a: Monitoring an umbrella of SARS-CoV-2 lineages that have similar Spike protein profiles and characterised by a specific set of mutations ( S:Q183E, S:F486P and S:F490S ). Convergent evolution of SARS-CoV-2 spike mutations, L452R, E484Q and P681R, in the second wave of COVID-19 in Maharashtra, India. c | The extent to which each spike residue becomes more or less accessible when the spike protein is in its open form is shown. J. Virol. Das, S. R. et al. Article MIT researchers have determined the virus protein-coding gene set and analyzed new mutations likelihood of helping the virus adapt. New variants will continue to emerge, and although it is important to understand the phenotypes of emerging variants in terms of infectivity, transmissibility, virulence and antigenicity, it is also important to quantify the phenotypic impacts of specific mutations present in variants, both individually and in combination with other mutations. Reduced antibody cross-reactivity following infection with B.1.1.7 than with parental SARS-CoV-2 strains. A cocktail of antibodies for COVID-19 therapy. Li, Q. et al. 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). COG-UK Mutation Explorer: Subsequent studies indicated that D614G confers a moderate advantage for infectivity8,9 and transmissibility10. and D.L.R. Genomic characterization of a novel SARS-CoV-2 lineage from rio de Janeiro, Brazil. What is the Omicron variant? However, substitutions at 477 were not identified as being important in DMS with convalescent plasma39. Updated working definitions and primary actions for SARS-CoV-2 variants Currently circulating variants of interest (VOIs) as of 21 April 2023 Currently circulating variants under monitoring (VUMs) (as of 26 April 2023) * Excludes XBB sublineages listed here as VOIs and VUMs Technical Advisory Groups There is no evidence for a notable impact of A222V on virus phenotype (that is, infectivity and transmissibility), and so its increase in frequency is generally presumed to have been fortuitous rather than a selective advantage. 5b). How Do Viruses Mutate and What it Means for a Vaccine? 6, 17221734 (2020). W.T.H., A.M.C., A.R., S.J.P. https://www.gisaid.org, Global Report Investigating Novel Coronavirus Haplotypes: Article https://www.preprints.org/manuscript/202101.0132/v1 (2021). This lineage is characterized by four amino acid differences, H69V70, Y453F, I692V and M1229I (Fig. 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). Hensley, S. E. et al. 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. Evolution of the SARS-CoV-2 Mutational Spectrum Shu, Y. Eurosurveillance 25, 2000291 (2020). The three B.1.351 variants investigated, representing the majority of deposited B.1.351 sequences, showed much larger decreases in neutralization activity, ranging from 34-fold to 42-fold (BNT162b2) and from 19.2-fold to 27.7-fold (mRNA-1273). Over 1.2 million sequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been generated during the past 15 months, and the scientific community has gained a lot of knowledge . 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. A., Orton, R. J., Singer, J. When the spike protein is in the open conformation, increased accessibility results in substantially higher potential epitope scores for S2 residues centred at 850854, which become more accessible on all three spike monomers (Fig. Repeated amino acid substitutions at position 677 and the independent emergence of Q677H in several lineages in the USA provides strong evidence of adaptation, potentially through an effect of this mutation on the proximal polybasic furin cleavage site, although further experiments are required to determine its impact74. 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. Postvaccination sera from individuals who received two doses of mRNA-1273 (28 days apart) showed reduced neutralization of the B.1.351 variant (6.4-fold reduction)88. High numbers of B.1.351 viruses also have the spike amino acid substitutions L18F, R246I and D614G. Similarly, neutralizing activity of sera elicited by the inactivated vaccine Covaxin (Bharat Biotech) against B.1.1.7 viruses was largely preserved87. SARS-CoV-2 has a genetic proofreading mechanism achieved by non-structure protein (NSP) 14 in synergy with NSP10 and NSP12 3, 4. The specific parts of an antigen recognized by the immune system: antibodies, B cells or T cells. 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. 4. 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. The locations of amino acid substitutions and deletions that define variants of concern are highlighted as red spheres. 383, 22912293 (2020). Glycans are bulky sugar molecules that may shield epitopes from antibody binding. Nat. Chi, X. et al. Science 369, 330 (2020). Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Emergence in late 2020 of multiple lineages of SARS-CoV-2 spike protein variants affecting amino acid position 677. Cryogenic electron microscopy was used to determine the antibody footprint of the neutralizing antibody 4A8, and showed key interactions involving spike residues Y145, H146, K147, K150, W152, R246 and W258 (ref.32). A few other regions were suspected to encode proteins, but they had not been definitively classified as protein-coding genes. Nat. The most accelerated region in the entire genome of SARS-CoV-2 is sitting smack in the middle of this nucleocapsid protein, he says. Avanzato, V. A. et al. The researchers also recognized that many previous papers used not only incorrect gene sets, but sometimes also conflicting gene names. The techniques are based on analyzing whether certain DNA or RNA bases are conserved between species, and comparing their patterns of evolution over time. Huang, B. et al. Preprint at medRxiv https://doi.org/10.1101/2021.02.23.21252268 (2021). Thank you for visiting nature.com. The process by which a virus can cloak underlying protein, impeding antibody binding. You may not alter the images provided, other than to crop them to size. Google Scholar. Preprint at bioRxiv https://doi.org/10.1101/2021.02.22.432189 (2021). This umbrella includes, for instance, the lineages XBB.1.5, XBB.1.9.1*, XBB.1.9.2*, and XBB.1.16 All sub-lineages of the listed lineages are also included in the variant 3). Baum, A. et al. Accessible amino-terminal domain (NTD) loops N1N5 are labelled, and a loop falling between these is indicated with an asterisk. 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 S1S2 boundary is at amino acid position 685. b | Spike protein monomer displaying an upright receptor-binding domain (RBD). https://doi.org/10.1038/s41579-021-00573-0, DOI: https://doi.org/10.1038/s41579-021-00573-0. 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. 5. The spike amino acid substitution N501Y, which increases ACE2-binding affinity19, has been described as emerging in individuals treated with convalescent plasma, potentially as a means of immune escape. Subsequently, many distinct lineages of SARS-CoV-2 have evolved. This is mediated by glycans, bulky sugar molecules that are covalently attached to amino acid side chains of the viral protein. Early structural characterization of NTD-specific antibodies 4A8 (ref.32) and 48 (ref.13) revealed similar epitope locations towards the upper side of the most prominently protruding area of the NTD. 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. The residues comprising the receptor-binding motif are revealed on the upright RBD, enabling binding to ACE2, which induces a progressively more open structure until a fully open, three-ACE2-bound structure is formed, initiating S2 unsheathing and membrane fusion101. SARS-CoV-2 Evolution - WHO Many seniors now eligible to get another COVID booster, CDC says Meredith, L. W. et al. Blood serum of a previously infected individual that usually contains a mixture of different antibodies referred to as polyclonal antibodies. 1a,b): ACE2-blocking antibodies that bind the spike protein in the open conformation (class 1); ACE2-blocking antibodies that bind the RBD in both the open conformation and the closed conformation (class 2); antibodies that do not block ACE2 and bind the RBD in both the open conformation and the closed conformation (class 3); and neutralizing antibodies that bind outside the ACE2 site and only in the open conformation (class 4)31. 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. Preprint at bioRxiv https://doi.org/10.1101/2021.03.17.435863 (2021). Emergence and spread of a SARS-CoV-2 variant through Europe in the summer of 2020. Prior analyses of SARS-CoV-2 mutation rates have generally focused on all nucleotide mutations (Neher 2022; Ruis, Peacock, et al. https://nextstrain.org/ncov/global?c=gt-S_477&gmax=24271&gmin=22482 (2021). 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. Preprint at medRxiv https://doi.org/10.1101/2020.12.21.20248640 (2020). 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. Lancet Infect. Commun. 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. Correspondence to Hemagglutinin receptor binding avidity drives influenza A virus antigenic drift. In the case of S protein, the consequences of mutations seem obvious: They make virus entry into the cell easier or help evade the immune system, whereas the effects of mutations in N protein. 5, 14031407 (2020). The SARS-CoV-2 spike protein is highly glycosylated, with 66 potential N-glycosylation sites per trimer98,99 (Fig. Hu, J. et al. 5b). 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. Cell https://doi.org/10.1016/j.cell.2021.03.028 (2021). https://cov-lineages.org/global_report.html. 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. Cell Rep. 30, 18621869.e1864 (2020). 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. Monoclonal antibodies for the S2 subunit of spike of SARS-CoV-1 cross-react with the newly-emerged SARS-CoV-2. SARS-CoV-2 escape in vitro from a highly neutralizing COVID-19 convalescent plasma. https://virological.org/t/genomic-characterisation-of-an-emergent-sars-cov-2-lineage-in-manaus-preliminary-findings/586 (2021). Feb 19, 2021. The emergence and ongoing convergent evolution of the N501Y lineages coincides with a major global shift in the SARS-CoV-2 selective landscape. Cell 183, 739751.e738 (2020). S-variant SARS-CoV-2 is associated with significantly higher viral load in samples tested by TaqPath polymerase chain reaction. The substitutions, insertions or deletions of one or more nucleotides in the virus RNA genome. Within the RBD, the positions at which amino acid substitutions are present at the highest frequency are located close to the RBDACE2 interface (Fig. Preprint at bioRxiv https://doi.org/10.1101/2021.02.14.431043 (2021). 