Preprint at medRxiv https://doi.org/10.1101/2021.02.12.21251658 (2021). Mahase, E. Covid-19: Novavax vaccine efficacy is 86% against UK variant and 60% against South African variant. 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. . 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). 2b. In the meantime, to ensure continued support, we are displaying the site without styles The emergence of SARS-CoV-2 in late 2019 was followed by a period of relative evolutionary stasis lasting about 11 months. Greater understanding of the correlates of immune protection is required to provide a context for the results of studies reporting changes in neutralization. One study described the structure of five previously unmodelled, protruding NTD loops, denoting them N1N5. The impact of spike mutations on SARS-CoV-2 neutralization. Glycans are bulky sugar molecules that may shield epitopes from antibody binding. Resurgence of Omicron BA.2 in SARS-CoV-2 infection-naive Hong Kong ISSN 1740-1534 (online) Article 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. As mentioned earlier, there is evidence indicating that D614G confers a moderate advantage for infectivity8,9 and increases transmissibility10. Temporal signal and the phylodynamic threshold of SARS-CoV-2. Nature 584, 450456 (2020). Suryadevara, N. et al. A new variant carrying E484K currently designated A.VOI.V2 was recently identified in Angola from cases involving travel from Tanzania79. Antibodies made by cloning a unique white blood cell, which usually has monovalent binding affinity for a specific epitope. No higher infectivity but immune escape of SARS-CoV-2 501Y.V2 variants. 35, 13481354 (2018). 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. de Oliveira, T. et al. Yurkovetskiy, L. et al. Preprint at bioRxiv https://doi.org/10.1101/2021.02.22.432189 (2021). 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. Martin, D. P. et al. 4b). are funded by the MRC (MC_UU_12014/12) and acknowledge the support of the G2P-UK National Virology Consortium (MR/W005611/1) funded by UK Research and Innovation. D.LR. J. Infect. Consequently, mutations that affect the antigenicity of the spike protein are of particular importance. Korber, B. et al. In addition to substitutions, several deletions have been observed, particularly within the amino-terminal domain (NTD). Based on current data, it seems as though SARS-CoV-2 mutates much more slowly than the seasonal flu. Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies. Although the RBD is immunodominant, there is evidence for a substantial role of other spike regions in antigenicity, most notably the NTD13,30,34. But some errors are beneficial, making it more contagious. A novel SARS-CoV-2 variant of concern, B.1.526, identified in New York. Dis. Nat. Mol. Case study: prolonged infectious SARS-CoV-2 shedding from an asymptomatic immunocompromised individual with cancer. Wise, J. Covid-19: the E484K mutation and the risks it poses. W.T.H., A.M.C., B.J., R.K.G., E.C.T., E.M.H., C.L., A.R. Investigations with pseudoviruses possessing RBD mutations carried by variants of concern demonstrated that the neutralizing activity of plasma from vaccinated individuals showed a small but significant decreases of onefold to threefold against E484K, N501Y or the K417N+E484K+N501Y triple mutant59. Researchers measured the viability of BA.1 and BA.5 Omicron variants on 4 shipping materials. SARS-CoV-2 variants, spike mutations and immune escape. A few other regions were suspected to encode proteins, but they had not been definitively classified as protein-coding genes. The authors declare no competing interests. In addition to substitutions at positions 417, 484 and 501 discussed above, the P.1 lineage has a cluster of substitutions close to the described antigenic regions of the NTD, including L18F, which is known to reduce neutralization by some antibodies30. The six strains of SARS-CoV-2 -- ScienceDaily Globally, the highest number of amino acid variants, mapped against the Wuhan-Hu-1 reference sequence (MN908947), are recorded at amino acid positions 614, 222 and 18 (Fig. Both RDR2 deletions, 141144 and 146, and 243244 (RDR4) abolished binding of 4A8 (ref.42). Structure-based antibody access scores for the spike protein in the closed and open conformations are shown. But the novel coronavirus is highly contagious and has spread almost unchecked throughout the world for the last year. Within the RBD, the positions at which amino acid substitutions are present at the highest frequency are located close to the RBDACE2 interface (Fig. The H69V70 deletion has been identified in variants associated with immune escape in immunocompromised individuals treated with convalescent plasma24. Benton, D. J. et al. A year after the first case of COVID-19 was reported in the U.S., more than 26 million Americans are confirmed to have had this disease, caused by the SARS-CoV-2 virus. There is also evidence that this lineage may be associated with a higher viral load62. Proposal for New Lineage within B.1 #4: B.1.525, cov-lineages/pango-designation. Deep mutational scanning of SARS-CoV-2 receptor binding domain reveals constraints on folding and ACE2 binding. 