Volz, E. et al. These authors contributed equally: William T. Harvey, Alessandro M. Carabelli. Globally, the highest number of amino acid variants, mapped against the Wuhan-Hu-1 reference sequence (MN908947), are recorded at amino acid positions 614, 222 and 18 (Fig. Evaluating the effects of SARS-CoV-2 Spike mutation D614G on transmissibility and pathogenicity. Nat. The amino-terminal domain (NTD) supersite30 is coloured in magenta. For RBD residues, the results of deep mutational scanning (DMS) studies show the escape fraction (that is, a quantitative measure of the extent to which a mutation reduced polyclonal antibody binding) for each mutant averaged across plasma (plasma average) and for the most sensitive plasma (plasma max)39. 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. 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. 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. SARS-CoV-2 Mutations Explained - Discovery's Edge 2c), and residues 978984, which become more accessible on the monomer anticlockwise adjacent to the upright RBD monomer (Fig. 2a), and amino acid substitutions at position 484 diminish neutralization by a range of RBD-targeting antibodies. Consequently, mutations that affect the antigenicity of the spike protein are of particular importance. Weisblum, Y. et al. Cell https://doi.org/10.1016/j.cell.2021.03.029 (2021). Nat. Antibodies made by cloning a unique white blood cell, which usually has monovalent binding affinity for a specific epitope. Google Scholar. Amino acid position 157 has been identified as an epitope residue, with F157A reducing neutralization by the mAb 2489 (ref.34). Characterizing the Contaminated Couriers of Omicron SARS-CoV-2 Variants 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). L452R is also present in the A.27 lineage associated with a cluster of cases identified on the island of Mayotte76. 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). A small minority of mutations are expected to impact virus phenotype in a way that confers a fitness advantage, in at least some contexts. Other novel variants have been identified spreading in California and New York, USA (B.1.427 and B.1.429, and B.1.526, respectively). Preprint at bioRxiv https://doi.org/10.1101/2020.11.05.369264 (2020). Cell https://doi.org/10.1016/j.cell.2021.02.042 (2021). 5a, and information on the structural context and consequences of mutations for antibody recognition and ACE2 binding are shown in Fig. 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. 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. Hodcroft, E. B. et al. A new method could provide detailed information about internal structures, voids, and cracks, based solely on data about exterior conditions. 5b). Tracking SARS-CoV-2 variants - WHO PubMed Another RBM amino acid change, Y453F associated with increased ACE2-binding affinity19 received considerable attention following its identification in sequences associated with infections in humans and mink; most notably one lineage identified in Denmark and initially named cluster 5 (now B.1.1.298)20. 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. . reviewed and/or edited the manuscript before submission. 5b). Cell Mol. 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. 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. Dis. Virus surface glycoproteins embedded in the membrane often have a role in interactions with host cells, including receptor binding, and are also commonly targeted by host antibodies. The deletion or insertion of residues has the potential to alter epitope conformation, diminishing antibody binding. 372, n597 (2021). Given the immunodominance of the RBD, this could explain the modest reductions in neutralizing activity of convalescent sera against authentic B.1.1.7 or pseudoviruses carrying the B.1.1.7 spike mutations64,65. NTD antibody escape mutations were not observed for the other samples of plasma investigated, and furthermore, the 148151 mutants exhibited only marginal reductions in sensitivity to the plasma tested, indicating individual immune responses may be differentially affected by mutations of RBD and NTD epitopes40. 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. Nature 592, 616622 (2021). 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. 