Similarly, a study showed that the neutralizing effect of convalescent plasma collected from 14 individuals was strongly reduced against a live (authentic) B.1.351 virus (with IC50 reduced by 3.2-fold to 41.9-fold relative to the first-wave virus)68. Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK, MRCUniversity of Glasgow Centre for Virus Research, Glasgow, UK, Department of Medicine, University of Cambridge, Cambridge, UK, Alessandro M. Carabelli,Ewan M. Harrison,Catherine Ludden&Sharon J. Peacock, Institute of Evolutionary Biology, University of Edinburgh, Edinburgh, UK, Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, UK, Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK, You can also search for this author in Of the lineages summarized in Fig. 95, e00119-21 (2021). 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. Similarly, the single-dose vaccine JNJ-78436735 (Johnson & Johnson/Janssen) has been shown to provide 72% protection against moderate to severe SARS-CoV-2 infections in the USA, but the proportion significantly decreased to 57% in South Africa (at a time when the B.1.351 variant was widespread)92. Such circumstances, involving long-term virus shedders, may have contributed to the sporadic emergence of the more heavily mutated variants (for example, seen in the B.1.1.7 and B.1.351 lineages). Biol. Variants with changed biological characteristics or antigenicity have been termed variants of interest, variants under investigation or variants of concern by public health bodies. Complete mapping of mutations to the SARS-CoV-2 spike receptor-binding domain that escape antibody recognition. In addition to E484K, further mutations that are shared by each of the three B.1.351 variants, but are not possessed by the P.1. Kemp, S. A. et al. COVID-19 has gone through many mutations. What makes the Omicron variant different from other variants? 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). 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. SARS-CoV-2 has a genetic proofreading mechanism achieved by non-structure protein (NSP) 14 in synergy with NSP10 and NSP12 3, 4. What is the Omicron variant? Scientists have identified several regions known to encode protein-coding genes, based on their similarity to protein-coding genes found in related viruses. Fonager J. et al. E484K is estimated to have emerged repeatedly in the global SARS-CoV-2 population53 and has been described in two other lineages originating from lineage B.1.1.28 in addition to lineage P.1 reported to be spreading in the state of Rio de Janeiro in Brazil (lineage P.2)56 and in the Philippines (lineage P.3)57. The researchers also showed that five other regions that had been proposed as possible genes do not encode functional proteins, and they also ruled out the possibility that there are any more conserved protein-coding genes yet to be discovered. The amino-terminal domain (NTD) supersite30 is coloured in magenta. Cell Host Microbe 29, 477488 e474 (2021). Degrading viral RNA to treat SARS-CoV-2 infection 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. Accessible amino-terminal domain (NTD) loops N1N5 are labelled, and a loop falling between these is indicated with an asterisk. 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. 2b. Nature Reviews Microbiology thanks Y. Wang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Andreano, E. et al. A novel SARS-CoV-2 variant of concern, B.1.526, identified in New York. 2c, green). Fewer data on the antigenic effects of S2 mutations exist, though D769H has been described as conferring decreased susceptibility to neutralizing antibodies24. SARS-CoV-2 Variants in Patients with Immunosuppression To evaluate potential antigenicity across the spike protein, we analysed the protein using BEpro, a program for the prediction of conformational epitopes based on tertiary structure49. 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). 3). Hoffmann, M., Kleine-Weber, H. & Pohlmann, S. A multibasic cleavage site in the spike protein of SARS-CoV-2 is essential for infection of human lung cells. And even if the effectiveness of vaccines dropped to, say, 75 or 85%, that would still provide important protection and prevent severe cases of the COVID-19 from occurring. The effect of mutations at these positions is likely to be greater for antibodies belonging to RBD class 1. Preprint at bioRxiv https://doi.org/10.1101/2021.02.22.432189 (2021). 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. Development of vaccines against SARS-CoV-2 has been rapid, but the rise of variants forces scientists to frequently modify treatments. https://doi.org/10.1038/s41591-021-01270-4 (2021). SARS-CoV-2 Viral Mutations: Impact on COVID-19 Tests | FDA Article 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. Cell https://doi.org/10.1016/j.cell.2021.03.029 (2021). 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). 