Greater understanding of the correlates of immune protection is required to provide a context for the results of studies reporting changes in neutralization. 1a,b). Singer, J., Gifford, R., Cotten, M. & Robertson, D. L. CoV-GLUE: A Web Application for Tracking SARS-CoV-2 Genomic Variation. Fitness costs limit influenza A virus hemagglutinin glycosylation as an immune evasion strategy. All of these processes will benefit from close international collaboration and the rapid and open sharing of data. a | The domain organization of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein showing amino acid sequence variability. 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. SARS-CoV-2 RBD in vitro evolution follows contagious mutation spread, yet generates an able infection inhibitor. In addition to single mutations of note, more heavily mutated SARS-CoV-2 lineages have emerged. ECDC. The spike protein mediates attachment of the virus to host cell-surface receptors and fusion between virus and cell membranes11 (Box1). Hodcroft, E. B. et al. Neutralization of SARS-CoV-2 spike 69/70 deletion, E484K, and N501Y variants by BNT162b2 vaccine-elicited sera. 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. The Biological Functions and Clinical Significance of SARS-CoV-2 The spike protein transiently undergoes conformational changes between a closed conformation and an open conformation in which a hinge-like movement raises the RBD50. 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. Preprint at bioRxiv https://doi.org/10.1101/2020.06.25.170688 (2020). Sci. E484 has been identified as an immunodominant spike protein residue, with various substitutions, including E484K, facilitating escape from several mAbs40,47,48 as well as antibodies in convalescent plasma39,40,41,48. RNA viruses have. Many health authorities differentiate hospitalizations in patients infected with SARS-CoV-2 as being "for COVID-19" (due to direct manifestations of SARS-CoV-2 infection) versus being an . https://virological.org/t/sars-cov-2-reinfection-by-the-new-variant-of-concern-voc-p-1-in-amazonas-brazil/596 (2021). It has over 50 mutations, many in the spike protein, which is how it gets into our cells in the first place. To obtain Bugembe, D. L. et al. 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. 5b). Nat. The researchers also recognized that many previous papers used not only incorrect gene sets, but sometimes also conflicting gene names. This gene-within-a-gene is rare in large genomes, but common in many viruses, whose genomes are under selective pressure to stay compact. Volz, E. et al. 2c, green). https://doi.org/10.1056/NEJMoa2102214 (2021). Complete mapping of mutations to the SARS-CoV-2 spike receptor-binding domain that escape antibody recognition. Br. Chi, X. et al. 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). mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants. 2a). But, while scientists have spotted. The P.1 lineage, a sublineage of B.1.1.28, was first detected in Brazil69 and in travellers from Brazil to Japan70. 2). Lancet https://doi.org/10.1016/S0140-6736(21)00628-0 (2021). The impact of mutations in SARS-CoV-2 spike on viral infectivity and antigenicity. 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 E484K amino acid substitution has received attention for its effect on monoclonal antibodies and convalescent plasma neutralizing activity. Mol. Avanzato, V. A. et al. Sars-Cov-2, the official name of the virus that causes the disease Covid-19, and continues to blaze a path of destruction across the globe, is mutating. Mobility-related data show the pandemic has had a lasting effect, limiting the breadth of places people visit in cities. Mutations at those sites (for example, C136Y and S12P, which alter the cleavage occurring between residues C15 and V16) have been shown to affect the neutralizing activity of several mAbs, likely disrupting the disulfide bond and therefore dislodging the supersite targeted by several antibodies30. W.T.H., A.M.C., A.R., S.J.P. 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. Science 370, 1464 (2020). WHO. As stated earlier, convalescent plasma from individuals infected with pre-B.1.1.7 viruses (that is, viruses that circulated before the emergence of the B.1.1.7 lineage) shows only a modest reduction in neutralization activity against B.1.1.7 or pseudovirus possessing B.1.1.7 spike mutations63,78, and results obtained with postvaccination sera are broadly consistent with this. 