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. Chi, X. et al. Shades of green depict the results of deep mutational scanning (DMS) experiments where yeast cells expressing RBD mutants are incubated with multiple samples of human convalescent plasma39. Nat. 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. The spike protein is also one of the most prominent exterior features of the virus that our immune system recognizes, responds to and uses to develop antibodies. A "mutation" is just a change in a virus's genetic code. N. Engl. The P.1 lineage has also been associated with a reinfection case in Manaus, Brazil27, indicating it is contributing to antigenic circumvention of what might have been an otherwise effective immune response. Wang, Z. et al. When this happens, new variants can develop. Liu, Z. et al. As SARS-CoV-2 spreads around the globe, it is mutating, in other words it is acquiring genetic changes. Wagner, C., Hodcroft, E., Bell, S. M., Neher, R. & Bedford, T. Resurgence of SARS-CoV-2 19B Clade Corresponds with Possible Convergent Evolution. 5b), and T20N introduces a potential glycosylation site that could result in glycan shielding (Box2) of part of the supersite. An approach that uses a competitive immunoassay to sort a library of monoclonal antibodies into discrete groups of antibodies that compete for access to overlapping epitopes. Med. Notability criteria. 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. 21, 7382 (2021). 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. For each spike monomer (upright receptor-binding domain (RBD) (yellow), closed RBD clockwise adjacent (green) and closed RBD anticlockwise adjacent (blue)), the difference relative to the score calculated for the closed form (shown in part a) is shown. A relative lack of glycan shielding may contribute to the immunodominance of the RBD33. 2c, green). Rev. The collective data on the effect of mutations on vaccines and convalescent serum efficacy show that the polyclonal antibody response is focused on a few immunodominant regions, indicating the high probability of future mutation-mediated escape from host immunity. As of 5 November 2020, 214 humans infected with SARS-CoV-2 related to mink were all carrying the mutation Y453F21. Feb 19, 2021. 383, 22912293 (2020). Internet Explorer). Escape mutations emerging in viruses exposed to convalescent plasma have been identified in both the NTD (F140, N148S, K150R, K150E, K150T, K150Q and S151P) and the RBD (K444R, K444N, K444Q, V445E and E484K)40,41 (Fig. Experimental studies are needed to figure out the functions of the uncharacterized genes, and by determining which ones are real, we allow other researchers to focus their attention on those genes rather than spend their time on something that doesnt even get translated into protein.. The spike protein mediates attachment of the virus to host cell-surface receptors and fusion between virus and cell membranes11 (Box1). Discovery of O-linked carbohydrate on HIV-1 envelope and its role in shielding against one category of broadly neutralizing antibodies. These areas are represented as yellow patches near the centre of the top-down view of the spike structure in Fig. Prospective mapping of viral mutations that escape antibodies used to treat COVID-19. To complement the experimental data provided by neutralization assays, there is emerging evidence from clinical trials on the impact of variants on vaccine efficacy. 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. When residues belong to epitopes of multiple classes, priority colouring is given to antibodies that block ACE2 and bind the closed spike protein. Multiple SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity. CAS McCarthy, K. R. et al. Faria, N. R. et al. MacLean, O. NTD antibody escape mutations were not observed for the other samples of plasma investigated, and furthermore, the 148151 mutants exhibited only marginal reductions in sensitivity to the plasma tested, indicating individual immune responses may be differentially affected by mutations of RBD and NTD epitopes40. The burden of incidental SARS-CoV-2 infections in hospitalized patients Scientists from The Federal Research Centre "Fundamentals of Biotechnology" of the Russian Academy of Sciences together with foreign colleagues demonstrated that human 14-3-3 proteins, that are known for their role in replication of many viruses, bind differentially with more often mutating regulatory part of nucleoprotein (N protein) of coronavirus SARS-CoV-2. 