Omicron escapes the majority of existing SARS-CoV-2 neutralizing antibodies

Nature, Journal Year: 2021, Volume and Issue: 602(7898), P. 657 - 663

Published: Dec. 23, 2021

The SARS-CoV-2 B.1.1.529 (Omicron) variant contains 15 mutations of the receptor-binding domain (RBD). How Omicron evades RBD-targeted neutralizing antibodies requires immediate investigation. Here we use high-throughput yeast display screening1,2 to determine profiles RBD escaping for 247 human anti-RBD and show that can be classified by unsupervised clustering into six epitope groups (A-F)-a grouping is highly concordant with knowledge-based structural classifications3-5. Various single impair different groups. Specifically, in A-D, epitopes which overlap ACE2-binding motif, are largely escaped K417N, G446S, E484A Q493R. Antibodies group E (for example, S309)6 F CR3022)7, often exhibit broad sarbecovirus activity, less affected Omicron, but a subset still G339D, N440K S371L. Furthermore, pseudovirus neutralization showed sustained could also escaped, owing multiple synergetic on their epitopes. In total, over 85% tested were Omicron. With regard neutralizing-antibody-based drugs, potency LY-CoV016, LY-CoV555, REGN10933, REGN10987, AZD1061, AZD8895 BRII-196 was greatly undermined whereas VIR-7831 DXP-604 functioned at reduced efficacy. Together, our data suggest infection would result considerable humoral immune evasion, targeting conserved region will remain most effective. Our results inform development antibody-based drugs vaccines against future variants.

Language: Английский

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BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicron infection

Nature, Journal Year: 2022, Volume and Issue: 608(7923), P. 593 - 602

Published: June 17, 2022

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages BA.2.12.1, BA.4 and BA.5 exhibit higher transmissibility than the BA.2 lineage 1 . The receptor binding immune-evasion capability of these recently emerged variants require immediate investigation. Here, coupled with structural comparisons spike proteins, we show that (BA.4 are hereafter referred collectively to as BA.4/BA.5) similar affinities for angiotensin-converting enzyme (ACE2) receptor. Of note, BA.2.12.1 BA.4/BA.5 display increased evasion neutralizing antibodies compared against plasma from triple-vaccinated individuals or who developed a BA.1 infection after vaccination. To delineate underlying antibody-evasion mechanism, determined escape mutation profiles , epitope distribution 3 Omicron-neutralization efficiency 1,640 directed receptor-binding domain viral protein, including 614 isolated people had recovered infection. vaccination predominantly recalls humoral immune memory ancestral (hereafter wild-type (WT)) SARS-CoV-2 protein. resulting elicited could neutralize both WT enriched on epitopes do not bind ACE2. However, most cross-reactive evaded by mutants L452Q, L452R F486V. can also induce new clones BA.1-specific potently BA.1. Nevertheless, largely owing D405N F486V mutations, react weakly pre-Omicron variants, exhibiting narrow neutralization breadths. therapeutic bebtelovimab 4 cilgavimab 5 effectively BA.4/BA.5, whereas S371F, R408S mutations undermine broadly sarbecovirus-neutralizing antibodies. Together, our results indicate may evolve evade immunity infection, suggesting BA.1-derived vaccine boosters achieve broad-spectrum protection variants.

Language: Английский

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mRNA vaccines for infectious diseases: principles, delivery and clinical translation

Nature Reviews Drug Discovery, Journal Year: 2021, Volume and Issue: 20(11), P. 817 - 838

Published: Aug. 25, 2021

Language: Английский

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Structural basis of SARS-CoV-2 Omicron immune evasion and receptor engagement

Science, Journal Year: 2022, Volume and Issue: 375(6583), P. 864 - 868

Published: Feb. 24, 2022

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern evades antibody-mediated immunity that comes from vaccination or infection with earlier variants due to accumulation numerous spike mutations. To understand the antigenic shift, we determined cryo–electron microscopy and x-ray crystal structures protein receptor-binding domain bound broadly neutralizing sarbecovirus monoclonal antibody (mAb) S309 (the parent mAb sotrovimab) human ACE2 receptor. We provide a blueprint for understanding marked reduction binding other therapeutic mAbs leads dampened activity. Remodeling interactions between likely explains enhanced affinity host receptor relative ancestral virus.

Language: Английский

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Mapping mutations to the SARS-CoV-2 RBD that escape binding by different classes of antibodies

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: July 7, 2021

Monoclonal antibodies targeting a variety of epitopes have been isolated from individuals previously infected with SARS-CoV-2, but the relative contributions these different antibody classes to polyclonal response remains unclear. Here we use yeast-display system map all mutations viral spike receptor-binding domain (RBD) that escape binding by representatives three potently neutralizing anti-RBD high-resolution structures. We compare antibody-escape maps similar for convalescent plasmas, including plasmas whom some were isolated. While plasma are affected across multiple RBD epitopes, plasma-escape most resemble those single class target an epitope on includes site E484. Therefore, although human immune can produce diverse in practice infection is skewed towards already undergoing rapid evolution.

