A list of members and their affiliations appears in Supplementary information. Also referred to as functional affinity, the accumulated binding strength of multiple affinities of individual interactions, such as between a virus receptor-binding site and its cellular receptor. 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. 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). 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. In early 2020, a few months after the Covid-19 pandemic began, scientists were able to sequence the full genome of SARS-CoV-2, the virus that causes the Covid-19 infection. However, many sites in the viral genome are under strong functional selection, and so the mutational patterns at those sites will represent the combined action of mutation and selection. Kumar, S., Maurya, V. K., Prasad, A. K., Bhatt, M. L. B. Early indications suggest that these are broadly consistent with the laboratory results, with the B.1.351 variant showing greater signs of vaccine escape. Nature https://doi.org/10.1038/s41586-021-03471-w (2021). Preprint at bioRxiv https://doi.org/10.1101/2021.01.07.425740 (2021). 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). Med. Dai, L. & Gao, G. F. Viral targets for vaccines against COVID-19. Cell https://doi.org/10.1016/j.cell.2021.02.042 (2021). The half-maximal inhibitory concentration, a quantitative measure that indicates how much of an inhibitory substance (for example, postvaccination serum) is required to inhibit a biological process (for example, virus forming plaques or regions of infected cells in culture) by 50%. It has over 50 mutations, many in the spike protein, which is how it gets into our cells in the first place. J. Med. Domains are coloured as in part a. Xie, X. et al. REGN-COV2 (Regeneron) (included in the RECOVERY trial in the UK) and AZD7742 (AstraZeneca) are two examples of mAbs cocktails that have been developed93. 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. Google Scholar. W.T.H., A.M.C., R.K.G., E.C.T., R.R., S.J.P. Preprint at medRxiv https://doi.org/10.1101/2021.02.08.21251393 (2021). This lineage has spread widely in Europe and is reported to have originated in Spain52. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. https://doi.org/10.1038/s41579-021-00573-0, DOI: https://doi.org/10.1038/s41579-021-00573-0. 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. https://www.krisp.org.za/publications.php?pubid=330 (2021). 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. Variants (retrieved from CoV-GLUE) are based on 426,623 high-quality sequences downloaded from the Global Initiative on Sharing All Influenza Data (GISAID) database on 3 February 2021. a | Points representing each spike amino acid residue are positioned according to the antibody accessibility score and the distance to the nearest residue in the receptor-binding site. 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. 1b). 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. 1b). & Saxena, S. K. Structural, glycosylation and antigenic variation between 2019 novel coronavirus (2019-nCoV) and SARS coronavirus (SARS-CoV). Deep mutational scanning of SARS-CoV-2 receptor binding domain reveals constraints on folding and ACE2 binding. Emergence and rapid spread of a new severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in South Africa. Huang, B. et al. Hodcroft, E. B. et al. The magenta spheres represent glycans, and the magenta triangles represent potantial N-linked glycosylation sites. More details of the frequency and geographic distribution of the P1 lineage can be found at the Pango lineages website72. The name of the mutation, del 69-70, or 69-70 del, or other similar notations, refers to the . 5b. This data could help other scientists focus their attention on the mutations that appear most likely to have significant effects on the virus infectivity, the researchers say. PubMed Creative Commons Attribution Non-Commercial No Derivatives license. https://www.preprints.org/manuscript/202101.0132/v1 (2021). Nature https://doi.org/10.1038/s41586-021-03412-7 (2021). The substitutions, insertions or deletions of one or more nucleotides in the virus RNA genome. Blood serum of a previously infected individual that usually contains a mixture of different antibodies referred to as polyclonal antibodies. Beyond shielding: the roles of glycans in the SARS-CoV-2 spike protein. the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in 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). CD, connecting domain; CT cytoplasmic tail; FP, fusion peptide; RBM, receptor-binding motif; TM, transmembrane domain. 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. 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. Rambaut, A. et al. Frost, S. D. W., Magalis, B. R. & Kosakovsky Pond, S. L. Neutral theory and rapidly evolving viral pathogens. 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. SARS-CoV-2 escape in vitro from a highly neutralizing COVID-19 convalescent plasma. Spike amino acid residues are coloured according to the frequency of amino acid substitutions or deletions. A. et al. What makes the Omicron variant different from other variants? Similarly, postvaccination serum includes polyclonal antibodies generated by vaccination. 