.1.429 (California). They focus on what factors contribute to variant emergence, mutations in and outside the spike protein, and studies needed to understand the impact of variants on infection, transmission, and vaccine efficacy.

Keywords: 2019-nCoV; COVID-19; SARS-CoV-2; coronavirus; furin cleavage; spike.

Figure 1

Variant substitutions in the conserved and NTD portions of the spike (A) Diagram of the coronavirus spike protein divided into four domains: N-terminal domain of S1 (NTD), RBD, C-terminal domain of S1 (CTS1), and S2 subunit (S2). Sequence identities were extracted from alignments constructed from representative 2B CoVs using alignment data paired with neighbor-joining phylogenetic trees built using Geneious (V.9.1.5) using accession numbers: QHU79204 (SARS-CoV-2 WA1), QHR63300.2 (RATG13), QND76034.1 (HKU3), and AYV99817.1(SARS-CoV Urbani). Heatmaps constructed using EvolView (ww.evolgenius.info/) with SARS-CoV-2 WA1 as the reference sequence. (B) SARS-CoV trimer (PDB: 6VSB ) defining the NTD (orange), RBD (red), CTS1 (pink), and S2 (gray) of spike. RBD noted in the up or down position. (C–D) Spike substitutions found in each variant of concern defined in (C) table and on (D) corresponding ribbon structure (PDB: 6VSB) by color. (E) NTD surface-exposed substitutions found on the SARS-CoV-2 trimer (PDB: 7DF3). (F) Reported NTD substitutions in each variant of concern, identified escape mutations, and proximity to glycosylation sites. Hashed boxes represent amino acid sites that are adjacent to escape or glycosylated residues.

Figure 2

RBD substitutions found across the variants of concern (A) Reported RBD substitutions in each variant of concern, identified escape mutations, and mouse-adapted SARS-CoV-2 strains. (B) Receptor-binding domain interaction with human ACE2 (PDB: 6M0J) highlighting substitutions in SARS-CoV-2 variants. (C–E) Predicted amino acid structure of substitutions: (C) N501 (red) to Y501 (blue), (D) K417 (green) to N417 (red) or T417 (blue); and (E) E484 (blue) to K484 (red).