Most random mutations are likely to be deleterious to the virus, and many will be lethal. Here's what scientists are watching for: Like all viruses, SARS-CoV-2 is mutating as it passes from person to person. 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. et al. Sign up for the Nature Briefing newsletter what matters in science, free to your inbox daily. b | Aligned heat maps showing properties of amino acid residues or of the specific amino acid substitution, as appropriate. To monitor vaccine efficacy and to better understand the implications of antigenic variation for vaccine effectiveness, it will be important to collect information on vaccine status and viral genome sequence data from individuals infected with SARS-CoV-2. Outside the NTD and the RBD, the highest-scoring residues are residues 676 and 689 (which lie on either side of the loop containing the S1S2 furin cleavage site, which is disordered in both the open conformation and the closed conformation50), 793794, 808812, 1,0991,100 and 1,1391,146 (Fig. Sapkal, G. N. et al. Med. The substitutions T20N and P26S also occur in or near the NTD supersite30 at residues with high antibody accessibility scores (Fig. Within the NTD, the highest-scoring spike residues in the closed form belong to a loop centred at residues 147150, which each have scores greater than 0.9 (Fig. SARS-CoV-2 RBD in vitro evolution follows contagious mutation spread, yet generates an able infection inhibitor. A campus summit with the leader and his delegation centered around dialogue on biotechnology and innovation ecosystems. Wagner, C., Hodcroft, E., Bell, S. M., Neher, R. & Bedford, T. Resurgence of SARS-CoV-2 19B Clade Corresponds with Possible Convergent Evolution. Other experiments with pseudotyped viruses showed that the B.1.351 variant was also resistant to the neutralizing activity of some mAbs (12 of 17; 70%)67. 2b. 27, 622625 (2021). The B.1.427 and B.1.429 variants carry an antigenically noteworthy substitution, L452R75, which has been shown to reduce neutralization by several mAbs43,45,48,59 and convalescent plasma43. Weisblum, Y. et al. What are variants of SARS-COV-2, the virus that causes COVID-19? Cele, S. et al. Cell https://doi.org/10.1016/j.cell.2020.11.020 (2020). How do variants of SARS-CoV-2, the virus that causes COVID-19, get their names? Madhi, S. A. et al. The spike protein transiently undergoes conformational changes between a closed conformation and an open conformation in which a hinge-like movement raises the RBD50. 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. 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. Garcia-Beltran, W. F. et al. Slider with three articles shown per slide. Modelling approaches to predict the evolutionary trajectories of emerging variants based on an understanding of the phenotypic effects of mutations will assist this process, as is the case for influenza virus94. Cell Host Microbe 29, 2331.E24 (2021). Morris, D. H. et al. Lineage B.1.1.7 is defined by the presence of 23 nucleotide mutations across the genome that map to a single branch of the phylogenetic tree3. 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. SARS-CoV-2 variants, spike mutations and immune escape, https://doi.org/10.1038/s41579-021-00573-0. Molnupiravir-induced elevated mutation rates have been shown to decrease viral load in animal models. Xie, X. et al. Preprint at bioRxiv https://doi.org/10.1101/2021.03.17.435863 (2021). Q613H is speculated to be important as it occurs at a position neighbouring D614G80. 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. In the open form, residues close to the ACE2-binding site (405, 415, 416, 417 and 468) become much more exposed on both the upright RBD and the clockwise adjacent closed RBD (Fig. Cell 78, 779784 e775 (2020). Eurosurveillance 25, 2000291 (2020). 35, 13481354 (2018). 2a, yellow patch to the extreme right of the structure viewed from the side in Fig. Emary, K. R. W. et al. In the new study, the researchers also analyzed more than 1,800 mutations that have arisen in SARS-CoV-2 since it was first identified. 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. Despite its mutations, the virus shows little variability, and this is good news for the researchers working on . A few other regions were suspected to encode proteins, but they had not been definitively classified as protein-coding genes. PubMed 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). 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). 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). Accessible amino-terminal domain (NTD) loops N1N5 are labelled, and a loop falling between these is indicated with an asterisk. 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). Korber, B. et al. The collective data on the effect of mutations on vaccines and convalescent serum efficacy show that the polyclonal antibody response is focused on a few immunodominant regions, indicating the high probability of future mutation-mediated escape from host immunity. 27, 763767 (2020). Substitutions that individually increase receptor-binding affinity can shift the binding equilibrium between glycoprotein and neutralizing antibodies in favour of a higher-avidity interaction between glycoprotein and the cellular receptor102. Preprint at medRxiv https://doi.org/10.1101/2021.03.03.21252812 (2021). Provided by the Springer Nature SharedIt content-sharing initiative, Nature Reviews Microbiology (Nat Rev Microbiol) 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. Li, Q. et al. 4. As mentioned earlier, there is evidence indicating that D614G confers a moderate advantage for infectivity8,9 and increases transmissibility10. Microbiol. This resulted in an unprecedented level of data sharing to open repositories, which has actively supported the identification of SARS-CoV-2 structure, molecular interactions, mutations and variants, and facilitated vaccine development and drug . This is caused by non-synonymous mutations. 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. Within the RBD, the two areas with high structure-based antibody accessibility scores for the closed spike structure (Fig. The authors thank all of the researchers who have shared genome data openly via the Global Initiative on Sharing All Influenza Data (GISAID). 