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Structural basis for broad sarbecovirus neutralization by a human monoclonal antibody.

ABSTRACT: The recent emergence of SARS-CoV-2 variants of concern (VOC) and the recurrent spillovers of coronaviruses in the human population highlight the need for broadly neutralizing antibodies that are not affected by the ongoing antigenic drift and that can prevent or treat future zoonotic infections. Here, we describe a human monoclonal antibody (mAb), designated S2X259, recognizing a highly conserved cryptic receptor-binding domain (RBD) epitope and cross-reacting with spikes from all sarbecovirus clades. S2X259 broadly neutralizes spike-mediated entry of SARS-CoV-2 including the B.1.1.7, B.1.351, P.1 and B.1.427/B.1.429 VOC, as well as a wide spectrum of human and zoonotic sarbecoviruses through inhibition of ACE2 binding to the RBD. Furthermore, deep-mutational scanning and in vitro escape selection experiments demonstrate that S2X259 possesses a remarkably high barrier to the emergence of resistance mutants. We show that prophylactic administration of S2X259 protects Syrian hamsters against challenges with the prototypic SARS-CoV-2 and the B.1.351 variant, suggesting this mAb is a promising candidate for the prevention and treatment of emergent VOC and zoonotic infections. Our data unveil a key antigenic site targeted by broadly-neutralizing antibodies and will guide the design of pan-sarbecovirus vaccines.

SUBMITTER: Tortorici MA

PROVIDER: S-EPMC8043460 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Structural basis for broad sarbecovirus neutralization by a human monoclonal antibody.

Tortorici M Alejandra MA Czudnochowski Nadine N Starr Tyler N TN Marzi Roberta R Walls Alexandra C AC Zatta Fabrizia F Bowen John E JE Jaconi Stefano S di Iulio Julia J Wang Zhaoqian Z De Marco Anna A Zepeda Samantha K SK Pinto Dora D Liu Zhuoming Z Beltramello Martina M Bartha Istvan I Housley Michael P MP Lempp Florian A FA Rosen Laura E LE Dellota Exequiel E Kaiser Hannah H Montiel-Ruiz Martin M Zhou Jiayi J Addetia Amin A Guarino Barbara B Culap Katja K Sprugasci Nicole N Saliba Christian C Vetti Eneida E Giacchetto-Sasselli Isabella I Silacci Fregni Chiara C Abdelnabi Rana R Caroline Foo Shi-Yan SY Havenar-Daughton Colin C Schmid Michael A MA Benigni Fabio F Cameroni Elisabetta E Neyts Johan J Telenti Amalio A Snell Gyorgy G Virgin Herbert W HW Whelan Sean P J SPJ Bloom Jesse D JD Corti Davide D Veesler David D Pizzuto Matteo Samuele MS

bioRxiv : the preprint server for biology 20210408

The recent emergence of SARS-CoV-2 variants of concern (VOC) and the recurrent spillovers of coronaviruses in the human population highlight the need for broadly neutralizing antibodies that are not affected by the ongoing antigenic drift and that can prevent or treat future zoonotic infections. Here, we describe a human monoclonal antibody (mAb), designated S2X259, recognizing a highly conserved cryptic receptor-binding domain (RBD) epitope and cross-reacting with spikes from all sarbecovirus c ...[more]

PMID: 33851169

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Project description:UnlabelledSince it was first recognized in 2004 that human parechoviruses (HPeV) are a significant cause of central nervous system and neonatal sepsis, their clinical importance, primarily in children, has started to emerge. Intravenous immunoglobulin treatment is the only treatment available in such life-threatening cases and has given moderate success. Direct inhibition of parechovirus infection using monoclonal antibodies is a potential treatment. We have developed two neutralizing monoclonal antibodies against HPeV1 and HPeV2, namely, AM18 and AM28, which also cross-neutralize other viruses. Here, we present the mapping of their epitopes using peptide scanning, surface plasmon resonance, fluorescence-based thermal shift assays, electron cryomicroscopy, and image reconstruction. We determined by peptide scanning and surface plasmon resonance that AM18 recognizes a linear epitope motif including the arginine-glycine-aspartic acid on the C terminus of capsid protein VP1. This epitope is normally used by the virus to attach to host cell surface integrins during entry and is found in 3 other viruses that AM18 neutralizes. Therefore, AM18 is likely to cause virus neutralization by aggregation and by blocking integrin binding to the capsid. Further, we show by electron cryomicroscopy, three-dimensional reconstruction, and pseudoatomic model fitting that ordered RNA interacts with HPeV1 VP1 and VP3. AM28 recognizes quaternary epitopes on the capsid composed of VP0 and VP3 loops from neighboring pentamers, thereby increasing the RNA accessibility temperature for the virus-AM28 complex compared to the virus alone. Thus, inhibition of RNA uncoating probably contributes to neutralization by AM28.ImportanceHuman parechoviruses can cause mild infections to severe diseases in young children, such as neonatal sepsis, encephalitis, and cardiomyopathy. Intravenous immunoglobulin treatment is the only treatment available in such life-threatening cases. In order to develop more targeted treatment, we have searched for human monoclonal antibodies that would neutralize human parechoviruses 1 and 2, associated with mild infections such as gastroenteritis and severe infections of the central nervous system, and thus allow safe treatment. In the current study, we show how two such promising antibodies interact with the virus, modeling the atomic interactions between the virus and the antibody to propose how neutralization occurs. Both antibodies can cause aggregation; in addition, one antibody interferes with the virus recognizing its target cell, while the other, recognizing only the whole virus, inhibits the genome uncoating and replication in the cell.

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Structural basis for broad sarbecovirus neutralization by a human monoclonal antibody.

Publications

Structural basis for broad sarbecovirus neutralization by a human monoclonal antibody.

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