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. 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 . Preprint at medRxiv https://doi.org/10.1101/2021.02.23.21252259 (2021). Mobility-related data show the pandemic has had a lasting effect, limiting the breadth of places people visit in cities. When residues belong to epitopes of multiple classes, priority colouring is given to antibodies that block ACE2 and bind the closed spike protein. For each gene, they compared how rapidly that particular gene has evolved in the past with how much it has evolved since the current pandemic began. PubMed Central 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. ECDC. The S1S2 boundary is at amino acid position 685. b | Spike protein monomer displaying an upright receptor-binding domain (RBD). Cell https://doi.org/10.1016/j.cell.2020.11.020 (2020). 5b). 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. Escape of SARS-CoV-2 501Y.V2 from neutralization by convalescent plasma. The B.1.1.7 spike mutations have been shown to diminish neutralization of a higher proportion of NTD-specific neutralizing antibodies (9 of 10; 90%) than RBD-specific neutralizing antibodies (5 of 31; 16%)63. Wise, J. Covid-19: the E484K mutation and the risks it poses. Preprint at medRxiv https://doi.org/10.1101/2021.02.08.21251393 (2021). 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. In addition to their antigenic effect, both K417N and K417T are expected to moderately decrease ACE2-binding affinity19 (Fig. 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. Immunol. A., Orton, R. J., Singer, J. Variant frequency is also moderately high at RBDACE2 interface amino acid positions 417, 453 and 446. reviewed and/or edited the manuscript before submission. SARS-CoV-2 D614G variant exhibits efficient replication ex vivo and transmission in vivo. Fonager J. et al. Following the emergence of D614G, an amino acid substitution within the receptor-binding motif (RBM), N439K, was noted as increasing in frequency in Scotland in March 2020. Multiple SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity. Tracking changes in SARS-CoV-2 spike: evidence that D614G increases infectivity of the COVID-19 virus. The amino-terminal domain (NTD) supersite30 is coloured in magenta. 4a). As of April 2021, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, accounted for more than 143 million infections and more than three million deaths worldwide1. SARS-CoV-2 has a genetic proofreading mechanism achieved by non-structure protein (NSP) 14 in synergy with NSP10 and NSP12 3, 4. 21, 7382 (2021). Lineages P.1 and P.2 each showed significant decreases, with both BNT162b2 (6.7-fold and 5.8-fold, respectively) and mRNA-1273 (4.5-fold and 2.9-fold, respectively) postvaccination sera90. One study described the structure of five previously unmodelled, protruding NTD loops, denoting them N1N5. The most accelerated region in the entire genome of SARS-CoV-2 is sitting smack in the middle of this nucleocapsid protein, he says. Thank you for visiting nature.com. PubMed Both RDR2 deletions, 141144 and 146, and 243244 (RDR4) abolished binding of 4A8 (ref.42). Of these positions, 446 occurs in a location in the spike structure that is predicted to be highly antigenic, and substitutions at this site are described as affecting neutralization by both mAbs and antibodies present in polyclonal serum39,43,46,48. 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). Sapkal, G. N. et al. DMS data on ACE2-binding affinity19 are shown by aggregation of scores and averaging across each mutant at a residue and alternatively the maximally binding mutant. Several animals like mink, dogs, domestic cats, lions, tigers and raccoon dogs have tested positive for SARS-CoV-2 after contact with infected humans. These areas are represented as yellow patches near the centre of the top-down view of the spike structure in Fig. Rees-Spear, C. et al. Choi, B. et al. Greaney, A. J. et al. Predictive modeling of influenza shows the promise of applied evolutionary biology. Recent studies have shown the potential selective pressure exerted by convalescent plasma and mAb treatments on SARS-CoV-2 evolution in immunocompromised individuals24,25,26. 372, n359 (2021). 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). An approach that uses a competitive immunoassay to sort a library of monoclonal antibodies into discrete groups of antibodies that compete for access to overlapping epitopes. 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. Evaluating the effects of SARS-CoV-2 Spike mutation D614G on transmissibility and pathogenicity. 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). This is mediated by glycans, bulky sugar molecules that are covalently attached to amino acid side chains of the viral protein. https://www.krisp.org.za/publications.php?pubid=330 (2021). Weisblum, Y. et al. Science 326, 734736 (2009). Domains are coloured as in part a. Importantly, some mutations in the RBM have already been identified in variants which are circulating in the UK (for example, N439K, T478I and V483I) and are likely to impact antigenicity. 3). https://www.preprints.org/manuscript/202101.0132/v1 (2021). 725422 ReservoirDOCS). Genomic characterization of a novel SARS-CoV-2 lineage from rio de Janeiro, Brazil. 