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. Prediction of the mutational pathways by which a virus such as SARS-CoV-2 will evolve is extremely challenging. a | Structure-based antibody accessibility scores for each spike protein ectodomain residue in the closed form were calculated with BEpro49. SARS-CoV-2 has a genetic proofreading mechanism achieved by non-structure protein (NSP) 14 in synergy with NSP10 and NSP12 3, 4. Temporal signal and the phylodynamic threshold of SARS-CoV-2. PubMed Central Science 369, 650 (2020). Recurrent emergence and transmission of a SARS-CoV-2 spike deletion H69/V70. N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2. SARS-CoV-2 Reinfection by the New Variant of Concern (VOC) P.1 in Amazonas, Brazil. Baum, A. et al. McCarthy, K. R. et al. B. Based on current data, it seems as though SARS-CoV-2 mutates much more slowly than the seasonal flu. Virus Evol. 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. 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. Zahradnk, J. et al. 5b). Annavajhala, M. K. et al. Persistence and evolution of SARS-CoV-2 in an immunocompromised host. 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. 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). Prospective mapping of viral mutations that escape antibodies used to treat COVID-19. Huang, B. et al. https://files.ssi.dk/Mink-cluster-5-short-report_AFO2 (2020). This lineage is characterized by four amino acid differences, H69V70, Y453F, I692V and M1229I (Fig. Viruses naturally change over time through the process of mutation. 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. Scientists have identified several regions known to encode protein-coding genes, based on their similarity to protein-coding genes found in related viruses. de Oliveira, T. et al. For example, the spike protein amino acid change D614G was noted to be increasing in frequency in April 2020 and to have emerged several times in the global SARS-CoV-2 population, and the coding sequence exhibits a high dN/dS ratio, suggesting positive selection at the codon position 614 (refs6,7). A subset of these residues has mutations described as emerging upon exposure (co-incubation) to mAbs40,47,48 or plasma40,41 in laboratory experiments (mAb emerge and plasma emerge, respectively). The P.1 lineage, a sublineage of B.1.1.28, was first detected in Brazil69 and in travellers from Brazil to Japan70. below, credit the images to "MIT.". The 140+E484K double mutant next acquired an 11-residue insertion in the NTD N5 loop between Y248 and L249, completely abolishing neutralization. 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. RNA viruses have. Such mutations may alter various aspects of virus biology, such as pathogenicity, infectivity, transmissibility and/or antigenicity. 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. 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Potentially, observed differences arise because mutations selected by convalescent plasma facilitate escape from multiple mAbs. The amino-terminal domain (NTD) supersite30 is coloured in magenta. Of these 23 mutations, 14 encode amino acid changes and three are deletions, including six amino acid substitutions in the spike protein (N501Y, A570D, P681H, T716I, S982A and D1118H) and two NTD deletions (H69V70 and Y144)3. In the context of viruses, genetically distinct viruses with mutations different from those of other viruses. Amino acid variants are present at high frequency in positions at the RBDACE2 interface. 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. 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. 2a). Additionally, lineages B.1.351 and P.1 possess alternative amino acid substitutions K417N and K417T, respectively. Preprint at medRxiv https://doi.org/10.1101/2020.10.25.20219063 (2020). Soh, W. T. et al. In this Review, we summarize the literature on mutations of the SARS-CoV-2 spike protein, the primary antigen, focusing on their impacts on antigenicity and contextualizing them in the protein structure, and discuss them in the context of observed mutation frequencies in global sequence datasets. 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. Pseudoviruses carrying the set of B.1.1.7 spike mutations evaluated with postvaccination serum from individuals who received the BNT162b2 vaccine (two doses)63,78,84 or mRNA-1273 vaccine (two doses)63 exhibited only a modest reduction in neutralization titres (less than threefold). 2a), and amino acid substitutions at position 484 diminish neutralization by a range of RBD-targeting antibodies. Typically, studies report a fold change in variant virus, or pseudovirus, neutralization relative to wild-type virus (the serum concentration at which 50% neutralization (IC50) is achieved with the variant divided by the average IC50 for the wild-type virus). 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. Wrobel, A. G. et al. More details of the frequency and geographic distribution of the P1 lineage can be found at the Pango lineages website72. The mutation N439K increases affinity for ACE2 (ref.19), is predicted to result in an additional salt bridge at the RBMACE2 interface and is thought to preferentially reduce the neutralization potential of plasma that already has low neutralizing activity18. A credit line must be used when reproducing images; if one is not provided https://doi.org/10.1093/ve/veaa061 (2020). Science 371, 11391142 (2021). Neutralization of SARS-CoV-2 VOC 501Y.V2 by human antisera elicited by both inactivated BBIBP-CorV and recombinant dimeric RBD ZF2001 vaccines. Bioinformatics 24, 14591460 (2008). eLife https://doi.org/10.7554/eLife.61312 (2020). McCallum, M. et al. Pseudoviruses were generated by the same system and tested with postvaccination sera from individuals who received two doses of either the BNT162b2 vaccine (n=30) or the mRNA-1273 vaccine (n=35)90. Nat. 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. Thank you for visiting nature.com. & Munster, V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and . A dynamic nomenclature proposal for SARS-CoV-2 lineages to assist genomic epidemiology. Residue 769 is positioned in a surface-exposed S2 loop, and D769H was found to arise, in linkage with 6970, in an immunocompromised individual treated with convalescent plasma24. 3). Complete mapping of mutations to the SARS-CoV-2 spike receptor-binding domain that escape antibody recognition. Nat. The original version of the virus, D614, was most widely seen in China and other parts of Asia. Andreano, E. et al. SARS-CoV-2 variants, spike mutations and immune escape. Nextstrain. Scores rescaled between 0 and 1 are plotted for the closed conformation in Fig. A change in the biophysical properties of an epitope residue directly diminishes antibody binding. The substitution L18F has occurred ~21 times in the global population53 and is associated with escape from multiple NTD-binding mAbs30.
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