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. These better-fit versions of the virus become the building blocks of selection, says Nathan Grubaugh, PhD, a Yale School of Public Health epidemiologist. However, many sites in the viral genome are under strong functional selection, and so the mutational patterns at those sites will represent the combined action of mutation and selection. In addition to evaluation of vaccine efficacy against SARS-CoV-2 variants and mutations, the effects of mutations on some mAbs used as therapeutics have been described (Supplementary Table 2). J. Med. The substitutions T20N and P26S also occur in or near the NTD supersite30 at residues with high antibody accessibility scores (Fig. Hodcroft, E. B. et al. By contrast, when tested with convalescent serum, neutralization of the S477N mutant was similar to that of the wild type48. The substitution L18F has occurred ~21 times in the global population53 and is associated with escape from multiple NTD-binding mAbs30. Volz, E. et al. The authors declare no competing interests. Although most mutations in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome are expected to be either deleterious and swiftly purged or relatively neutral, a small. and D.L.R. More than 104 million cases have been confirmed globally. Identification of SARS-CoV-2 spike mutations that attenuate monoclonal and serum antibody neutralization. A new variant carrying E484K currently designated A.VOI.V2 was recently identified in Angola from cases involving travel from Tanzania79. Preprint at bioRxiv https://doi.org/10.1101/2021.04.22.440932 (2021). D.LR. Mutations that are present in a variant but that are also widespread in the virus population in which a variant emerged, or exhibit high diversity within a lineage, are marked with a dagger. Cell https://doi.org/10.1016/j.cell.2020.11.020 (2020). More generally, a broader understanding of the phenotypic impacts of mutations across the SARS-CoV-2 genome and their consequences for variant fitness will help elucidate drivers of transmission and evolutionary success. Barnes, C. O. et al. In the context of viruses, genetically distinct viruses with mutations different from those of other viruses. The research was funded by the National Human Genome Research Institute and the National Institutes of Health. In addition to N501Y, for which there is some evidence that it reduces neutralization by a small proportion of RBD antibodies63, there is evidence for an antigenic effect of Y144 (Fig. 5, several amino acid substitutions are convergent, having arisen independently in different lineages: N501Y, which is present in lineages B.1.1.7, B.1.351 and P.1; E484K, which is present in lineages B.1.351 and P.1 and has been detected as emerging within the B.1.1.7 lineage55; and H69V70 in lineages B.1.1.298 and B.1.1.7. 11, 2688 (2020). Med. Reports of lineages with N501Y circulating in the UK were followed by reports of another lineage possessing N501Y circulating in South Africa (lineage B.1.351), which has been rapidly expanding in frequency since December 2020 (ref.66). A protein with oligosaccharide chains (glycans) covalently attached to amino acid side chains. J. Med. The use of pathogen genomes on this scale to track the spread of the virus internationally, study local outbreaks and inform public health policy signifies a new age in virus genomic investigations3. Predictive modeling of influenza shows the promise of applied evolutionary biology. Shu, Y. 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. 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. 5a, and information on the structural context and consequences of mutations for antibody recognition and ACE2 binding are shown in Fig. Over the length of its 30,000-base-pair genome, SARS-CoV-2 accumulates an average of about one to two mutations per month, Rambaut says. Cryogenic electron microscopy was used to determine the antibody footprint of the neutralizing antibody 4A8, and showed key interactions involving spike residues Y145, H146, K147, K150, W152, R246 and W258 (ref.32). https://www.cogconsortium.uk, CoV-GLUE A Web Application for Tracking SARS-CoV-2 Genomic Variation: 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. & Munster, V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Similarly to deletions or insertions, an amino acid substitution outside an epitope footprint may affect antibody binding by changing the protein conformation in such a way that an epitope is altered or differently displayed. Acquisition of the L452R mutation in the ACE2-binding interface of spike protein triggers recent massive expansion of SARS-Cov-2 variants. Although care has to be taken not to confound mutations being merely present in growing lineages with mutations that change virus biology5, fitness-enhancing mutations were first detected to have arisen within a few months of the evolution of SARS-CoV-2 within the human population. 2c), and residues 978984, which become more accessible on the monomer anticlockwise adjacent to the upright RBD monomer (Fig. Mobility-related data show the pandemic has had a lasting effect, limiting the breadth of places people visit in cities. 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. c | A close-up view of the receptor-binding domain (RBD) bound to ACE2 (RCSB Protein Data Bank ID 6M0J95), with RBD residues shown as spheres coloured by amino acid variant frequency and ACE2 shown in gold. Preprint at bioRxiv https://doi.org/10.1101/2020.11.05.369264 (2020). Pseudoviruses were generated by the same system and tested with postvaccination sera from individuals who received two doses of either the BNT162b2 vaccine (n=30) or the mRNA-1273 vaccine (n=35)90. Matthews, D. B. Science 369, 650 (2020). Kidd, M. et al. The RCSB Protein Data Bank IDs for the SARS-CoV-2 spike protein structures are 6ZGG and 6ZGE50. They also determined that the region that encodes a gene called ORF3a also encodes an additional gene, which they name ORF3c. In addition to N3, high-scoring residues (greater than 0.7) are found at positions 2226 (N1), 70 (N2), 173187 (N4), 207213 (Fig. We can now go and actually study the evolutionary context of these variants and