Identification of SARS-CoV-2 spike mutations that attenuate monoclonal and serum antibody neutralization

Liu, Zhuoming; VanBlargan, Laura A.; Bloyet, Louis-Marie; Rothlauf, Paul W.; Chen, Rita E.; Stumpf, Spencer; Zhao, Haiyan; Errico, John M.; Theel, Elitza S.; Liebeskind, Mariel J.; Alford, Brynn; Buchser, William J.; Ellebedy, Ali H.; Fremont, Daved H.; Diamond, Michael S.; Whelan, Sean P. J.

doi:10.1016/j.chom.2021.01.014

Cited by 742 publications

(834 citation statements)

References 35 publications

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“…Though the notorious N501Y mutation was not identified in our samples, five samples contained mutation E484K that is found in lineages from various countries and present in the ‘Brazil’ variant B.1.1.28. E484K is located in the receptor-binding ridge epitope and was shown to provide marked resistance to neutralizing antibodies in multiple studies [8, 11, 12].…”

Section: Resultsmentioning

confidence: 99%

Acquisition of the L452R mutation in the ACE2-binding interface of Spike protein triggers recent massive expansion of SARS-Cov-2 variants

Tchesnokova

Kulakesara

Larson

et al. 2021

Preprint

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The recent rise in mutational variants of SARS-CoV-2, especially with changes in the Spike protein, is of significant concern due to the potential ability for these mutations to increase viral infectivity, virulence and/or ability to escape protective antibodies. Here, we investigated genetic variations in a 414-583 amino acid region of the Spike protein, partially encompassing the ACE2 receptor-binding domain (RBD), across a subset of 570 nasopharyngeal samples isolated between April 2020 and February 2021, from Washington, California, Arizona, Colorado, Minnesota and Illinois. We found that samples isolated since November have an increased number of amino acid mutations in the region, with L452R being the dominant mutation. This mutation is associated with a recently discovered CAL.20C viral variant from clade 20C, lineage B.1.429, that since November-December 2020 is associated with multiple outbreaks and is undergoing massive expansion across California. In some samples, however, we found a distinct L452R-carrying variant of the virus that, upon detailed analysis of the GISAID database genomes, is also circulating primarily in California, but emerged even more recently. The newly identified variant derives from the clade 20A (lineage B.1.232) and is named CAL.20A. We also found that the SARS-CoV-2 strain that caused the only recorded case of infection in an ape - gorillas in the San Diego Zoo, reported in January 2021 - is CAL.20A. In contrast to CAL.20C that carries two additional to L452R mutations in the Spike protein, L452R is the only mutation found in CAL.20A. According to the phylogenetic analysis, however, emergence of CAL.20C was also specifically triggered by acquisition of the L452R mutation. Further analysis of GISAID-deposited genomes revealed that several independent L452R-carrying lineages have recently emerged across the globe, with over 90% of the isolates reported between December 2020 -February 2021. Taken together, these results indicate that the L452R mutation alone is of significant adaptive value to SARS-CoV-2 and, apparently, the positive selection for this mutation became particularly strong only recently, possibly reflecting viral adaptation to the containment measures or increasing population immunity. While the functional impact of L452R has not yet been extensively evaluated, leucine-452 is positioned in the receptor-binding motif of RBD, in the interface of direct contact with the ACE2 receptor. Its replacement with arginine is predicted to result in both a much stronger binding to the receptor and escape from neutralizing antibodies. If true, this in turn might lead to significantly increased infectivity of the L452R variants, warranting their close surveillance and in-depth functional studies.

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Section: Resultsmentioning

confidence: 99%

Acquisition of the L452R mutation in the ACE2-binding interface of Spike protein triggers recent massive expansion of SARS-Cov-2 variants

Tchesnokova

Kulakesara

Larson

et al. 2021

Preprint

View full text Add to dashboard Cite

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“…More broadly, our maps suggest that it may be advisable to more systematically consider possible escape mutations when devising antibodies for clinical use against SARS-CoV-2. It is now clear that human coronaviruses undergo antigenic evolution in response to immune pressure [26,27], and we and others have begun to map out the key sites in the RBD that are targeted by human antibody immunity [19,28–30]. The recent rise in frequency of mutations at site E484 suggests that this immunity may be beginning to drive antigenic variation within immunodominant positions in the RBD.…”

