Compared with wild type, pseudoviruses with D614G or the mutations defining lineages B.1.1.7, B.1.1.298 and B.1.429 each showed non-statistically significant decreases in neutralization90. In addition to understanding the transmissibility and pathogenicity of these emerging variants, it is crucially important to characterize their antigenicity and the level of cross-protection provided by infection by earlier viruses that are genetically and antigenically similar to the virus that first emerged in December 2019 and which is used in all of the current vaccine preparations. In common with N439K and N501Y, S477N results in increased affinity for the ACE2 receptor, although to a lesser extent19,54. 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. SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies. Subsequently, many distinct lineages of SARS-CoV-2 have evolved. The Omicron variant, which emerged in November 2021, has many lineages. There have been a number of missense mutations observed of SARS-CoV-2. Sci. This is because although high-effect mutations that contribute to virus adaption and fitness do occur, they tend to be in the minority compared with tolerated low-effect or no-effect neutral amino acid changes4. W.T.H., A.M.C., A.R., S.J.P. PubMed Neutralizing and protective human monoclonal antibodies recognizing the N-terminal domain of the SARS-CoV-2 spike protein. 1b. 95, e00119-21 (2021). Sapkal, G. N. et al. Watanabe, Y., Allen, J. D., Wrapp, D., McLellan, J. S. & Crispin, M. Site-specific glycan analysis of the SARS-CoV-2 spike. 21, 7382 (2021). Prediction of the mutational pathways by which a virus such as SARS-CoV-2 will evolve is extremely challenging. Science 372, 815821 (2021). Increasingly, lineages possessing independent occurrences of mutations in common with the variants of concern B.1.1.7, B.1.351 and P.1 are being detected, demonstrating convergent evolution. Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and . Virus Evol. https://cov-lineages.org/global_report.html (2020). Comparisons with reporting of antibody footprints and the impact of mutations on antigenicity indicate that residues with mutations described as affecting recognition by mAbs or antibodies in convalescent plasma (Fig. SARS-CoV-2 RBD in vitro evolution follows contagious mutation spread, yet generates an able infection inhibitor. Microbiol. SARS-CoV-2 can enter cells by two main pathways. Immunol. & Baldi, P. PEPITO: improved discontinuous B-cell epitope prediction using multiple distance thresholds and half sphere exposure. Rees-Spear, C. et al. 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. 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. The first genomes belonging to the B.1.1.7 lineage were sequenced in the south of England in September 2020. The role for this new gene, as well as several other SARS-CoV-2 genes, is not known yet. Dis. To obtain a | Spike heterotrimer in the open conformation overlaid with the surface representation (RCSB Protein Data Bank ID 6ZGG50). & Bjorkman, P. J. SARS-CoV-2 lineage B.1.526 emerging in the New York region detected by software utility created to query the spike mutational landscape. 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Recurrent deletions in the SARS-CoV-2 spike glycoprotein drive antibody escape. Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies. 2c). 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. SARS-CoV-2 variants, spike mutations and immune escape, https://doi.org/10.1038/s41579-021-00573-0. MIT News | Massachusetts Institute of Technology, A comprehensive map of the SARS-CoV-2 genome. The specific parts of an antigen recognized by the immune system: antibodies, B cells or T cells. 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. The mutation N439K increases affinity for ACE2 (ref.19), is predicted to result in an additional salt bridge at the RBMACE2 interface and is thought to preferentially reduce the neutralization potential of plasma that already has low neutralizing activity18. The co-occurrence of K417N, E484K and these NTD substitutions suggests that lineage B.1.351 may overcome the polyclonal antibody response by reducing neutralization by class 1 and class 2 RBD-specific antibodies and NTD-specific antibodies (Fig. A change in the biophysical properties of an epitope residue directly diminishes antibody binding. https://doi.org/10.1093/ve/veaa034 (2020). Here's what scientists are watching for: Like all viruses, SARS-CoV-2 is mutating as it passes from person to person. 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. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. COVID-19: How many strains of the new coronavirus are there? Due to this aggregation, calculated scores are relatively insensitive to the effects of single amino acid substitutions. https://doi.org/10.1093/infdis/jiab082 (2021). The P.1 lineage, a sublineage of B.1.1.28, was first detected in Brazil69 and in travellers from Brazil to Japan70. Science 371, 850 (2021). Korber, B. et al. Here's how scientists are tracking the genetic evolution of & Munster, V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Analysis of SARS-CoV-2 mutations in the United States suggests - Nature Cell Host Microbe 29, 2331.E24 (2021). Using these techniques, the researchers confirmed six protein-coding genes in the SARS-CoV-2 genome in addition to the five that are well established in all coronaviruses. Harvey, W.T., Carabelli, A.M., Jackson, B. et al. Structural and functional analysis of the D614G SARS-CoV-2 spike protein variant. Nature 588, 327330 (2020). 