understand how the current pandemic fits in that larger history, Kellis says. All of these processes will benefit from close international collaboration and the rapid and open sharing of data. Mol. Pseudovirus and live-virus neutralization assays showed that the neutralizing activity of sera from individuals after the two doses of the ChaAdOx1 vaccine against the B.1.351 variant was reduced or abrogated86. Circulating SARS-CoV-2 spike N439K variants maintain fitness while evading antibody-mediated immunity. SARS-CoV-2 spreads primarily through human-to-human transmission, but there is evidence of transmission between humans and animals. In the new study, the researchers also analyzed more than 1,800 mutations that have arisen in SARS-CoV-2 since it was first identified. Following the emergence of D614G, an amino acid substitution within the receptor-binding motif (RBM), N439K, was noted as increasing in frequency in Scotland in March 2020. The escape fraction (that is, a quantitative measure of the extent to which a mutation reduced polyclonal antibody binding) averaged across all amino acid substitutions at a residue (plasma average) and the maximally resistant substitution (plasma max) are indicated. 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. Like all viruses, SARS-CoV-2 evolves over time through random mutations, only some of which are caught and corrected by the virus's error correction machinery. SARS-CoV-2 Mutations Explained. Cherian, S. et al. The event was spotted in infrared data also a first suggesting further searches in this band could turn up more such bursts. Med. Kemp, S. A. et al. The research team also analyzed nearly 2,000 mutations that have arisen in different SARS-CoV-2 isolates since it began infecting humans, allowing them to rate how important those mutations may be in changing the virus' ability to evade the immune system or become more infectious. Other experiments with pseudotyped viruses showed that the B.1.351 variant was also resistant to the neutralizing activity of some mAbs (12 of 17; 70%)67. Mutational escape from the polyclonal antibody response to SARS-CoV-2 infection is largely shaped by a single class of antibodies. Lineage B.1.1.7 is defined by the presence of 23 nucleotide mutations across the genome that map to a single branch of the phylogenetic tree3. https://covid19.who.int/ (2021). It has over 50 mutations, many in the spike protein, which is how it gets into our cells in the first place. In addition to substitutions, several deletions have been observed, particularly within the amino-terminal domain (NTD). Genomic characterization of a novel SARS-CoV-2 lineage from rio de Janeiro, Brazil. 27, 622625 (2021). There is now clear evidence of the changing antigenicity of the SARS-CoV-2 spike protein and of the amino acid changes that affect antibody neutralization. The mechanism of neutralization by which NTD-specific antibodies act remains to be fully determined, although it may involve the inhibition of conformational changes or proposed interactions with auxiliary receptors such as DC-SIGN or L-SIGN32,35. PubMed There are various distinct mechanisms by which mutations can alter the antigenic properties of a glycoprotein. Each mutation is classified as having evidence for mutations affecting neutralization by either monoclonal antibodies (mAbs) or antibodies in convalescent plasma39 or vaccinated individuals59, and emerging in selection experiments using mAbs40,47,48 or post-infection serum40,47,48. Currently, scientists are optimistic that the two mRNA vaccines available in the U.S.Pfizer-BioNTech and Modernawill continue to provide protection. Microbiol. The gene has RNA bases that overlap with ORF3a but occur in a different reading frame. Genomic Evidence of a SARS-Cov-2 Reinfection Case with E484K Spike Mutation in Brazil. a | Spike heterotrimer in the open conformation overlaid with the surface representation (RCSB Protein Data Bank ID 6ZGG50). Domains are coloured as in part a. 5b. Eurosurveillance 22, 30494 (2017). 2a). acknowledges the support of the Wellcome Trust (Collaborators Award 206298/Z/17/Z ARTIC network) and the European Research Council (grant agreement no. Evol. What is the Omicron variant? wrote the article. One study described multiple mAbs that selected for the emergence of S477N and found this mutant to be resistant to neutralization by the entire panel of RBD-targeting mAbs that were tested. http://cov-glue.cvr.gla.ac.uk/, Global Initiative on Sharing All Inflenza Data (GISAID): Alessandro M. Carabelli, Thomas P. Peacock, David L. Robertson, Jessica A. Plante, Yang Liu, Pei-Yong Shi, Sandra Isabel, Luca Graa-Miraglia, Susan M. Poutanen, Steven A. Kemp, Dami A. Collier, Ravindra K. Gupta, Marciela M. DeGrace, Elodie Ghedin, Mehul S. Suthar, Kaiming Tao, Philip L. Tzou, Robert W. Shafer, Kizzmekia S. Corbett, Darin K. Edwards, Barney S. Graham, Nature Reviews Microbiology 20, 591 (2020). Mahase, E. Covid-19: Novavax vaccine efficacy is 86% against UK variant and 60% against South African variant. ACS Cent. Garcia-Beltran, W. F. et al. We analyzed the entire genome and are very confident that there are no other conserved protein-coding genes, says Irwin Jungreis, lead author of the study and a CSAIL research scientist. Kumar, S., Maurya, V. K., Prasad, A. K., Bhatt, M. L. B. The ratio of non-synonymous mutations per non-synonymous site (dN) to synonymous mutations per synonymous site (dS), which is used to estimate the balance between neutral mutations, purifying selection and positive selection acting on gene or a specific codon. To monitor vaccine efficacy and to better understand the implications of antigenic variation for vaccine effectiveness, it will be important to collect information on vaccine status and viral genome sequence data from individuals infected with SARS-CoV-2. Starr, T. N. et al. Therefore, mutations in that region may help the virus evade the human immune system, Kellis says. Nat. This deletion is expected to alter the conformation of the N3 NTD loop (amino acid positions 140156) and has been demonstrated to abolish neutralization by a range of neutralizing antibodies30.
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