Section: Discussionmentioning

confidence: 99%

Complete map of SARS-CoV-2 RBD mutations that escape the monoclonal antibody LY-CoV555 and its cocktail with LY-CoV016

Starr

Greaney

Dingens

et al. 2021

Preprint

121

119

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Monoclonal antibodies and antibody cocktails are a promising therapeutic and prophylaxis for COVID-19. However, ongoing evolution of SARS-CoV-2 can render monoclonal antibodies ineffective. Here we completely map all mutations to the SARS-CoV-2 spike receptor binding domain (RBD) that escape binding by a leading monoclonal antibody, LY-CoV555, and its cocktail combination with LY-CoV016. Individual mutations that escape binding by each antibody are combined in the circulating B.1.351 and P.1 SARS-CoV-2 lineages (E484K escapes LY-CoV555, K417N/T escape LY-CoV016). Additionally, the L452R mutation in the B.1.429 lineage escapes LY-CoV555. Furthermore, we identify single amino acid changes that escape the combined LY-CoV555+LY-CoV016 cocktail. We suggest that future efforts should diversify the epitopes targeted by antibodies and antibody cocktails to make them more resilient to antigenic evolution of SARS-CoV-2.

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“…In areas where SARS-CoV-2 seroprevalence is high due to elevated rates of transmission during primary waves of the pandemic, selection pressures may have favored the emergence of variants that escape neutralizing antibodies. Such circumstances are thought to have contributed to the emergence of lineages B.1.351 and P.1 (501Y.V2 and 501Y.V3), which in addition to Spike N501Y, harbor at least two other non-synonymous substitutions, K417N/T and E484K, which have been found to confer escape from neutralizing antibodies Cele et al, 2021;Liu et al, 2021;Wang et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Emergence in late 2020 of multiple lineages of SARS-CoV-2 Spike protein variants affecting amino acid position 677

Hodcroft

Domman

Snyder³

et al. 2021

Preprint

122

116

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein (S) plays critical roles in host cell entry. Non-synonymous substitutions affecting S are not uncommon and have become fixed in a number of SARS-CoV-2 lineages. A subset of such mutations enable escape from neutralizing antibodies or are thought to enhance transmission through mechanisms such as increased affinity for the cell entry receptor, angiotensin-converting enzyme 2 (ACE2). Independent genomic surveillance programs based in New Mexico and Louisiana contemporaneously detected the rapid rise of numerous clade 20G (lineage B.1.2) infections carrying a Q677P substitution in S. The variant was first detected in the US on October 23, yet between 01 Dec 2020 and 19 Jan 2021 it rose to represent 27.8% and 11.3% of all SARS-CoV-2 genomes sequenced from Louisiana and New Mexico, respectively. Q677P cases have been detected predominantly in the south central and southwest United States; as of 03 Feb 2021, GISAID data show 499 viral sequences of this variant from the USA. Phylogenetic analyses revealed the independent evolution and spread of at least six distinct Q677H sub-lineages, with first collection dates ranging from mid-August to late November 2020. Four 677H clades from clade 20G (B.1.2), 20A (B.1.234), and 20B (B.1.1.220, and B.1.1.222) each contain roughly 100 or fewer sequenced cases, while a distinct pair of clade 20G clusters are represented by 754 and 298 cases, respectively. Although sampling bias and founder effects may have contributed to the rise of S:677 polymorphic variants, the proximity of this position to the polybasic cleavage site at the S1/S2 boundary are consistent with its potential functional relevance during cell entry, suggesting parallel evolution of a trait that may confer an advantage in spread or transmission. Taken together, our findings demonstrate simultaneous convergent evolution, thus providing an impetus to further evaluate S:677 polymorphisms for effects on proteolytic processing, cell tropism, and transmissibility.

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Identification of SARS-CoV-2 spike mutations that attenuate monoclonal and serum antibody neutralization

Cited by 742 publications

References 35 publications

Acquisition of the L452R mutation in the ACE2-binding interface of Spike protein triggers recent massive expansion of SARS-Cov-2 variants

Acquisition of the L452R mutation in the ACE2-binding interface of Spike protein triggers recent massive expansion of SARS-Cov-2 variants

Complete map of SARS-CoV-2 RBD mutations that escape the monoclonal antibody LY-CoV555 and its cocktail with LY-CoV016

Emergence in late 2020 of multiple lineages of SARS-CoV-2 Spike protein variants affecting amino acid position 677

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