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 proportion will affect functional properties and may alter infectivity, disease severity or interactions with host immunity. Greaney, A. J. et al. However, one study tested eight SARS-CoV-2 variants of interest or concern, including B.1.1.298, B.1.1.7 and P.1, as well as three B.1.351 variants, distinguished by their combination of NTD mutations, representing sequence diversity in circulating viruses of this lineage. Further evidence of the role of RDR2 deletions in immune escape was provided by a study that describes the emergence of 140 in SARS-CoV-2 co-incubated with potently neutralizing convalescent plasma, causing a fourfold reduction in neutralization titre41. The role of mutation in nucleoproteins of SARS-CoV-2 SARS-CoV-2 Variant Classifications and Definitions - CDC Antibodies made by cloning a unique white blood cell, which usually has monovalent binding affinity for a specific epitope. Suryadevara, N. et al. Naveca, F. et al. Nature 581, 215220 (2020). The six strains of SARS-CoV-2 -- ScienceDaily 2a). Predictive modeling of influenza shows the promise of applied evolutionary biology. 27, 763767 (2020). Experimental determination of the binding site, or epitope, of an antibody. 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. Dis. Development of vaccines against SARS-CoV-2 has been rapid, but the rise of variants forces scientists to frequently modify treatments. and E.C.T. The emergence of SARS-CoV-2 in late 2019 was followed by a period of relative evolutionary stasis lasting about 11 months. Weird SARS-CoV-2 outbreak in mink suggests hidden source of virus in There have been a number of missense mutations observed of SARS-CoV-2. 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. If we all put effort into doing our part, these variants wont be able to take a foothold in our community., Therapeutic Radiology, Thoracic Radiotherapy, Head & Neck Radiotherapy, Thoracic Oncology, Breast Oncology, Hematologic Oncology. J. & 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. Temporal signal and the phylodynamic threshold of SARS-CoV-2. 372, n597 (2021). 18, 10611063 (2021). Faulkner, N. et al. Nature Reviews Microbiology thanks Y. Wang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. This website is managed by the MIT News Office, part of the Institute Office of Communications. 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. Provided by the Springer Nature SharedIt content-sharing initiative, Nature Reviews Microbiology (Nat Rev Microbiol) Neutralization of SARS-CoV-2 spike 69/70 deletion, E484K, and N501Y variants by BNT162b2 vaccine-elicited sera. MIT News | Massachusetts Institute of Technology, A comprehensive map of the SARS-CoV-2 genome. J. Med. How long Omicron variants persist on shipping materials may be influenced by temperature, humidity and material. https://doi.org/10.1093/ve/veaa061 (2020). Characterizing the Contaminated Couriers of Omicron SARS-CoV-2 Variants J. Med. Alessandro M. Carabelli, Thomas P. Peacock, David L. Robertson, Jessica A. Plante, Yang Liu, Pei-Yong Shi, Sandra Isabel, Luca Graa-Miraglia, Susan M. Poutanen, Steven A. Kemp, Dami A. Collier, Ravindra K. Gupta, Marciela M. DeGrace, Elodie Ghedin, Mehul S. Suthar, Kaiming Tao, Philip L. Tzou, Robert W. Shafer, Kizzmekia S. Corbett, Darin K. Edwards, Barney S. Graham, Nature Reviews Microbiology For example, recently detected viruses of lineage B.1.617.1 were anticipated to show altered antigenicity due to the presence of the substitutions L452R and E484Q, which have been described as affecting antibody recognition39,43,45,48,81. Science 370, 1464 (2020). 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. Several studies have contributed to the current understanding of how mutations in the SARS-CoV-2 spike protein affect neutralization. Google Scholar. 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. A similar NTD deletion, 243244, abolishes binding by the antibody 4A8 (ref.42), and L18F and R246I also occur within the NTD supersite and likely affect antibody binding as well30. 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. This indicates that, generally, the amino acid positions at which antibody escape mutations have been detected in vitro tolerate mutations at least to some degree in vivo. The Biological Functions and Clinical Significance of SARS-CoV-2 MacLean, O. 6. 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. SARS-CoV-2 Mutations Explained - Discovery's Edge 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. 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. We speculate that those variants that don't mutate that region get recognized by the human immune system and eliminated, whereas those variants that randomly accumulate mutations in that region are in fact better able to evade the human immune system and remain in circulation.. 2. Volz E, Hill V, McCrone J, et al. SARS-CoV-2 and Immunosuppression In this article, . REGN-COV2 (Regeneron) (included in the RECOVERY trial in the UK) and AZD7742 (AstraZeneca) are two examples of mAbs cocktails that have been developed93. 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.
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