But some errors are beneficial, making it more contagious. Over time, the cumulative effects of these mutations may be enough to change how the virus behaves. W.T.H., A.M.C. Preprint at bioRxiv https://doi.org/10.1101/2021.01.06.425392 (2021). Nat. The authors declare no competing interests. Subsequently, many distinct lineages of SARS-CoV-2 have evolved. Analysis of SARS-CoV-2 mutations in the United States suggests - Nature SARS-CoV-2 variants, spike mutations and immune escape, https://doi.org/10.1038/s41579-021-00573-0. Cell 182, 12841294.e1289 (2020). Zhan, X.-Y. Science 369, 330 (2020). West, A. P., Barnes, C. O., Yang, Z. J. Virol. Role of mutation in nucleoprotein SARS-CoV-2 - sciencex.com 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). a | The domain organization of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein showing amino acid sequence variability. https://doi.org/10.1056/NEJMoa2102214 (2021). 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. By convention, an amino acid substitution is written in the form N501Y to denote the wild-type amino acid (N (asparagine)) and the substituted amino acid (Y (tyrosine)) at site 501 in the amino acid sequence. However, the researchers also identified exceptions to these patterns, which may shed light on how the virus has evolved as it has adapted to its new human host, Kellis says. Korber, B. et al. Prediction of the mutational pathways by which a virus such as SARS-CoV-2 will evolve is extremely challenging. This lineage is characterized by four amino acid differences, H69V70, Y453F, I692V and M1229I (Fig. SARS-CoV-2 genome mutations display convergent evolution indicating 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. Madhi, S. A. et al. Science 370, 1464 (2020). 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. Nat. 2c). Watanabe, Y., Allen, J. D., Wrapp, D., McLellan, J. S. & Crispin, M. Site-specific glycan analysis of the SARS-CoV-2 spike. PubMed Central On average, variant frequency is higher at amino acid positions where mutations are described as affecting antibody recognition than at positions with no described substitutions of antigenic importance (Supplementary Fig. 372, n296 (2021). While many of its genes were already known at that point, the full complement of protein-coding genes was unresolved. Lancet Infect. Provided by the Springer Nature SharedIt content-sharing initiative, Nature Reviews Microbiology (Nat Rev Microbiol) SARS-CoV-2 RBD in vitro evolution follows contagious mutation spread, yet generates an able infection inhibitor. A change in a specific amino acid of a protein. ISSN 1740-1526 (print). The plasma neutralizing activity and the numbers of RBD-specific memory B cells were found to be equivalent to those of plasma from individuals who had recovered from natural SARS-CoV-2 infection59. 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. Commun. J. SARS-CoV-2 Mutations Explained - Discovery's Edge Lineage P.1 is characterized by the presence of several amino acid substitutions in the spike protein: L18F, T20N, P26S, D138Y, R190S, K417T, E484K, N501Y, H655Y and T1027I69. Garcia-Beltran, W. F. et al. A.R. 4. Notability criteria. & McCauley, J. GISAID: Global initiative on sharing all influenza datafrom vision to reality. Residues at positions 614 and 222 have relatively low antibody access scores and are positioned ~50 from the RBS residues when the spike protein is in the open conformation (Fig. What Mutations of SARS-CoV-2 are Causing Concern? Preprint at medRxiv https://doi.org/10.1101/2020.12.21.20248640 (2020). In addition, Y453F has been described as reducing neutralization by mAbs47. Google Scholar. Specifically, SARS-CoV-2 seems to have a mutation rate of less than 25 mutations. 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. b | Spike protein in closed form with all residues coloured according to the frequency scale shown; a trimer axis vertical view (left) and an orthogonal top-down view along this axis (right) are shown. Preprint at bioRxiv https://doi.org/10.1101/2021.01.26.426986 (2021). 2c, yellow). Nature 581, 215220 (2020). 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. http://cov-glue.cvr.gla.ac.uk/, Global Initiative on Sharing All Inflenza Data (GISAID): Choi, B. et al. Image from the Saphire Lab, La Jolla Institute for Immunology. Genomic Evidence of a SARS-Cov-2 Reinfection Case with E484K Spike Mutation in Brazil. 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. 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. 2c, green). However, there is growing evidence that mutations that change the antigenic phenotype of SARS-CoV-2 are circulating and affect immune recognition to a degree that requires immediate attention. 