Dataset Information

SARS-CoV-2 B.1.617 Mutations L452R and E484Q Are Not Synergistic for Antibody Evasion.

ABSTRACT: The SARS-CoV-2 B.1.617 variant emerged in the Indian state of Maharashtra in late 2020. There have been fears that 2 key mutations seen in the receptor-binding domain, L452R and E484Q, would have additive effects on evasion of neutralizing antibodies. We report that spike bearing L452R and E484Q confers modestly reduced sensitivity to BNT162b2 mRNA vaccine-elicited antibodies following either first or second dose. The effect is similar in magnitude to the loss of sensitivity conferred by L452R or E484Q alone. These data demonstrate reduced sensitivity to vaccine-elicited neutralizing antibodies by L452R and E484Q but lack of synergistic loss of sensitivity.

SUBMITTER: Ferreira IATM

PROVIDER: S-EPMC8420622 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Publications

SARS-CoV-2 B.1.617 Mutations L452R and E484Q Are Not Synergistic for Antibody Evasion.

Ferreira Isabella A T M IATM Kemp Steven A SA Datir Rawlings R Saito Akatsuki A Meng Bo B Rakshit Partha P Takaori-Kondo Akifumi A Kosugi Yusuke Y Uriu Keiya K Kimura Izumi I Shirakawa Kotaro K Abdullahi Adam A Agarwal Anurag A Ozono Seiya S Tokunaga Kenzo K Sato Kei K Gupta Ravindra K RK

The Journal of infectious diseases 20210901 6

The SARS-CoV-2 B.1.617 variant emerged in the Indian state of Maharashtra in late 2020. There have been fears that 2 key mutations seen in the receptor-binding domain, L452R and E484Q, would have additive effects on evasion of neutralizing antibodies. We report that spike bearing L452R and E484Q confers modestly reduced sensitivity to BNT162b2 mRNA vaccine-elicited antibodies following either first or second dose. The effect is similar in magnitude to the loss of sensitivity conferred by L452R o ...[more]

PMID: 34260717

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Project description:The effectiveness of SARS-CoV-2 therapeutic antibodies targeting the spike (S) receptor-binding domain (RBD) has been hampered by the emergence of variants of concern (VOCs), which have acquired mutations to escape neutralizing antibodies (nAbs). These mutations are not evenly distributed on the RBD surface but cluster on several distinct surfaces, suggesting an influence of the targeted epitope on the capacity to neutralize a broad range of VOCs. Here, we identified a potent nAb from convalescent patients targeting the receptor-binding domain of a broad range of SARS-CoV-2 VOCs. Except for the Lambda and BA.2.86 variants, this nAb efficiently inhibited the entry of most tested VOCs, including Omicron subvariants BA.1, BA.2, XBB.1.5, and EG.5.1 and to a limited extent also BA.4/5, BA.4.6, and BQ.1.1. It bound recombinant S protein with picomolar affinity, reduced the viral load in the lung of infected hamsters, and prevented the severe lung pathology typical for SARS-CoV-2 infections. An X-ray structure of the nAb-RBD complex revealed an epitope that does not fall into any of the conventional classes and provided insights into its broad neutralization properties. Our findings highlight a conserved epitope within the SARS-CoV-2 RBD that should be preferably targeted by therapeutic antibodies and inform rational vaccine development.IMPORTANCETherapeutic antibodies are effective in preventing severe disease from SARS-CoV-2 infection and constitute an important option in pandemic preparedness, but mutations within the S protein of virus variants (e.g., a mutation of L452) confer resistance to many of such antibodies. Here, we identify a human antibody targeting the S protein receptor-binding domain (RBD) with an elevated escape barrier and characterize its interaction with the RBD functionally and structurally at the atomic level. A direct comparison with reported antibodies targeting the same epitope illustrates important differences in the interface, providing insights into the breadth of antibody binding. These findings highlight the relevance of an extended neutralization profiling in combination with biochemical and structural characterization of the antibody-RBD interaction for the selection of future therapeutic antibodies, which may accelerate the control of potential future pandemics.

Dataset Information

SARS-CoV-2 B.1.617 Mutations L452R and E484Q Are Not Synergistic for Antibody Evasion.

Publications

SARS-CoV-2 B.1.617 Mutations L452R and E484Q Are Not Synergistic for Antibody Evasion.

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