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. Residues centred at 444447 and 498500 maintain high scores on the upright RBD and are joined by residues in areas 413417 and 458465. PubMed This is caused by non-synonymous mutations. COVID-19 Variants: Symptoms, Transmissibility, and More - Verywell Health The COVID-19 pandemic has seen large-scale pathogen genomic sequencing efforts, becoming part of the toolbox for surveillance and epidemic research. Hou, Y. J. et al. The substitutions T20N and P26S also occur in or near the NTD supersite30 at residues with high antibody accessibility scores (Fig. Soh, W. T. et al. is funded by the UK Biotechnology and Biological Sciences Research Council (BB/R012679/1). Molecular evolution of SARS-CoV-2 structural genes: evidence of positive selection in spike glycoprotein. This lineage has spread widely in Europe and is reported to have originated in Spain52. Genomic epidemiology of novel coronavirus - Global subsampling. PubMedGoogle Scholar. Preprint at medRxiv https://doi.org/10.1101/2020.12.30.20249034 (2021). By contrast, neutralizing activity of sera elicited by the inactivated vaccine BBIBP-CorV (Sinopharm) against the authentic virus B.1.351 showed only a slight reduction (less than twofold)89. Scores rescaled between 0 and 1 are plotted for the closed conformation in Fig. Science 370, eabd4250 (2020). Cell https://doi.org/10.1016/j.cell.2020.11.020 (2020). These areas are represented as yellow patches near the centre of the top-down view of the spike structure in Fig. SARS-CoV-2 variants, spike mutations and immune escape. Data reported in one study showed that nearly half of examined convalescent plasma samples (21 of 44; 48%) had no detectable neutralization activity against the B.1.351 variant58. The impact of spike mutations on SARS-CoV-2 neutralization. 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. 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. The position 417 mutation also weakened virus binding to host cells. These variants, relative to the Wuhan-Hu-1 reference sequence, were identified with use of CoV-GLUE96, which filters out Global Initiative on Sharing All Influenza Data (GISAID) sequences97 identified as being of low quality or from non-human hosts (sequences retrieved from the GISAID database on 3 February 2021). Mol. Experimental determination of the binding site, or epitope, of an antibody. For example, the neutralizing antibody 4A8 forms salt bridges with spike protein residues K147 and K150, and therefore substitutions at these residues are likely to inhibit binding. 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). Virus Evol. "Evidence is now available that most of the U.S. population 5 years of age and older has antibodies to SARS-CoV-2, the virus that causes COVID-19, either from vaccination or infection that can . 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. 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. W.T.H., A.M.C., B.J., R.K.G., E.C.T., E.M.H., C.L., A.R. Evol. Tegally, H. et al. Casalino, L. et al. Cell 78, 779784 e775 (2020). A group of coronaviruses that share the same inherited set of distinctive. Science 371, 11391142 (2021). Its position has been described as belonging to the footprint of several antibodies, and a change in charge caused by replacement of a glutamate residue with a lysine residue has the potential to diminish antibody binding. Kumar, S., Maurya, V. K., Prasad, A. K., Bhatt, M. L. B. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. E484K has also been identified as an escape mutation that emerges during exposure to mAbs C121 and C144 (ref.40) and convalescent plasma41, and was the only mutation described in one study as able to reduce the neutralizing ability of a combination of mAbs (REGN10989 and REGN10934) to an unmeasurable level47. Natl Acad. 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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. Consequently, mutations that affect the antigenicity of the spike protein are of particular importance. 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. PubMed Wang, Z. et al. Compared with SARS-CoV, SARS-CoV-2 binds to ACE2 an estimated 2-4 times more strongly, because several changes in the RBD stabilize its virus-binding hot spots . Tracking SARS-CoV-2 Spike mutations - Los Alamos National Laboratory SARS-CoV-2 RBD in vitro evolution follows contagious mutation spread, yet generates an able infection inhibitor. 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. The risk is likely to be reduced with the use of cocktails of two or more mAbs targeting non-overlapping epitopes. Molnupiravir, an antiviral medication that has been widely used against SARS-CoV-2, acts by inducing mutations in the virus genome during replication. Letko, M., Marzi, A. 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. Tablizo, F. A. et al. 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). Potentially, observed differences arise because mutations selected by convalescent plasma facilitate escape from multiple mAbs. Persistence and evolution of SARS-CoV-2 in an immunocompromised host. D.L.R. A. et al. Virusdisease 31, 1321 (2020). 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. Tchesnokova, V. et al. The first genomes belonging to the B.1.1.7 lineage were sequenced in the south of England in September 2020. Receptor-binding domain (RBD) antibody classes 14 (ref.31) are shown: green for class 1 (ACE2-blocking antibodies that bind the spike protein in the open conformation), yellow for class 2 (ACE2-blocking antibodies that bind the RBD in both the open conformation and the closed conformations), blue for class 3 (antibodies that do not block ACE2 and bind the RBD in both the open conformation and the closed conformations) and red for class 4 (neutralizing antibodies that bind outside the ACE2 site and only in the open conformation). https://cov-lineages.org/global_report.html (2020). A comprehensive understanding of the consequences of spike mutations for antigenicity will encompass both T cell-mediated immunity and non-spike epitopes recognized by antibodies. 