Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody

Pinto, Dora; Park, Young-Jun; Beltramello, Martina; Walls, Alexandra C.; Tortorici, M. Alejandra; Bianchi, Siro; Jaconi, Stefano; Culap, Katja; Zatta, Fabrizia; Marco, Anna De; Peter, Alessia; Guarino, Barbara; Spreafico, Roberto; Cameroni, Elisabetta; Case, James Brett; Chen, Rita E.; Havenar-Daughton, Colin; Snell, Gyorgy; Telenti, Amalio; Virgin, Herbert W.; Lanzavecchia, Antonio; Diamond, Michael S.; Fink, Katja; Veesler, David; Corti, Davide

doi:10.1038/s41586-020-2349-y

Cited by 1,891 publications

(2,411 citation statements)

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“…While all cryo-EM structural studies to date on SARS-CoV-2 Spike have identified only the "closed" or "one-up" RBD conformation (Cao et al, 2020;Pinto et al, 2020;Walls et al, 2020;Wrapp, Wang, et al, 2020), our split reporter assay identified a population of Spike in "two-up" or "three-up" conformation. The relative population of these RBD conformers and whether they exist in an ACE2-unbound state or emerge only upon ACE2 binding remains unknown ( Figure 6F).…”

Section: Discussionmentioning

confidence: 63%

Trimeric SARS-CoV-2 Spike interacts with dimeric ACE2 with limited intra-Spike avidity

Lui

Zhou

Lim

et al. 2020

Preprint

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A serious public health crisis is currently unfolding due to the SARS-CoV-2 pandemic. SARS-CoV-2 viral entry depends on an interaction between the receptor binding domain of the trimeric viral Spike protein (Spike-RBD) and the dimeric human angiotensin converting enzyme 2 (ACE2) receptor. While it is clear that strategies to block the Spike/ACE2 interaction are promising as anti-SARS-CoV-2 therapeutics, our current understanding is insufficient for the rational design of maximally effective therapeutic molecules. Here, we investigated the mechanism of Spike/ACE2 interaction by characterizing the binding affinity and kinetics of different multimeric forms of recombinant ACE2 and Spike-RBD domain. We also engineered ACE2 into a split Nanoluciferase-based reporter system to probe the conformational landscape of Spike-RBDs in the context of the Spike trimer. Interestingly, a dimeric form of ACE2, but not monomeric ACE2, binds with high affinity to Spike and blocks viral entry in pseudotyped virus and live SARS-CoV-2 virus neutralization assays. We show that dimeric ACE2 interacts with an RBD on Spike with limited intra-Spike avidity, which nonetheless contributes to the affinity of this interaction.Additionally, we demonstrate that a proportion of Spike can simultaneously interact with multiple ACE2 dimers, indicating that more than one RBD domain in a Spike trimer can adopt an ACE2accessible "up" conformation. Our findings have significant implications on the design strategies of therapeutic molecules that block the Spike/ACE2 interaction. The constructs we describe are freely available to the research community as molecular tools to further our understanding of SARS-CoV-2 biology. Introduction:In late 2019, a novel, pathogenic coronavirus (SARS-CoV-2) entered the human population and has since spread throughout the world. The number of people suffering from the associated disease (COVID-19) continues to rise, increasing the need for effective therapeutic interventions. SARS-CoV-1 and SARS-CoV-2 Spike proteins are highly homologous (~76% sequence identity). Similar to SARS-CoV-1, the interaction between the SARS-CoV-2 Spike protein and the angiotensinconverting enzyme 2 (ACE2) on human cells is critical for viral entry into host cells (Gralinski & Menachery, 2020;Tai et al., 2020;Wu et al., 2020). SARS-CoV-2 Spike is an obligate trimer, while ACE2 presents as a dimer on the cell surface (Chen, Liu, & Guo, 2020). Several highresolution structures of SARS-CoV-2 Spike receptor binding domain (Spike-RBD) bound to ACE2 have been published (Lan et al., 2020;Yan et al., 2020). However, as of this writing, structures of SARS-CoV-2 Spike trimer in complex with either the dimeric or monomeric form of ACE2 have not been reported, resulting in an incomplete understanding of the nature of this interaction.Structural studies of trimeric SARS-CoV-2 and SARS-CoV-1 Spike protein demonstrate that each of the Spike-RBDs, as in other coronaviruses, can undergo hinge-like movements to transition between "up" or "down" conformations. The...