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 501Y.V2 escapes neutralization by South African COVID-19 donor plasma. and D.L.R. The S1S2 boundary is at amino acid position 685. b | Spike protein monomer displaying an upright receptor-binding domain (RBD). The original version of the virus, D614, was most widely seen in China and other parts of Asia. 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). SARS-CoV-2 is an enveloped RNA virus, which means that its genetic material is encoded in single-stranded RNA. https://www.krisp.org.za/publications.php?pubid=330 (2021). Rapid implementation of SARS-CoV-2 sequencing to investigate cases of health-care associated COVID-19: a prospective genomic surveillance study. In this video, Iwasaki and Grubaugh discuss the science behind the SARS-CoV-2 mutations and explain why its important to continue wearing masks, avoiding crowds, and washing your hands. 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 tested how well antibodies from COVID-19 patients bound to viruses that had these mutations. MIT News | Massachusetts Institute of Technology, A comprehensive map of the SARS-CoV-2 genome. 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. The first genomes belonging to the B.1.1.7 lineage were sequenced in the south of England in September 2020. A change in the biophysical properties of an epitope residue directly diminishes antibody binding. Avanzato, V. A. et al. 5b. Given the immunodominance of the RBD, this could explain the modest reductions in neutralizing activity of convalescent sera against authentic B.1.1.7 or pseudoviruses carrying the B.1.1.7 spike mutations64,65. https://doi.org/10.1038/s41591-021-01270-4 (2021). As mentioned earlier, there is evidence indicating that D614G confers a moderate advantage for infectivity8,9 and increases transmissibility10. The other substitution, S477N, is estimated to have emerged at least seven times in the global SARS-CoV-2 population and has persisted at a frequency of between 4% and 7% of sequences globally since mid-June 2020 (ref.53). 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. 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). Temporal signal and the phylodynamic threshold of SARS-CoV-2. Med. Preprint at bioRxiv https://doi.org/10.1101/2021.01.25.427948 (2021). N. Eng. Kemp, S. A. et al. A novel SARS-CoV-2 variant of concern, B.1.526, identified in New York. A group of coronaviruses that share the same inherited set of distinctive. Spike amino acid substitutions and deletions that impact neutralizing antibodies are present at significant frequencies in the global virus population, and there is emerging evidence of variants exhibiting resistance to antibody-mediated immunity elicited by vaccines. 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. Evolution of the SARS-CoV-2 Mutational Spectrum Med. 1b) tend to occur at residues with higher structure-based antibody accessibility scores compared with other residues belonging to epitope footprints and residues not implicated in antigenicity (Supplementary Fig, 1b). Science 371, 850 (2021). Thank you for visiting nature.com. In addition to N3, high-scoring residues (greater than 0.7) are found at positions 2226 (N1), 70 (N2), 173187 (N4), 207213 (Fig. David L. Robertson. Med. Antibody footprints were generated by structural analyses of the spike residues considering potential hydrogen bonds and van der Waals interactions with a mAb atom that were less than 4.0. 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. 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. 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. Feb 19, 2021. https://www.ecdc.europa.eu/sites/default/files/documents/COVID-19-risk-related-to-spread-of-new-SARS-CoV-2-variants-EU-EEA.pdf (2020). reviewed and/or edited the manuscript before submission. 5b). D.L.R. Molecular evolution of SARS-CoV-2 structural genes: evidence of positive selection in spike glycoprotein. The emergence of SARS-CoV-2 in late 2019 was followed by a period of relative evolutionary stasis lasting about 11 months. Sweredoski, M. J. Science 372, 815821 (2021). Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Arguably the first variant of interest defined by the presence of several spike mutations, and referred to as B.1.1.298 (cluster 5), was detected in Denmark spreading among farmed mink and a small number of people20. Many seniors now eligible to get another COVID booster, CDC says Tracking SARS-CoV-2 Spike mutations - Los Alamos National Laboratory When an observation includes a deletion, this is indicated by a red cross. Other data indicate that the effect of N501Y alone on neutralization is relatively modest, and other studies using sera from 20 participants in a trial of the BNT162b2 vaccine showed neutralizing titres equivalent to those of pseudoviruses carrying the N501 and Y501 mutations82. Nature Reviews Microbiology thanks Y. Wang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Hodcroft, E. B. et al. Complete mapping of mutations to the SARS-CoV-2 spike receptor-binding domain that escape antibody recognition. 