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). 18, 10611063 (2021). A new variant carrying E484K currently designated A.VOI.V2 was recently identified in Angola from cases involving travel from Tanzania79. Mapping neutralizing and immunodominant sites on the SARS-CoV-2 spike receptor-binding domain by structure-guided high-resolution serology. Weissman, D. et al. Creative Commons Attribution Non-Commercial No Derivatives license. Based on current data, it seems as though SARS-CoV-2 mutates much more slowly than the seasonal flu. 2c, blue). R.R. 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. In addition to substitutions at positions 417, 484 and 501 discussed above, the P.1 lineage has a cluster of substitutions close to the described antigenic regions of the NTD, including L18F, which is known to reduce neutralization by some antibodies30. is funded by the UK Biotechnology and Biological Sciences Research Council (BB/R012679/1). Amino acid position 157 has been identified as an epitope residue, with F157A reducing neutralization by the mAb 2489 (ref.34). Further to understanding epidemiology, sequencing enables identification of emerging SARS-CoV-2 variants and sets of mutations potentially linked to changes in viral properties. Cell Mol. The spike amino acid substitution with the second highest frequency is A222V, which is present in the 20A.EU1 SARS-CoV-2 cluster (also designated lineage B.1.177). Several other spike mutations of note have now arisen and are discussed in this Review, with particular focus on mutations affecting antigenicity. Nat. 1a,b). SARS-CoV-2 and Immunosuppression In this article, . Science 372, 815821 (2021). Br. 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. The mean change in binding affinity averaged across all mutations at each site (binding average) and alternatively the maximally binding mutant (binding max) is shown. Silver, Z. http://cov-glue.cvr.gla.ac.uk/, Global Initiative on Sharing All Inflenza Data (GISAID): This lineage has spread widely in Europe and is reported to have originated in Spain52. 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. 1b). https://cov-lineages.org/global_report.html (2020). acknowledges the support of the Wellcome Trust (Collaborators Award 206298/Z/17/Z ARTIC network) and the European Research Council (grant agreement no. Starr, T. N. et al. "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 . The mRNA technology is very flexible and can accommodate new mutations, says Iwasaki. 2c), and residues 978984, which become more accessible on the monomer anticlockwise adjacent to the upright RBD monomer (Fig. Experiments have shown that H69V70 does not reduce neutralization by a panel of convalescent sera; however, it may compensate for infectivity deficits associated with affinity-boosting RBM mutations that may emerge due to immune-mediated selection22. Dai, L. & Gao, G. F. Viral targets for vaccines against COVID-19. 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. 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. https://doi.org/10.1038/s41591-021-01270-4 (2021). In addition to N501Y, for which there is some evidence that it reduces neutralization by a small proportion of RBD antibodies63, there is evidence for an antigenic effect of Y144 (Fig. 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 change in the biophysical properties of an epitope residue directly diminishes antibody binding. Genomic Characterisation of an Emergent SARS-CoV-2 Lineage in Manaus: Preliminary Findings. This approach calculates a structure-based epitope score, which approximates antibody accessibility for each amino acid position. Worobey, M. et al. These constellations of viral mutationsknown as variantsmay take hold if there is evolutionary pressure for them to do so. 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/10.1101/2021.03.17.435863 (2021). Genome sequencing and analysis of an emergent SARS-CoV-2 variant characterized by multiple spike protein mutations detected from the Central Visayas Region of the Philippines. Med. Emary, K. R. W. et al. & Munster, V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. 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. Emerging SARS-CoV-2 variants reduce neutralization sensitivity to convalescent sera and monoclonal antibodies. This variant carries several amino acid substitutions in the spike protein and three deletions in the NTD, some of which are within the antigenic supersite79. SARS-CoV-2 evolution during treatment of chronic infection. https://virological.org/t/sars-cov-2-reinfection-by-the-new-variant-of-concern-voc-p-1-in-amazonas-brazil/596 (2021). Tracking the emergence of these viruses flagged as potential antigenically significant variants will help to guide the implementation of targeted control measures and further laboratory characterization. Whereas this first lineage with N439K (designated B.1.141 with the Pango nomenclature system17) quickly became extinct, another lineage that independently acquired N439K (B.1.258) emerged and circulated widely in many European countries18. Most mutations . Cell Host Microbe 29, 463476 e466 (2021). And, we know all too well that SARS-CoV-2 has spread quickly throughout the world. Zahradnk, J. et al. Information on how spike mutations affect antigenic profiles can be derived from structural studies, mutations identified in viruses exposed to mAbs or plasma containing polyclonal antibodies, targeted investigations of variants using site-directed mutagenesis and deep mutational scanning (DMS) experiments that systematically investigate the possibility of mutations arising. 