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Section: Discussionmentioning

confidence: 63%

Trimeric SARS-CoV-2 Spike interacts with dimeric ACE2 with limited intra-Spike avidity

Lui

Zhou

Lim

et al. 2020

Preprint

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“…suggesting that the majority of the IgG responses from these plasmas were focused on the RBD, often a target of neutralizing antibodies in coronavirus infections (Hwang et al, 2006;Pinto et al, 2020;Prabakaran et al, 2006;Reguera et al, 2012;Rockx et al, 2008;Walls et al, 2020;Walls et al, 2019;Widjaja et al, 2019;Wrapp et al, 2020). The only appreciable reactivity with SARS-CoV and MERS-CoV RBDs was exhibited by COV21 IgG, which bound to SARS-CoV RBD ( Figure 3B).…”

Section: Convalescent Plasma Igg and Fab Binding Properties Demonstramentioning

confidence: 95%

“…Coronavirus S proteins contain three copies of an S1 subunit comprising the S1 A through S1 D domains, which mediates attachment to target cells, and three copies of an S2 subunit, which contains the fusion peptide and functions in membrane fusion ( Figure 1A). Neutralizing antibody responses against SARS-CoV-2, SARS-CoV, and MERS-CoV S proteins often target the receptor-binding domain (RBD; also called the S1 B domain) (Hwang et al, 2006;Pinto et al, 2020;Prabakaran et al, 2006;Reguera et al, 2012;Rockx et al, 2008;Walls et al, 2020;Walls et al, 2019;Widjaja et al, 2019;Wrapp and McLellan, 2019;Wrapp et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Structures of human antibodies bound to SARS-CoV-2 spike reveal common epitopes and recurrent features of antibodies

Barnes

West

Huey-Tubman

et al. 2020

Preprint

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339

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Neutralizing antibody responses to coronaviruses focus on the trimeric spike, with most against the receptor-binding domain (RBD). Here we characterized polyclonal IgGs and Fabs from COVID-19 convalescent individuals for recognition of coronavirus spikes. Plasma IgGs differed in their degree of focus on RBD epitopes, recognition of SARS-CoV, MERS-CoV, and mild coronaviruses, and how avidity effects contributed to increased binding/neutralization of IgGs over Fabs. Electron microscopy reconstructions of polyclonal plasma Fab-spike complexes showed recognition of both S1 A and RBD epitopes. A 3.4Å cryo-EM structure of a neutralizing monoclonal Fab-S complex revealed an epitope that blocks ACE2 receptor-binding on "up" RBDs. Modeling suggested that IgGs targeting these sites have different potentials for interspike crosslinking on viruses and would not be greatly affected by identified SARS-CoV-2 spike mutations. These studies structurally define a recurrent anti-SARS-CoV-2 antibody class derived from VH3-53/VH3-66 and similarity to a SARS-CoV VH3-30 antibody, providing criteria for evaluating vaccine-elicited antibodies.

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“…We tentatively assign the PAMF-65 patient to re-infection based on the high IgG against SARS-CoV-2 S1 at 6 days post symptom onset, low positive IgM, and unusually high IgG avidity. It was possible that the patient was previously exposed to a closely related infection including SARS-CoV-1 with antibodies cross-react with SARS-CoV-2 45 . This case was intriguing and underscored the usefulness and importance of antibody avidity testing for COVID-19.…”

mentioning

confidence: 99%

High-Accuracy Multiplexed SARS-CoV-2 Antibody Assay with Avidity and Saliva Capability on a Nano-Plasmonic Platform

Liu¹,

Hsiung²,

Zhao³

et al. 2020

Preprint

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The outbreak and rapid spread of SARS-CoV-2 virus has led to a dire global pandemic with millions of people infected and ~ 400,000 deaths thus far. Highly accurate detection of antibodies for COVID-19 is an indispensable part of the effort to combat the pandemic 1,2 . Here we developed two-plex antibody detection against SARS-CoV-2 spike proteins 3 (the S1 subunit and receptor binding domain RBD) in human serum and saliva on a near-infrared nanoplasmonic gold (pGOLD) platform 4-8 . By testing nearly 600 serum samples, pGOLD COVID-19 assay achieved ~ 99.78 % specificity for detecting both IgG and IgM with 100 % sensitivity in sera collected > 14 days post disease symptom onset, with zero cross-reactivity to other diseases. Two-plex correlation analysis revealed higher binding of serum IgM to RBD than to S1. IgG antibody avidity toward multiple antigens were measured, shedding light on antibody maturation in COVID-19 patients and affording a powerful tool for differentiating recent from remote infections and identifying re-infection by SARS-CoV-2. Just as important, due to high analytical sensitivity, the pGOLD COVID-19 assay detected minute amounts of antibodies in human saliva, offering the first non-invasive detection of SARS-CoV-2 antibodies.

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Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody

Cited by 1,891 publications

References 78 publications

Trimeric SARS-CoV-2 Spike interacts with dimeric ACE2 with limited intra-Spike avidity

Trimeric SARS-CoV-2 Spike interacts with dimeric ACE2 with limited intra-Spike avidity

Structures of human antibodies bound to SARS-CoV-2 spike reveal common epitopes and recurrent features of antibodies

High-Accuracy Multiplexed SARS-CoV-2 Antibody Assay with Avidity and Saliva Capability on a Nano-Plasmonic Platform

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