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. Spike amino acid residues are coloured according to the frequency of amino acid substitutions or deletions. The COVID-19 Genomics UK (COG-UK) Consortium is supported by funding from the UK Medical Research Council (MRC), part of UK Research and Innovation, the UK National Institute of Health Research and Genome Research Limited, operating as the Wellcome Sanger Institute. Hou, Y. J. et al. Even as SARS-CoV-2 mutates, some human antibodies fight back Greaney, A. J. et al. Viral epitope profiling of COVID-19 patients reveals cross-reactivity and correlates of severity. Potent neutralizing antibodies against multiple epitopes on SARS-CoV-2 spike. Of all RBD residues for which substitutions affected recognition by convalescent sera, DMS identified E484 as being of principal importance, with amino acid changes to K, Q or P reducing neutralization titres by more than an order of magnitude39. W.T.H., A.M.C., R.K.G., E.C.T., R.R., S.J.P. The process by which a virus can cloak underlying protein, impeding antibody binding. 6, 17221734 (2020). & Robertson, D. L. No evidence for distinct types in the evolution of SARS-CoV-2. Several studies have probed the antigenicity of the SARS-CoV-2 spike protein by epitope mapping approaches, including solving the structure of the spike protein in complex with the antigen-binding fragment of particular antibodies13,30,31,32. The co-occurrence of Y144 and E484K is concerning with respect to the polyclonal antibody response as the N3 loop, which Y144 changes, is predicted to be among the most immunogenic regions of the spike protein (Fig. 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. The techniques are based on analyzing whether certain DNA or RNA bases are conserved between species, and comparing their patterns of evolution over time. On average, variant frequency is higher at amino acid positions where mutations are described as affecting antibody recognition than at positions with no described substitutions of antigenic importance (Supplementary Fig. Fonager J. et al. COVID-19 has gone through many mutations. SARS-CoV-2 may spread through contaminated shipping containers. 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. 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.. 2c), and N501Y has been shown experimentally to result in one of the highest increases in ACE2 affinity conferred by a single RBD mutation19. Yurkovetskiy, L. et al. 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). Barnes, C. O. et al. Viruses like SARS-CoV-2 continuously evolve as changes in the genetic code (caused by genetic mutations or viral recombination) occur during replication of the genome. Preprint at bioRxiv https://doi.org/10.1101/2021.02.01.429069 (2021). Mutational escape from the polyclonal antibody response to SARS-CoV-2 infection is largely shaped by a single class of antibodies. Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies. 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). PubMed Central Of the four RDRs, RDR1, RDR2 and RDR4 correspond to NTD loops N2, N3 and N5, whereas RDR3 falls between N4 and N5 in another accessible loop (Fig. The first strain of SARS-CoV-2, the virus that causes COVID-19, was detected in Wuhan, China in December 2019. Using these techniques, the researchers confirmed six protein-coding genes in the SARS-CoV-2 genome in addition to the five that are well established in all coronaviruses. Cell 184, 11711187 e1120 (2021). 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. How COVID-19 variants evade immune response They are defined by multiple convergent mutations that are hypothesized to have arisen either in the context of chronic infections or in previously infected individuals24,25,26,27,28,29. What makes the Omicron variant different from other variants? SARS-CoV-2 RBD in vitro evolution follows contagious mutation spread, yet generates an able infection inhibitor. 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. These areas are represented as yellow patches near the centre of the top-down view of the spike structure in Fig. Deletions in the NTD have been observed repeatedly in the evolution of SARS-CoV-2 and have been described as changing NTD antigenicity30,41,42. Most antibodies elicited against SARS-CoV-2 belong to two main classes. PubMedGoogle Scholar. Viruses generally acquire mutations over time, giving rise to new variants. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. 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. Transmission of SARS-CoV-2 lineage B.1.1.7 in England: insights from linking epidemiological and genetic data. Lancet https://doi.org/10.1016/S0140-6736(21)00628-0 (2021). The role for this new gene, as well as several other SARS-CoV-2 genes, is not known yet. Case study: prolonged infectious SARS-CoV-2 shedding from an asymptomatic immunocompromised individual with cancer. The scissors represent the S1S2 boundary at amino acid position 685.
Gallup Poll Margin Of Error,
Rush Hospital Billing Department,
Most Consecutive Stanley Cup Wins By A Single Player,
Andrew Greeley Accident,
North Texas Professor Fired,
Articles H