Language: Английский

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Structural and functional characterizations of infectivity and immune evasion of SARS-CoV-2 Omicron

Cell, Journal Year: 2022, Volume and Issue: 185(5), P. 860 - 871.e13

Published: Jan. 25, 2022

The SARS-CoV-2 Omicron variant with increased fitness is spreading rapidly worldwide. Analysis of cryo-EM structures the spike (S) from reveals amino acid substitutions forging interactions that stably maintain an active conformation for receptor recognition. relatively more compact domain organization confers improved stability and enhances attachment but compromises efficiency viral fusion step. Alterations in local conformation, charge, hydrophobic microenvironments underpin modulation epitopes such they are not recognized by most NTD- RBD-antibodies, facilitating immune escape. Structure S bound human ACE2, together analysis sequence conservation ACE2 binding region 25 sarbecovirus members, as well heatmaps immunogenic sites their corresponding mutational frequencies, sheds light on conserved structurally restrained regions can be used development broad-spectrum vaccines therapeutics.

Language: Английский

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Defining variant-resistant epitopes targeted by SARS-CoV-2 antibodies: A global consortium study

Science, Journal Year: 2021, Volume and Issue: 374(6566), P. 472 - 478

Published: Sept. 23, 2021

Community of antibodies against COVID-19 The severe acute respiratory syndrome coronavirus 2 spike protein is the basis many vaccines and a primary target neutralizing after infection. Coronavirus Immunotherapeutic Consortium (CoVIC), comprising 56 partners across world, has analyzed panel 269 monoclonal (mAbs) and, on competition profiles, sorted 186 mAbs that receptor binding domain into seven communities. Hastie et al . went to structurally analyze representative antibody used pseudovirus neutralization assays study effect mutations function, including combinations found in certain variants concern. These results are important guide both treatment prevention efforts. —VV

Language: Английский

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Membrane fusion and immune evasion by the spike protein of SARS-CoV-2 Delta variant

Science, Journal Year: 2021, Volume and Issue: 374(6573), P. 1353 - 1360

Published: Oct. 26, 2021

Delta’s spike Understanding the molecular mechanisms of increased transmissibility and immune evasion severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants is critical to guiding current future intervention strategies. Zhang et al . determined cryo–electron microscopy structures full-length protein trimers Delta, Kappa, Gamma SARS-CoV-2 studied their function antigenic properties. The Delta fused membranes more efficiently at low levels cellular receptor ACE2, its pseudotyped viruses infected target cells substantially rapidly than all other tested, possibly least partly accounting for heightened transmissibility. Mutations each variant rearranged surface N-terminal domain but only caused local changes in receptor-binding domain, consistent with greater resistance neutralizing antibodies. These findings elucidate events that have led these adapt human communities evade host immunity. —VV

Language: Английский

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Molecular basis of immune evasion by the Delta and Kappa SARS-CoV-2 variants

Science, Journal Year: 2021, Volume and Issue: 374(6575), P. 1621 - 1626

Published: Dec. 23, 2021

How the Delta variant evades defenses In course of COVID-19 epidemic, variants severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to emerge, some which evade immunity or increase transmission. late 2020, and Kappa were detected, became globally dominant by June 2021. McCallum et al . show that vaccine-elicited serum-neutralizing activity is reduced against these variants. Based on biochemistry structural studies, authors mutations in domain binds ACE2 receptor abrogate binding monoclonal antibodies but do not improve binding, suggesting they emerged escape immune recognition. Remodeling N-terminal allows recognition most neutralizing target it. The work could guide development next-generation vaccines antibody therapies. —VV

Language: Английский

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Structures of the Omicron spike trimer with ACE2 and an anti-Omicron antibody

Science, Journal Year: 2022, Volume and Issue: 375(6584), P. 1048 - 1053

Published: Feb. 8, 2022

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant has become the dominant infective strain. We report structures of spike trimer on its own and in complex with angiotensin-converting enzyme (ACE2) or an anti-Omicron antibody. Most mutations are located surface protein change binding epitopes to many current antibodies. In ACE2-binding site, compensating strengthen receptor domain (RBD) ACE2. Both RBD apo form thermodynamically unstable. An unusual RBD-RBD interaction ACE2-spike supports open conformation further reinforces ACE2 trimer. A broad-spectrum therapeutic antibody, JMB2002, which completed a phase 1 clinical trial, maintains neutralizing activity against Omicron. JMB2002 binds differently from other characterized antibodies inhibits binding.

Language: Английский

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