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. Pseudoviruses carrying the set of B.1.1.7 spike mutations evaluated with postvaccination serum from individuals who received the BNT162b2 vaccine (two doses)63,78,84 or mRNA-1273 vaccine (two doses)63 exhibited only a modest reduction in neutralization titres (less than threefold). Nextstrain. Working paper on SARS-CoV-2 spike mutations arising in Danish mink, their spread to humans and neutralization data. Science 369, 330 (2020). Nat. Wang, Z. et al. Single mAb treatment can exert a selective pressure that potentially increases the possibility of mutational escape of the targeted antigen. Mol. Science 370, 1464 (2020). It is also the principal target of neutralizing antibodies generated following infection by SARS-CoV-2 (refs12,13), and is the SARS-CoV-2 component of both mRNA and adenovirus-based vaccines licensed for use and others awaiting regulatory approval14. Complete mapping of mutations to the SARS-CoV-2 spike receptor-binding domain that escape antibody recognition. 4b). Nature 588, 682687 (2020). Scientists can track mutations as they are passed down through a lineage, a branch of the coronavirus family tree. Q613H is speculated to be important as it occurs at a position neighbouring D614G80. Cell 183, 19011912 e1909 (2020). N. Eng. Scores were calculated for the spike protein in both the closed conformation and the open conformation (Fig. 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. Get the most important science stories of the day, free in your inbox. Antibodies made by cloning a unique white blood cell, which usually has monovalent binding affinity for a specific epitope. Huang, B. et al. What is the Omicron variant? Li, Q. et al. Emerging SARS-CoV-2 variants reduce neutralization sensitivity to convalescent sera and monoclonal antibodies. This is caused by non-synonymous mutations. Cell https://doi.org/10.1016/j.cell.2021.03.028 (2021). mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants. Of the four RDRs, RDR1, RDR2 and RDR4 correspond to NTD loops N2, N3 and N5, whereas RDR3 falls between N4 and N5 in another accessible loop (Fig. SARS-CoV-2 has been acquiring minor random mutations ever since it jumped from animals to humans. Within the RBD, the positions at which amino acid substitutions are present at the highest frequency are located close to the RBDACE2 interface (Fig. Virus genomic sequences are being generated and shared at an unprecedented rate, with more than one million SARS-CoV-2 sequences available via the Global Initiative on Sharing All Influenza Data (GISAID), permitting near real-time surveillance of the unfolding pandemic2. Residue 501 is at the RBDACE2 interface (Fig. Convergent evolution of SARS-CoV-2 spike mutations, L452R, E484Q and P681R, in the second wave of COVID-19 in Maharashtra, India. 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. acknowledges the support of the Wellcome Trust (Collaborators Award 206298/Z/17/Z ARTIC network) and the European Research Council (grant agreement no. This is mediated by glycans, bulky sugar molecules that are covalently attached to amino acid side chains of the viral protein. However, assays using pseudovirus carrying B.1.1.7 spike mutations and with the addition of E484K, a combination that has been observed in sequencing of circulating isolates, showed larger, more significant drops (6.7-fold) in neutralization with postvaccination sera isolated from individuals who received the BNT162b2 vaccine85. Identification of SARS-CoV-2 spike mutations that attenuate monoclonal and serum antibody neutralization. They are defined by multiple convergent mutations that are hypothesized to have arisen either in the context of chronic infections or in previously infected individuals24,25,26,27,28,29. In their study, which appears today in Nature Communications, they confirmed several protein-coding genes and found that a few others that had been suggested as genes do not code for any proteins. Cele, S. et al. Google Scholar. In the spike NTD, changes to disulfide bonds are thought to reduce binding by multiple monoclonal antibodies through this mechanism30. Silver, Z. 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. For RBD residues, the results of deep mutational scanning (DMS) studies show the escape fraction (that is, a quantitative measure of the extent to which a mutation reduced polyclonal antibody binding) for each mutant averaged across plasma (plasma average) and for the most sensitive plasma (plasma max)39. The phenomenon by which the host immune response against a viral particle is mostly focused on a few antigens and mediated by potently neutralizing antibodies. The impact of spike mutations on SARS-CoV-2 neutralization. A campus summit with the leader and his delegation centered around dialogue on biotechnology and innovation ecosystems. A mutation that speeds up Covid-19's spread might explain why the virusknown as SARS-CoV-2 has so rapidly moved through North America and Europe, where the G614 mutated version is predominant. To assess the impact of spike mutations and their immunological role in the global SARS-CoV-2 population, we combined structural analyses with the observed frequency of mutations in circulating variants (Fig. The deletion or insertion of residues has the potential to alter epitope conformation, diminishing