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. The Omicron variant, which emerged in November 2021, has many lineages. Spike E484K Mutation in the First SARS-CoV-2 Reinfection Case Confirmed in Brazil, 2020. https://virological.org/t/spike-e484k-mutation-in-the-first-sars-cov-2-reinfection-case-confirmed-in-brazil-2020/584 (2021). Resurgence of Omicron BA.2 in SARS-CoV-2 infection-naive Hong Kong Coronavirus seems to mutate much slower than seasonal flu 5b). The researchers performed their analysis on SARS-CoV-2, SARS-CoV (which caused the 2003 SARS outbreak), and 42 strains of bat sarbecoviruses. 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. 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). https://virological.org/t/genomic-characterisation-of-an-emergent-sars-cov-2-lineage-in-manaus-preliminary-findings/586 (2021). 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. Nat. Within the RBD, the positions at which amino acid substitutions are present at the highest frequency are located close to the RBDACE2 interface (Fig. West, A. P., Barnes, C. O., Yang, Z. 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). 2a, yellow patch to the extreme right of the structure viewed from the side in Fig. Variants with changed biological characteristics or antigenicity have been termed variants of interest, variants under investigation or variants of concern by public health bodies. 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. The role of mutation in nucleoproteins of SARS-CoV-2 Mobilisation and analyses of publicly available SARS-CoV-2 data for http://sars2.cvr.gla.ac.uk/cog-uk/, COVID-19 Genomics UK (COG-UK) Consortium: 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. Silver, Z. A mutation (also referred to as viral mutation or genetic mutation) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus is a change in the genetic sequence of. J. COVID-19: Studying variants' mutations overturns assumptions SARS-CoV-2 Reinfection by the New Variant of Concern (VOC) P.1 in Amazonas, Brazil. A change in a specific amino acid of a protein. Genomic epidemiology of novel coronavirus - Global subsampling. PubMed Central 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. Hundreds packed Killian and Hockfield courts to enjoy student performances, amusement park rides, and food ahead of Inauguration Day. Preliminary data from clinical trials reported that the NVX-CoV2373 (Novavax) protein-based vaccine provides 95.6% efficacy against the wild-type virus and that this is moderately lower for the B.1.1.7 variant (85.6%) and is further reduced for the B.1.351 variant (60.0%)91. Notably, mutations emerging under selective pressure from convalescent plasma may be different from those selected by the most frequent mAb isolated from the same plasma40. The N-terminal domain of spike glycoprotein mediates SARS-CoV-2 infection by associating with L-SIGN and DC-SIGN. More than 104 million cases have been confirmed globally. Slider with three articles shown per slide. These authors contributed equally: William T. Harvey, Alessandro M. Carabelli. Degrading viral RNA to treat SARS-CoV-2 infection These studies include traditional escape mutation work that identifies mutations that emerge in virus populations exposed to either mAbs39 or convalescent plasma containing polyclonal antibodies40,41; targeted characterization of particular mutations18,42; and wider investigations of either large numbers of circulating variants43 or all possible amino acid substitutions in the RBD39,44,45,46. J. The risk is likely to be reduced with the use of cocktails of two or more mAbs targeting non-overlapping epitopes. Proc. 725422 ReservoirDOCS). 1b). SARS-CoV-2 Variant Classifications and Definitions - CDC 27, 763767 (2020). 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). Relatively little is known of antigenicity in the S2 subunit, with immunogenicity thought to be impeded by extensive glycan shielding36, and although both linear and cross-reactive conformational S2 epitopes have been described37,38, the biological significance of these is not yet known. SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies. Wibmer, C. K. et al. What is the Omicron variant? 