1b). Although our understanding of the functional consequences of spike mutations is rapidly expanding, much of this knowledge involves the reactive investigation of amino acid changes identified as rapidly increasing in frequency or being associated with unusual epidemiological characteristics. 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. del 69-70. N-linked glycans are typically prominent in glycan shielding of virus surface glycoprotein epitopes33, although O-linked glycans can also contribute103. 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. Cell https://doi.org/10.1016/j.cell.2021.03.013 (2021). 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. Cherian, S. et al. Characterizing the Contaminated Couriers of Omicron SARS-CoV-2 Variants 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. 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. B. 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. 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. In addition to their antigenic effect, both K417N and K417T are expected to moderately decrease ACE2-binding affinity19 (Fig. 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. Substitutions at amino acid positions 417 and 453 are described in the next section in the context of variants of concern. To remedy the situation, they brought together the SARS-CoV-2 community and presented a set of recommendations for naming SARS-CoV-2 genes, in a separate paper published a few weeks ago in Virology. 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. SARS-CoV-2 variants of concern tend to emerge mutations in the S1 unit of the spike protein, which includes the RBDs and is responsible for binding to the ACE2 receptor. Cross-reactive immunity between circulating lineages can be assessed by measuring the ability of sera to neutralize panels of circulating viruses. 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. Collier, D. A. et al. 1a,b). 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. Commun. D614G spike mutation increases SARS CoV-2 susceptibility to neutralization. Lancet https://doi.org/10.1016/S0140-6736(21)00628-0 (2021). Cell Rep. 30, 18621869.e1864 (2020). SARS-CoV-2 spreads primarily through human-to-human transmission, but there is evidence of transmission between humans and animals. 5, 562569 (2020). What Mutations of SARS-CoV-2 are Causing Concern? . Hemagglutinin receptor binding avidity drives influenza A virus antigenic drift. Epitope binning of 41 NTD-specific mAbs led to the identification of six antigenic sites, one of which is recognized by all known NTD-specific neutralizing antibodies and has been termed the NTD supersite, consisting of residues 1420, 140158 and 245264 (ref.30) (Fig. D.LR. J. Serological analyses of almost 650 individuals infected with SARS-CoV-2 indicated that ~90% of the plasma or serum neutralizing antibody activity targets the spike receptor-binding domain (RBD)12. April 24, 2023. D614G refers to an amino acid mutation in this protein that has become increasingly common in SARS-CoV-2 viruses from around the world. Similarly, postvaccination serum includes polyclonal antibodies generated by vaccination. http://cov-glue.cvr.gla.ac.uk/#/home (2020). In addition, Y453F has been described as reducing neutralization by mAbs47. The Omicron variant, which emerged in November 2021, has many lineages. and D.L.R. The lineage has been associated with a rapidly increasing proportion of reported SARS-CoV-2 cases, and phylogenetic analyses indicate that this lineage was associated with a growth rate estimated to be 4070% higher than that of other lineages60,61. Despite its mutations, the virus shows little variability, and this is good news for the researchers working on . Nature https://doi.org/10.1038/s41586-021-03412-7 (2021). How Viral Mutations Occur in SARS-CoV-2 - Yale Medicine Coronavirus (COVID-19) Dashboard. SARS-CoV-2 can enter cells by two main pathways. 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. 1a), and high levels of amino acid substitutions are observed at some amino acid positions where mutations are described as affecting recognition by antibodies in convalescent plasma, including positions 439 and 484. The spike protein mediates attachment of the virus to host cell-surface receptors and fusion between virus and cell membranes11 (Box1). Science 369, 650 (2020). eLife https://doi.org/10.7554/eLife.61312 (2020). 11, 2688 (2020). Get the most important science stories of the day, free in your inbox. Preprint at bioRxiv https://doi.org/10.1101/2020.06.25.170688 (2020). This finding further demonstrates the structural plasticity of the NTD and indicates that insertions and the acquisition of additional glycosylation motifs in the NTD are further mechanisms in addition to deletion that lead to immune evasion. 5b. Hodcroft, E. B. et al. Such mutations may alter various aspects of virus biology, such as pathogenicity, infectivity, transmissibility and/or antigenicity. Though SARS-CoV-2 is changing gradually, it's still much less . Cele, S. et al. Bugembe, D. L. et al. Postvaccination sera from a cohort of 20 volunteers immunized with the mRNA vaccine mRNA-1273 (Moderna) or BNT162b2 (PfizerBioNTech) showed high binding titres for anti-SARS-CoV-2 spike IgM and IgG with plasma neutralizing activity and relative numbers of RBD-specific antibodies equivalent to those in natural infection59.
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