4a).The SARS-CoV-2 spike protein is post-translationally cleaved by mammalian furin into two subunits: S1 and S2 (Fig. But some errors are beneficial, making it more contagious. In addition to evaluation of vaccine efficacy against SARS-CoV-2 variants and mutations, the effects of mutations on some mAbs used as therapeutics have been described (Supplementary Table 2). Risk Related to Spread of New SARSCoV-2 Variants of Concern in the EU/EEA. Mutational escape from the polyclonal antibody response to SARS-CoV-2 infection is largely shaped by a single class of antibodies. Li, Q. et al. 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. MIT News | Massachusetts Institute of Technology, A comprehensive map of the SARS-CoV-2 genome. Subsequent studies indicated that D614G confers a moderate advantage for infectivity8,9 and transmissibility10. The authors declare no competing interests. The acquisition of epitope-masking glycans during the evolution of human influenza viruses is well described104. 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. It has over 50 mutations, many in the spike protein, which is how it gets into our cells in the first place. 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). In an escape mutation study using 19 mAbs, substitutions at E484 emerged more frequently than at any other residue (in response to four mAbs), and each of the four 484 mutants identified (E484A, E484D, E484G and E484K) subsequently conferred resistance to each of four convalescent sera tested48. SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma. Scientists from The Federal Research Centre "Fundamentals of Biotechnology" of the Russian Academy of Sciences together with foreign colleagues demonstrated that human 14-3-3 proteins, that are known for their role in replication of many viruses, bind differentially with more often mutating regulatory part of nucleoprotein (N protein) of coronavirus SARS-CoV-2. 4. Several studies have contributed to the current understanding of how mutations in the SARS-CoV-2 spike protein affect neutralization. Most random mutations are likely to be deleterious to the virus, and many will be lethal. 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. Biol. 1b). 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%. The S1 subunit largely consists of the amino-terminal domain and the receptor-binding domain (RBD), and is responsible for binding to the host cell-surface receptor, ACE2, whereas the S2 subunit includes the trimeric core of the protein and is responsible for membrane fusion (Fig. Scores were calculated for the spike protein in both the closed conformation and the open conformation (Fig. Similarly, neutralizing activity of sera elicited by the inactivated vaccine Covaxin (Bharat Biotech) against B.1.1.7 viruses was largely preserved87. 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. Neutralization of SARS-CoV-2 VOC 501Y.V2 by human antisera elicited by both inactivated BBIBP-CorV and recombinant dimeric RBD ZF2001 vaccines. Wrobel, A. G. et al. Cell Host Microbe 29, 2331.E24 (2021). 2). 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. Recurrent emergence and transmission of a SARS-CoV-2 spike deletion H69/V70. The SARS-CoV-2 spike protein is highly glycosylated, with 66 potential N-glycosylation sites per trimer98,99 (Fig. The researchers also analyzed mutations that have arisen in variants of concern, such as the B.1.1.7 strain from England, the P.1 strain from Brazil, and the B.1.351 strain from South Africa. For strains that have many mutations, we can see which of these mutations are likely to be host-specific adaptations, and which mutations are perhaps nothing to write home about.. An important part of this process will be the preparation of updated vaccines tailored to emerging antigenic variants that are maximally cross-reactive against all circulating variants. In a DMS study, researchers assessed all possible single amino acid variants using a yeast-display system and detected variants that escape either nine neutralizing SARS-CoV-2 mAbs45 or convalescent plasma from 11 individuals taken at two time points after infection39 (shades of green in Fig. 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. Global Report Investigating Novel Coronavirus Haplotypes. SARS-CoV-2 and bat RaTG13 spike glycoprotein structures inform on virus evolution and furin-cleavage effects. The process by which a virus can cloak underlying protein, impeding antibody binding. In laboratory experiments, a multiresidue insertion in the spike NTD has been described as emerging and contributing to escape from polyclonal antibodies in convalescent plasma41. 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. Ideally, therapies would target mutation-resistant viral . 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. J. Nat. Nat. Starr, T. N. et al.

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