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. Matthews, D. B. Google Scholar. Experimental data on the emergence of mutations under selective pressure from polyclonal antibodies are relatively rare, although these trends for higher scores associated with such mutations indicate that information from structural analysis approaches of this kind can contribute to the ranking of residues at which substitutions are likely to impact the polyclonal antibody response. Google Scholar. Internet Explorer). Molnupiravir, an antiviral medication that has been widely used against SARS-CoV-2, acts by inducing mutations in the virus genome during replication. A lineage is a genetically closely related group of virus variants derived from a common ancestor. 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. 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. 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. A new variant carrying E484K currently designated A.VOI.V2 was recently identified in Angola from cases involving travel from Tanzania79. 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. A neutralizing human antibody binds to the N-terminal domain of the spike protein of SARS-CoV-2. This loop, known as the N3 loop, is described as forming key interactions with the neutralizing antibody 4A8 (ref.32). 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. Structural and functional analysis of the D614G SARS-CoV-2 spike protein variant. Cell 182, 12841294.e1289 (2020). However, substitutions at 477 were not identified as being important in DMS with convalescent plasma39. 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. Working paper on SARS-CoV-2 spike mutations arising in Danish mink, their spread to humans and neutralization data. Meredith, L. W. et al. wrote the article. 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. J. Med. 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. Rees-Spear, C. et al. Whereas K417 is described in the epitopes of RBD class 1 and class 2 antibodies31, alterations to K417 tend to affect class 1 antibody binding and are therefore somewhat less important for the polyclonal antibody response to the RBD, which is dominated by class 2 antibody responses, which are more susceptible to substitutions such as E484K44,58,59. Prior analyses of SARS-CoV-2 mutation rates have generally focused on all nucleotide mutations (Neher 2022; Ruis, Peacock, et al. Beyond shielding: the roles of glycans in the SARS-CoV-2 spike protein. Escape of SARS-CoV-2 501Y.V2 from neutralization by convalescent plasma. Sweredoski, M. J. ISSN 1740-1534 (online) Watanabe, Y. et al. The position 417 mutation also weakened virus binding to host cells. Hou, Y. J. et al. Convergent evolution of SARS-CoV-2 spike mutations, L452R, E484Q and P681R, in the second wave of COVID-19 in Maharashtra, India. Cell 78, 779784 e775 (2020). Das, S. R. et al. PubMed Preprint at medRxiv https://doi.org/10.1101/2021.02.12.21251658 (2021). Of the lineages summarized in Fig. In addition to N3, high-scoring residues (greater than 0.7) are found at positions 2226 (N1), 70 (N2), 173187 (N4), 207213 (Fig. 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. Among 426,623 genomes after filtering, 5,106 different amino acid replacements or substitutions across 1,267 spike positions were identified, of which 320 at 259 positions were observed in at least 100 sequences. Med. Tablizo, F. A. et al. The B.1.1.298 lineage also has 6970, an amino-terminal domain (NTD) deletion that has emerged several times across the global SARS-CoV-2 population, including in the second N439K lineage, B.1.258. Immunol. Nextstrain. b | Aligned heat maps showing properties of amino acid residues where substitutions affect binding by antibodies in polyclonal human blood plasma or emerge as antibody escape mutations. Nat. Article 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. Tracking Omicron and Other Coronavirus Variants D.LR. As highly deleterious mutations are rapidly purged, most mutations observed in genomes sampled from circulating SARS-CoV-2 virions are expected to be either neutral or mildly deleterious. Preprint at bioRxiv https://doi.org/10.1101/2021.02.01.429069 (2021). https://virological.org/t/preliminary-genomic-characterisation-of-an-emergent-sars-cov-2-lineage-in-the-uk-defined-by-a-novel-set-of-spike-mutations/563 (2020). The effect of mutations at these positions is likely to be greater for antibodies belonging to RBD class 1. Transmission of SARS-CoV-2 lineage B.1.1.7 in England: insights from linking epidemiological and genetic data. 1b). Many seniors now eligible to get another COVID booster, CDC says 2c, yellow). The name of the mutation, del 69-70, or 69-70 del, or other similar notations, refers to the .