The distance to the ACE2-contacting residues that form the receptor-binding site RBS is shown (for residue 681, this is estimated with use of the nearest residues present in published structures). Based on current data, it seems as though SARS-CoV-2 mutates much more slowly than the seasonal flu. 2c, yellow). 95, e00119-21 (2021). Garcia-Beltran, W. F. et al. This variant carries several amino acid substitutions in the spike protein and three deletions in the NTD, some of which are within the antigenic supersite79. Viruses like SARS-CoV-2 continuously evolve as changes in the genetic code (caused by genetic mutations or viral recombination) occur during replication of the genome. The first genomes belonging to the B.1.1.7 lineage were sequenced in the south of England in September 2020. https://virological.org/t/phylogenetic-relationship-of-sars-cov-2-sequences-from-amazonas-with-emerging-brazilian-variants-harboring-mutations-e484k-and-n501y-in-the-spike-protein/585 (2021). In this Review, we summarize the literature on mutations of the SARS-CoV-2 spike protein, the primary antigen, focusing on their impacts on antigenicity and contextualizing them in the protein structure, and discuss them in the context of observed mutation frequencies in global sequence datasets. Sapkal, G. N. et al. Provided by the Springer Nature SharedIt content-sharing initiative, Nature Reviews Microbiology (Nat Rev Microbiol) The virus causing the COVID-19 pandemic, SARS-CoV-2, presents at least six strains. Article Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. and E.C.T. Watanabe, Y. et al. 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 . Beyond shielding: the roles of glycans in the SARS-CoV-2 spike protein. Nat. Preprint at medRxiv https://doi.org/10.1101/2020.12.21.20248640 (2020). As antigenically different variants are continuing to emerge, it will become necessary to routinely collect serum samples from vaccinated individuals and from individuals who have been infected with circulating variants of known sequence. Nat. Soh, W. T. et al. 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 . As SARS-CoV-2 spreads around the globe, it is mutating, in other words it is acquiring genetic changes. Information on how spike mutations affect antigenic profiles can be derived from structural studies, mutations identified in viruses exposed to mAbs or plasma containing polyclonal antibodies, targeted investigations of variants using site-directed mutagenesis and deep mutational scanning (DMS) experiments that systematically investigate the possibility of mutations arising. Whereas this first lineage with N439K (designated B.1.141 with the Pango nomenclature system17) quickly became extinct, another lineage that independently acquired N439K (B.1.258) emerged and circulated widely in many European countries18. This website is managed by the MIT News Office, part of the Institute Office of Communications. The risk is likely to be reduced with the use of cocktails of two or more mAbs targeting non-overlapping epitopes. Genomic epidemiology of novel coronavirus - Global subsampling. Among the 5,106 independent substitutions observed in the spike protein (Box1), 161 are described as affecting recognition by mAbs or polyclonal antibodies in sera, of which 22 are present in more than 100 sequences. Preprint at bioRxiv https://doi.org/10.1101/2021.02.22.432189 (2021). https://covid19.who.int/ (2021). PubMed Further lineages with these mutations have also been identified; for example, an independent emergence of N501Y in the B.1.1.70 lineage, which is largely circulating in Wales. Most random mutations are likely to be deleterious to the virus, and many will be lethal. 27, 763767 (2020). https://doi.org/10.1056/NEJMoa2102214 (2021). 1b). Although significant interperson and intraperson heterogeneity in the impact of mutations on neutralization by polyclonal serum has been described, the mutations that reduce antibody binding the most occur at a relatively small number of RBD residues, indicating substantial immunodominance within the RBD39. David L. Robertson. Experimental determination of the binding site, or epitope, of an antibody. Despite its mutations, the virus shows little variability, and this is good news for the researchers working on . 2c, blue). The spike protein transiently undergoes conformational changes between a closed conformation and an open conformation in which a hinge-like movement raises the RBD50. Outside the NTD and the RBD, the highest-scoring residues are residues 676 and 689 (which lie on either side of the loop containing the S1S2 furin cleavage site, which is disordered in both the open conformation and the closed conformation50), 793794, 808812, 1,0991,100 and 1,1391,146 (Fig. 1b). 