The authors declare no competing interests. The presence of a polybasic furin cleavage site at the S1S2 boundary, which is unique within the subgenus Sarbecovirus, is important for infectivity and virulence100, with furin cleavage facilitating the conformational change required for receptor binding50. ISSN 1740-1526 (print). Given that therapeutics (vaccines and antibody-based therapies) target mainly the SARS-CoV-2 spike protein, the selection pressures that favour the emergence of new variants carrying immune escape mutations generated in chronic infections24,25,26 will be similar to those selecting for mutations that allow reinfections within the wider population27,28,29. Frost, S. D. W., Magalis, B. R. & Kosakovsky Pond, S. L. Neutral theory and rapidly evolving viral pathogens. For example, the spike protein amino acid change D614G was noted to be increasing in frequency in April 2020 and to have emerged several times in the global SARS-CoV-2 population, and the coding sequence exhibits a high dN/dS ratio, suggesting positive selection at the codon position 614 (refs6,7). Within the RBD, the two areas with high structure-based antibody accessibility scores for the closed spike structure (Fig. An important part of this process will be the preparation of updated vaccines tailored to emerging antigenic variants that are maximally cross-reactive against all circulating variants. One study identified four recurrently deleted regions (RDRs) within the NTD and tested five frequently observed deletions within these: 6970 (RDR1), 141144 and 146 (RDR2), 210 (RDR3) and 243244 (RDR4)42. Silver, Z. Notability criteria. The emergence and ongoing convergent evolution of the N501Y lineages coincides with a major global shift in the SARS-CoV-2 selective landscape. This insertion, which also introduced a new glycosylation motif in the vicinity of RDR4, is predicted to alter the structure of the antigenic N3 and N5 NTD loops41. A similar NTD deletion, 243244, abolishes binding by the antibody 4A8 (ref.42), and L18F and R246I also occur within the NTD supersite and likely affect antibody binding as well30. Science https://doi.org/10.1126/science.abd0831 (2020). The LJI team found these antibodies can neutralize many SARS-CoV-2 variants by binding to vulnerable sites on the viral structure (gray). Cell https://doi.org/10.1016/j.cell.2021.03.029 (2021). PubMedGoogle Scholar. Tegally, H. et al. Rambaut, A. et al. Other examples of mutations that impact the epitopeparatope interface indirectly include mutations in the signal peptide region and at cysteine residues 15 and 136, which form a disulfide bond that staples the NTD amino terminus against the galectin-like -sandwich30. SARS-CoV-2 escape in vitro from a highly neutralizing COVID-19 convalescent plasma. Immunol. Lancet Infect. Tablizo, F. A. et al. b | Aligned heat maps showing properties of amino acid residues or of the specific amino acid substitution, as appropriate. The mean change in binding affinity averaged across all mutations at each site (binding average) and alternatively the maximally binding mutant (binding max) is shown. Specifically, SARS-CoV-2 seems to have a mutation rate of less than 25 mutations. In January 2022, Hong Kong experienced a surge of SARS-CoV-2 Omicron subvariant infections that quickly overwhelmed the health care system, isolation facilities, and track-and-trace capacities . Typically, studies report a fold change in variant virus, or pseudovirus, neutralization relative to wild-type virus (the serum concentration at which 50% neutralization (IC50) is achieved with the variant divided by the average IC50 for the wild-type virus). A Novel Variant of Interest of SARS-CoV-2 with Multiple Spike Mutations Detected Through Travel Surveillance in Africa. https://github.com/cov-lineages/pango-designation/issues/4 (2021). 2c), and N501Y has been shown experimentally to result in one of the highest increases in ACE2 affinity conferred by a single RBD mutation19. Hu, J. et al. COVID-19: How many strains of the new coronavirus are there? the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in A substitution can introduce an additional N-linked glycosylation motif. mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants. As new variants with unforeseen combinations of mutations continue to emerge, such insights will allow predictions of virus phenotype. Suryadevara, N. et al. https://cov-lineages.org/global_report.html (2020). and D.L.R. Nature 588, 327330 (2020). These mutations can take the form of single-letter typos in the viral genetic code or. D.LR. Google Scholar. 2c, green). Across the spike protein, some mutations that confer escape to neutralizing mAbs have little impact on serum antibody binding39,40,44, possibly because those mAbs are rare in polyclonal sera, targeting subdominant epitopes12,39,44. MacLean, O. A relative lack of glycan shielding may contribute to the immunodominance of the RBD33. One study reported structural, biophysical and bioinformatics analyses of 15 SARS-CoV-2 RBD-binding neutralizing antibodies31. Sci. PubMed Global Report Investigating Novel Coronavirus Haplotypes. The spike protein is synthesized as a 1,273 amino acid polypeptide, and the frequency of amino acid variants, including both substitutions and deletions, at each of the positions is shown. Cell 78, 779784 e775 (2020). In the case of S protein, the consequences of mutations seem obvious: They make virus entry into the cell easier or help evade the immune system, whereas the effects of mutations in N protein. Of these 23 mutations, 14 encode amino acid changes and three are deletions, including six amino acid substitutions in the spike protein (N501Y, A570D, P681H, T716I, S982A and D1118H) and two NTD deletions (H69V70 and Y144)3. Previous studies of SARS-CoV-2 variants have also shown that not every variant remains viable for the same duration on shipping materials, suggesting a link between genetic mutations and viral . Structural analysis indicates NTD-binding antibodies are likely able to bind epitopes when the spike protein is in either the closed conformation or open the conformation (Fig. Greater understanding of the correlates of immune protection is required to provide a context for the results of studies reporting changes in neutralization. Therefore, mutations in that region may help the virus evade the human immune system, Kellis says. What Mutations of SARS-CoV-2 are Causing Concern? The mutations at positions 417 and 484 prevented binding by antibodies from these classes. Complete mapping of mutations to the SARS-CoV-2 spike receptor-binding domain that escape antibody recognition. Non-synonymous nucleotide substitutions in protein-coding sequence result in a change in amino acid (referred to as a substitution or replacement), whereas synonymous nucleotide substitutions do not change the amino acid. & Robertson, D. L. No evidence for distinct types in the evolution of SARS-CoV-2. For example, recently detected viruses of lineage B.1.617.1 were anticipated to show altered antigenicity due to the presence of the substitutions L452R and E484Q, which have been described as affecting antibody recognition39,43,45,48,81. Nature https://doi.org/10.1038/s41586-021-03471-w (2021). Within the RBD, RBM epitopes overlapping the ACE2 site are immunodominant, whereas other RBD sites generate lower and variable responses in different individuals12. 1b). As of April 2021, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, accounted for more than 143 million infections and more than three million deaths worldwide1. There is no evidence for a notable impact of A222V on virus phenotype (that is, infectivity and transmissibility), and so its increase in frequency is generally presumed to have been fortuitous rather than a selective advantage. Garcia-Beltran, W. F. et al. Science 371, 11391142 (2021). Correspondence to This data could help other scientists focus their attention on the mutations that appear most likely to have significant effects on the virus infectivity, the researchers say. It has over 50 mutations, many in the spike protein, which is how it gets into our cells in the first place. a | Spike heterotrimer in the open conformation overlaid with the surface representation (RCSB Protein Data Bank ID 6ZGG50). Compared with SARS-CoV, SARS-CoV-2 binds to ACE2 an estimated 2-4 times more strongly, because several changes in the RBD stabilize its virus-binding hot spots . http://sars2.cvr.gla.ac.uk/cog-uk/, COVID-19 Genomics UK (COG-UK) Consortium: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome is thought to be around 27-31 kb in length, which increases the overall number of mutations acquired, without. Google Scholar. a | Structure-based antibody accessibility scores for each spike protein ectodomain residue in the closed form were calculated with BEpro49. The extent to which mutations affecting the antigenic phenotype of SARS-CoV-2 will enable variants to circumvent immunity conferred by natural infection or vaccination remains to be determined. . Zheng, Z. et al. Accessible amino-terminal domain (NTD) loops N1N5 are labelled, and a loop falling between these is indicated with an asterisk. contracts here. d | Spike protein in open form with residues where at least 100 sequences possessing a substitution are highlighted; a trimer axis vertical view (left) and an orthogonal top-down view along this axis (right) are shown. To assess the impacts of mutations on vaccine efficacy, authentic viruses and pseudoviruses possessing particular spike mutations (either individually or in combination) and larger sets of mutations representing variants of concern and other circulating spike mutations have been assessed by neutralization assays with postvaccination sera (Supplementary Table 1). Variants (retrieved from CoV-GLUE) are based on 426,623 high-quality sequences downloaded from the Global Initiative on Sharing All Influenza Data (GISAID) database on 3 February 2021. a | Points representing each spike amino acid residue are positioned according to the antibody accessibility score and the distance to the nearest residue in the receptor-binding site. Neutralization of UK-variant VUI-202012/01 with COVAXIN vaccinated human serum. There is emerging evidence of reduced neutralization of some SARS-CoV-2 variants by postvaccination serum; however, a greater understanding of correlates of protection is required to evaluate how this may impact vaccine effectiveness. Biol. Meredith, L. W. et al. Emary, K. R. W. et al. https://doi.org/10.1093/infdis/jiab082 (2021). Beyond shielding: the roles of glycans in the SARS-CoV-2 spike protein. Hodcroft, E. B. et al. Zhan, X.-Y. Virus particles can be saturated with mAbs, and the structure can be solved to determine the antibody footprint or mAbs can be used to select for mutations that escape recognition. The lineage B.1.526 has been found to carry either S477N or E484K, among other lineage-defining mutations77,78, both of which were described as antigenically important above. Moving forwards, the experimental characterization of SARS-CoV-2 spike mutations to date will continue to provide extremely useful information on individual mutations or combinations of mutations that may not yet have been seen in circulating viruses. Preprint at bioRxiv https://doi.org/10.1101/2021.01.26.426986 (2021). Circulating SARS-CoV-2 spike N439K variants maintain fitness while evading antibody-mediated immunity. Importantly, some mutations in the RBM have already been identified in variants which are circulating in the UK (for example, N439K, T478I and V483I) and are likely to impact antigenicity. In the NTD, most of the evidence for immune evasion focuses on a region centred at a conformational epitope consisting of residues 140156 (N3 loop) and 246260 (N5 loop), which includes the epitope of the antibody 4A832 (Fig.

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