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. The original version of the virus, D614, was most widely seen in China and other parts of Asia. 1 ). Genomic analyses indicate a change in host environment and signatures of increased selective pressures acting upon immunologically important SARS-CoV-2 genes sampled from around November 2020 (ref.23). Most random mutations are likely to be deleterious to the virus, and many will be lethal. Preprint at medRxiv https://doi.org/10.1101/2020.10.25.20219063 (2020). The first genomes belonging to the B.1.1.7 lineage were sequenced in the south of England in September 2020. The research was funded by the National Human Genome Research Institute and the National Institutes of Health. Preprint at bioRxiv https://doi.org/10.1101/2021.02.01.429069 (2021). Cell 182, 12841294.e1289 (2020). Cell 182, 812827 e819 (2020). Identification of SARS-CoV-2 spike mutations that attenuate monoclonal and serum antibody neutralization. Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. 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. 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. Currently, scientists are optimistic that the two mRNA vaccines available in the U.S.Pfizer-BioNTech and Modernawill continue to provide protection. The role for this new gene, as well as several other SARS-CoV-2 genes, is not known yet. SARS-CoV-2 Mutations Explained - Discovery's Edge Other novel variants have been identified spreading in California and New York, USA (B.1.427 and B.1.429, and B.1.526, respectively). Emerging SARS-CoV-2 variants reduce neutralization sensitivity to convalescent sera and monoclonal antibodies. 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. SARS-CoV-2 is an enveloped RNA virus, which means that its genetic material is encoded in single-stranded RNA. A. et al. But, says Akiko Iwasaki, PhD, a Yale immunobiologist and leading COVID-19 researcher, When viruses enter the host cells and replicate and make copies of their genomes, they inevitably introduce some errors into the code. Iwasaki, who studies the mechanisms of immune defense against viruses, compares the changes introduced by these errors to a faulty spell-checker. Even as SARS-CoV-2 mutates, some human antibodies fight back Scientists can track mutations as they are passed down through a lineage, a branch of the coronavirus family tree. Soh, W. T. et al. These data indicate that NVX-CoV2373 and JNJ-78436735 are clinically efficacious against the B.1.1.7 variant and variants circulating in the USA, and are consistent in that the B.1.351 variant is associated with a larger reduction in vaccine efficacy. 372, n296 (2021). To date, vaccines have been licensed and rolled out very successfully in several countries, but the number of individuals vaccinated still represents a small fraction of the global population (Supplementary Table 1). 1b). 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. Tegally, H. et al. Cell https://doi.org/10.1016/j.cell.2021.02.042 (2021). Recurrent emergence and transmission of a SARS-CoV-2 spike deletion H69/V70. Taken together, these data indicate that E484K is the primary determinant of the decreases in neutralization titres, which distinguish P.1, P.2 and the three B.1.351 variants from the other pseudoviruses tested. As new variants with unforeseen combinations of mutations continue to emerge, such insights will allow predictions of virus phenotype. 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. The spike protein transiently undergoes conformational changes between a closed conformation and an open conformation in which a hinge-like movement raises the RBD50. MIT News | Massachusetts Institute of Technology, A comprehensive map of the SARS-CoV-2 genome. However, a DMS study39 did not find that the mutation N439K significantly alters neutralization by polyclonal antibodies in plasma, in contrast to previous studies that found that N439K reduced neutralization by mAbs and convalescent plasma18. A neutralizing human antibody binds to the N-terminal domain of the spike protein of SARS-CoV-2. del 69-70. 6. 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. 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. Tablizo, F. A. et al. The substitutions T20N and P26S also occur in or near the NTD supersite30 at residues with high antibody accessibility scores (Fig. Immunol. Science 370, 1464 (2020). They found that in most cases, genes that evolved rapidly for long periods of time before the current pandemic have continued to do so, and those that tended to evolve slowly have maintained that trend. 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. 