21, 7382 (2021). Correspondence to In an escape mutation study using 19 mAbs, substitutions at E484 emerged more frequently than at any other residue (in response to four mAbs), and each of the four 484 mutants identified (E484A, E484D, E484G and E484K) subsequently conferred resistance to each of four convalescent sera tested48. Andreano, E. et al. Wrobel, A. G. et al. 372, n359 (2021). High numbers of B.1.351 viruses also have the spike amino acid substitutions L18F, R246I and D614G. Most mutations . The amino-terminal domain (NTD) supersite30 is coloured in magenta. volume19,pages 409424 (2021)Cite this article. The impact of spike mutations on SARS-CoV-2 neutralization. Wagner, C., Hodcroft, E., Bell, S. M., Neher, R. & Bedford, T. Resurgence of SARS-CoV-2 19B Clade Corresponds with Possible Convergent Evolution. . SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies. In an effort to predict future evolutionary maneuvers of SARS-CoV-2, a research team led by investigators at Harvard Medical School has identified several likely mutations that would allow the virus to evade immune defenses, including natural immunity acquired through infection or from vaccination, as well as antibody-based treatments. 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. 1a,b). What are the new variants and how are they different from the older variants? Early indications suggest that these are broadly consistent with the laboratory results, with the B.1.351 variant showing greater signs of vaccine escape. 1b. What is the Omicron variant? SARS-CoV-2 variants, spike mutations and immune escape During that time, researchers have tracked changes to the virus' genome . Of the lineages summarized in Fig. 2a, yellow patch to the extreme right of the structure viewed from the side in Fig. Nat. 3). Google Scholar. A. et al. SARS-CoV-2, the new coronavirus that causes COVID-19, is no exception to this.. As . Images for download on the MIT News office website are made available to non-commercial entities, press and the general public under a The LJI team found these antibodies can neutralize many SARS-CoV-2 variants by binding to vulnerable sites on the viral structure (gray). Several studies have contributed to the current understanding of how mutations in the SARS-CoV-2 spike protein affect neutralization. How long Omicron variants persist on shipping materials may be influenced by temperature, humidity and material. Specifically, SARS-CoV-2 seems to have a mutation rate of less than 25 mutations. Mobility-related data show the pandemic has had a lasting effect, limiting the breadth of places people visit in cities. Other investigations with recombinant viruses carrying N501Y, H69V70+N501Y+D614G or E484K+N501Y+D614G demonstrated that compared with the Wuhan-Hu-1 reference virus, only E484K+N501Y+D614G resulted in a small and modest reduction in neutralization by postvaccination sera elicited by two BNT162b2 doses, and only modest differences in neutralization were seen compared with the Wuhan-Hu-1 reference virus83. Tablizo, F. A. et al. In addition to N3, high-scoring residues (greater than 0.7) are found at positions 2226 (N1), 70 (N2), 173187 (N4), 207213 (Fig. https://doi.org/10.1038/s41579-021-00573-0, DOI: https://doi.org/10.1038/s41579-021-00573-0. Preprint at bioRxiv https://doi.org/10.1101/2021.01.25.427948 (2021). Mutations can reveal how the coronavirus movesbut they're easy to Its position has been described as belonging to the footprint of several antibodies, and a change in charge caused by replacement of a glutamate residue with a lysine residue has the potential to diminish antibody binding. The substitutions T20N and P26S also occur in or near the NTD supersite30 at residues with high antibody accessibility scores (Fig. c | Spike protein structure in the closed conformation overlaid with surface representations shown with a trimer axis vertical view (left) and an orthogonal top-down view along this axis (right). We have all the tools needed to stop the spread of these new variants, Grubaugh emphasized. The researchers also showed that five other regions that had been proposed as possible genes do not encode functional proteins, and they also ruled out the possibility that there are any more conserved protein-coding genes yet to be discovered. Preprint at bioRxiv https://doi.org/10.1101/2020.12.28.424451 (2020). Preprint at medRxiv https://doi.org/10.1101/2021.02.23.21252268 (2021). http://cov-glue.cvr.gla.ac.uk/, Global Initiative on Sharing All Inflenza Data (GISAID): CDC coordinates collaborative partnerships which continue to fuel the largest viral genomic sequencing effort to date. There are certain mutations in some of these variants that seem to decrease the effectiveness of really important antibodies, says Grubaugh. As described in Box2, substitutions may facilitate immune escape by increasing receptor-binding affinity independently of any effect that they may have on antibody recognition of epitopes; therefore, it is possible that such a mechanism contributes to the impact of S477N on neutralization. Emergence and rapid spread of a new severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in South Africa. Neutralization of SARS-CoV-2 spike 69/70 deletion, E484K, and N501Y variants by BNT162b2 vaccine-elicited sera. Tracking SARS-CoV-2 variants - WHO 5b. https://www.krisp.org.za/publications.php?pubid=330 (2021).
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