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. This 140 spike mutant subsequently acquired the E484K mutation, resulting in a further fourfold drop in neutralization titre, and thus a two-residue change across the NTD and the RBD can drastically evade the polyclonal antibody response. Obtenga ms informacin acerca de las variantes actuales que generan mayor preocupacin. 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. As of 5 November 2020, 214 humans infected with SARS-CoV-2 related to mink were all carrying the mutation Y453F21. Greaney, A. J. et al. Nonetheless, manufacturers are preparing platforms for a possible update of vaccine sequences, and it is crucial that surveillance of genetic and antigenic changes in the global virus population is done alongside experiments to elucidate the phenotypic impacts of mutations. How COVID-19 variants evade immune response Cele, S. et al. Wu, K. et al. W.T.H., A.M.C., B.J., R.K.G., E.C.T., E.M.H., C.L., A.R. The Omicron variant, which emerged in November 2021, has many lineages. No higher infectivity but immune escape of SARS-CoV-2 501Y.V2 variants. 5, 14031407 (2020). Mol. Convergent evolution of SARS-CoV-2 spike mutations, L452R, E484Q and P681R, in the second wave of COVID-19 in Maharashtra, India. Preprint at medRxiv https://doi.org/10.1101/2021.02.08.21251393 (2021). 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. Cell Rep. 30, 18621869.e1864 (2020). Experimental determination of the binding site, or epitope, of an antibody. 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. Residue 769 is positioned in a surface-exposed S2 loop, and D769H was found to arise, in linkage with 6970, in an immunocompromised individual treated with convalescent plasma24. PubMedGoogle Scholar. 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. 383, 22912293 (2020). Preprint at bioRxiv https://doi.org/10.1101/2020.12.14.422555 (2020). Das, S. R. et al. 5). 2a, asterisk). Proc. 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. The Coronavirus Is Mutating. What Does That Mean for a Vaccine? 4a).The SARS-CoV-2 spike protein is post-translationally cleaved by mammalian furin into two subunits: S1 and S2 (Fig. Microbiol. 1b). But luckily with vaccines, you dont just create one antibodyor two or threeyou create many different antibodies that recognize different parts of the virus.. Molnupiravir, an antiviral medication that has been widely used against SARS-CoV-2, acts by inducing mutations in the virus genome during replication. This is mediated by glycans, bulky sugar molecules that are covalently attached to amino acid side chains of the viral protein. Coronavirus seems to mutate much slower than seasonal flu Recurrent emergence and transmission of a SARS-CoV-2 spike deletion H69/V70. and D.L.R. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Black diamonds at the top and bottom of the plot indicate the positions of ACE2-contacting residues. The mutations at positions 417 and 484 prevented binding by antibodies from these classes. 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. PubMed For example, viruses of lineage B.1.525, which has been observed in several countries, albeit at low frequency to date, have NTD deletions H69V70 and Y144 in common with viruses of the B.1.1.7 lineage; E484K in common with the B.1.351 and P.1 lineages; and spike amino acid substitutions Q52R, Q677H and F888L73. Detection of new SARS-CoV-2 Variants Related to Mink. Cell https://doi.org/10.1016/j.cell.2021.02.042 (2021). Fewer data on the antigenic effects of S2 mutations exist, though D769H has been described as conferring decreased susceptibility to neutralizing antibodies24. The locations of amino acid substitutions and deletions that define variants of concern are highlighted as red spheres. Preprint at bioRxiv https://doi.org/10.1101/2020.12.28.424451 (2020). 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. While the idea of "viral mutation" may sound concerning, it's important to understand that many of these mutations are minor, and don't have an overall impact on how fast a virus spreads or potentially how severe a viral infection might be. Neutralization of SARS-CoV-2 spike 69/70 deletion, E484K, and N501Y variants by BNT162b2 vaccine-elicited sera. As with other coronaviruses, the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into host cells is mediated by the transmembrane spike glycoprotein, which forms homotrimers on the surface of the virion. 2a, peaks with consecutive residues with scores greater than 0.8) are centred at residues 444447 and residues 498500. below, credit the images to "MIT.". Cherian, S. et al. Case study: prolonged infectious SARS-CoV-2 shedding from an asymptomatic immunocompromised individual with cancer. Highlights. 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.