2c), and residues 978984, which become more accessible on the monomer anticlockwise adjacent to the upright RBD monomer (Fig. This approach calculates a structure-based epitope score, which approximates antibody accessibility for each amino acid position. These constellations of viral mutationsknown as variantsmay take hold if there is evolutionary pressure for them to do so. 2a), and amino acid substitutions at position 484 diminish neutralization by a range of RBD-targeting antibodies. Several RBD-specific antibodies are able to bind only the open spike protein (RBD classes 1 and 4 (ref.31)), and interestingly, it has been observed that D614G makes the spike protein more vulnerable to neutralizing antibodies by increasing the tendency for the open conformation to occur51. R.R. Greaney, A. J. et al. The E484K amino acid substitution has received attention for its effect on monoclonal antibodies and convalescent plasma neutralizing activity. volume19,pages 409424 (2021)Cite this article. J. Cell Host Microbe 29, 4457 e49 (2021). d | Two surface colour representations of antibody accessibility scores for the spike protein in the open conformation with a single monomer with an upright RBD are shown: a trimer axis vertical view (left) and an orthogonal top-down view along this axis (right). PubMed Science 372, 815821 (2021). Monoclonal antibodies for the S2 subunit of spike of SARS-CoV-1 cross-react with the newly-emerged SARS-CoV-2. 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. For spike residues where mutations have been shown to influence polyclonal antibody recognition, the observation of an effect on either mAbs or plasma is indicated in Fig. Furthermore, epitope mapping of mAbs isolated from postvaccination sera showed they targeted a range of RBD epitopes similar to those isolated from naturally infected individuals59. A.R. Efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 variant of concern 202012/01 (B.1.1.7): an exploratory analysis of a randomised controlled trial. N439K is noteworthy as it enhances the binding affinity for the ACE2 receptor and reduces the neutralizing activity of some monoclonal antibodies (mAbs) and polyclonal antibodies present in sera from people who have recovered from infection18. Prior analyses of SARS-CoV-2 mutation rates have generally focused on all nucleotide mutations (Neher 2022; Ruis, Peacock, et al. The SARS-CoV-2 spike protein is highly glycosylated, with 66 potential N-glycosylation sites per trimer98,99 (Fig. Google Scholar. Singer, J., Gifford, R., Cotten, M. & Robertson, D. L. CoV-GLUE: A Web Application for Tracking SARS-CoV-2 Genomic Variation. In addition to N501Y, lineage B.1.351 is defined by the presence of five further spike amino acid substitutions (D80A, D215G, K417N, E484K and A701V) and a deletion in the NTD, 242244. The effect of mutations at these positions is likely to be greater for antibodies belonging to RBD class 1. researched data for the article. 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. Q613H is speculated to be important as it occurs at a position neighbouring D614G80. Rapid implementation of SARS-CoV-2 sequencing to investigate cases of health-care associated COVID-19: a prospective genomic surveillance study. What is the difference between a variant of interest and a variant of concern? Circulating SARS-CoV-2 spike N439K variants maintain fitness while evading antibody-mediated immunity. https://nextstrain.org/ncov/global?c=gt-S_477&gmax=24271&gmin=22482 (2021). In one example, the researchers identified a region of the nucleocapsid protein, which surrounds the viral genetic material, that had many more mutations than expected from its historical evolution patterns. This gene-within-a-gene is rare in large genomes, but common in many viruses, whose genomes are under selective pressure to stay compact. Article Mahase, E. Covid-19: Where are we on vaccines and variants? Molnupiravir-induced elevated mutation rates have been shown to decrease viral load in animal models. Transmission of SARS-CoV-2 lineage B.1.1.7 in England: insights from linking epidemiological and genetic data. J. Vulnerabilities in coronavirus glycan shields despite extensive glycosylation. Rachel Sealfon, a research scientist at the Flatiron Institute Center for Computational Biology, is also an author of the paper. 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. Cell 184, 11711187 e1120 (2021). 26, 102118 (2018). D614G spike mutation increases SARS CoV-2 susceptibility to neutralization. The integration of these data and emerging SARS-CoV-2 sequences has the potential to facilitate the automated detection of potential variants of concern at low frequency (that is, before they are spreading widely). Starr, T. N. et al. Morris, D. H. et al. 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. J. Virol. & Saxena, S. K. Structural, glycosylation and antigenic variation between 2019 novel coronavirus (2019-nCoV) and SARS coronavirus (SARS-CoV).

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