antibody binding. No other mAb-selected escape mutants escaped each of the four sera, although the mutations K444E, G446V, L452R and F490S escaped three of the four sera tested48. Immunol. Within the RBD, the two areas with high structure-based antibody accessibility scores for the closed spike structure (Fig. Both RDR2 deletions, 141144 and 146, and 243244 (RDR4) abolished binding of 4A8 (ref.42). For each residue, the calculated score accounts for the local protein structure: half-sphere exposure measures and propensity scores each depend on all atoms within 816 of the target residue, with weighting towards closer atoms. No higher infectivity but immune escape of SARS-CoV-2 501Y.V2 variants. A change in a specific amino acid of a protein. Science 369, 650 (2020). https://www.gisaid.org, Global Report Investigating Novel Coronavirus Haplotypes: 5b). 4. Most random mutations are likely to be deleterious to the virus, and many will be lethal. These better-fit versions of the virus become the building blocks of selection, says Nathan Grubaugh, PhD, a Yale School of Public Health epidemiologist. The authors declare no competing interests. Cell 183, 10241042 e1021 (2020). PubMed Coronavirus seems to mutate much slower than seasonal flu Chi, X. et al. The substitutions T20N and P26S also occur in or near the NTD supersite30 at residues with high antibody accessibility scores (Fig. CAS In the meantime, to ensure continued support, we are displaying the site without styles COVID-19: Studying variants' mutations overturns assumptions also acknowledges support of the Wellcome Trust (220977/Z/20/Z). Proposal for New Lineage within B.1 #4: B.1.525, cov-lineages/pango-designation. Cell 182, 812827 e819 (2020). We have all the tools needed to stop the spread of these new variants, Grubaugh emphasized. The rate of evolution of SARS-CoV-2 from December 2019 to October 2020 was consistent with the virus acquiring approximately two mutations per month in the global population15,16. The research team tested how well antibodies from COVID-19 patients bound to viruses that had these mutations. The most accelerated region in the entire genome of SARS-CoV-2 is sitting smack in the middle of this nucleocapsid protein, he says. 2c, yellow). Notably, scores for residues with mutations described as affecting plasma antibody recognition are also slightly higher on average compared with those with mutations described as affecting mAbs only. Sci. In a live-virus neutralization assay, neutralizing titres of ChAdOx1 nCoV-19 (OxfordAstraZeneca) postvaccination sera were nine times lower than titres against the B.1.1.7 lineage relative to a canonical non-B.1.1.7 lineage (Wuhan-Hu-1 with the S247R spike mutation)86. The systematic surveillance of antigenic SARS-CoV-2 variants will be enhanced by the establishment of a network similar to the WHO-coordinated Global Influenza Surveillance and Response System (GISRS), a collaborative global effort responsible for tracking the antigenic evolution of human influenza viruses and making recommendations on vaccine composition. 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. J. Cell https://doi.org/10.1016/j.cell.2020.11.020 (2020). A Novel Variant of Interest of SARS-CoV-2 with Multiple Spike Mutations Detected Through Travel Surveillance in Africa. The burden of incidental SARS-CoV-2 infections in hospitalized patients 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. 3). Of the three RBD amino acid substitutions present in several thousand sequences, N439K and N501Y were described earlier, and N501Y is discussed in more detail in the next section in the context of variants of concern. 3). Rambaut, A. et al. In this video, Iwasaki and Grubaugh discuss the science behind the SARS-CoV-2 mutations and explain why it's important to continue wearing masks, avoiding crowds, and washing your hands. 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. The COVID-19 Genomics UK (COG-UK) Consortium is supported by funding from the UK Medical Research Council (MRC), part of UK Research and Innovation, the UK National Institute of Health Research and Genome Research Limited, operating as the Wellcome Sanger Institute. 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. Deep mutational scanning of SARS-CoV-2 receptor binding domain reveals constraints on folding and ACE2 binding. 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). DMS data on ACE2-binding affinity19 are shown in shades of red or blue representing higher or lower ACE2 affinity, respectively. SARS-CoV-2 escape in vitro from a highly neutralizing COVID-19 convalescent plasma. Black diamonds at the top and bottom of the plot indicate the positions of ACE2-contacting residues. The distance in angstroms to the ACE2-contacting residues that form the receptor-binding site (RBS) is shown in shades of orange; each residue is classified as having evidence for mutations affecting neutralization by either monoclonal antibodies (mAbs)40,43,47,48 or polyclonal antibodies in plasma from previously infected individuals (convalescent)39,40,41,43,48 or vaccinated individuals59 (mAb effect and plasma effect, respectively). Immunol. Similarly, neutralizing activity of sera elicited by the inactivated vaccine Covaxin (Bharat Biotech) against B.1.1.7 viruses was largely preserved87. Tablizo, F. A. et al. The mRNA technology is very flexible and can accommodate new mutations, says Iwasaki.
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