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. Residues with at least 100 sequences possessing a substitution or deletion are coloured according to the frequency scale shown, with the remainder shaded grey. Viral epitope profiling of COVID-19 patients reveals cross-reactivity and correlates of severity. Immunol. Preprint at bioRxiv https://doi.org/10.1101/2021.04.22.440932 (2021). 2c, blue). & Munster, V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Wang, Z. et al. 3a,b). To assess the impacts of mutations on vaccine efficacy, authentic viruses and pseudoviruses possessing particular spike mutations (either individually or in combination) and larger sets of mutations representing variants of concern and other circulating spike mutations have been assessed by neutralization assays with postvaccination sera (Supplementary Table 1). The COVID-19 pandemic has seen large-scale pathogen genomic sequencing efforts, becoming part of the toolbox for surveillance and epidemic research. High numbers of B.1.351 viruses also have the spike amino acid substitutions L18F, R246I and D614G. Monoclonal antibodies for the S2 subunit of spike of SARS-CoV-1 cross-react with the newly-emerged SARS-CoV-2. Fitness costs limit influenza A virus hemagglutinin glycosylation as an immune evasion strategy. 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. Greaney, A. J. et al. One study described the emergence of escape mutations in viruses exposed to convalescent plasma from two individuals, one of which selected for NTD mutations only (N148S, K150R, K150E, K150T, K150Q and S151P)40. acknowledges the support of the Wellcome Trust (Collaborators Award 206298/Z/17/Z ARTIC network) and the European Research Council (grant agreement no. Cell https://doi.org/10.1016/j.cell.2020.11.020 (2020). Hu, J. et al. and E.C.T. Rev. Sapkal, G. N. et al. Internet Explorer). 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. Collier, D. A. et al. Google Scholar. contracts here. Discovery of O-linked carbohydrate on HIV-1 envelope and its role in shielding against one category of broadly neutralizing antibodies. Weisblum, Y. et al. SARS-CoV-2 has a genetic proofreading mechanism achieved by non-structure protein (NSP) 14 in synergy with NSP10 and NSP12 3, 4. 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. Additionally, lineages B.1.351 and P.1 possess alternative amino acid substitutions K417N and K417T, respectively. David L. Robertson. Shu, Y. Google Scholar. W.T.H., A.M.C., A.R., S.J.P. Evol. 5, 562569 (2020). and P.2 lineages, are D80A, 242244, K417N (though K417T is present in P.1) and A701V. SARS-CoV-2, the new coronavirus that causes COVID-19, is no exception to this.. As . SARS-CoV-2 and Immunosuppression In this article, . 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. 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. Genomic Characterisation of an Emergent SARS-CoV-2 Lineage in Manaus: Preliminary Findings. Shrock, E. 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. 1b. 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. Over time, the cumulative effects of these mutations may be enough to change how the virus behaves. This approach calculates a structure-based epitope score, which approximates antibody accessibility for each amino acid position. 2b. PubMed Central Liu, Z. et al. 2). Figure2c shows that, in general, residues become more accessible and are likelier to form epitopes when the spike protein is in the open conformation, and this is especially true for the RBD, particularly for the upright RBD (Fig. 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. 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. Lancet Infect. Preprint at bioRxiv https://doi.org/10.1101/2020.11.05.369264 (2020). 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. The P.1 lineage, a sublineage of B.1.1.28, was first detected in Brazil69 and in travellers from Brazil to Japan70. This coincided with the emergence of variants with higher numbers of mutations relative to previous circulating variants. 5b), and T20N introduces a potential glycosylation site that could result in glycan shielding (Box2) of part of the supersite. RNA viruses have. Google Scholar. Prospective mapping of viral mutations that escape antibodies used to treat COVID-19. However, assays using pseudovirus carrying B.1.1.7 spike mutations and with the addition of E484K, a combination that has been observed in sequencing of circulating isolates, showed larger, more significant drops (6.7-fold) in neutralization with postvaccination sera isolated from individuals who received the BNT162b2 vaccine85. Recurrent deletions in the SARS-CoV-2 spike glycoprotein drive antibody escape. Neutralization of SARS-CoV-2 spike 69/70 deletion, E484K, and N501Y variants by BNT162b2 vaccine-elicited sera. Molnupiravir, an antiviral medication that has been widely used against SARS-CoV-2, acts by inducing mutations in the virus genome during replication.
