Structures of Human Antibodies Bound to SARS-CoV-2 Spike Reveal Common Epitopes and Recurrent Features of Antibodies

Barnes, Christopher O.; West, Anthony P.; Huey-Tubman, Kathryn E.; Hoffmann, Magnus A.G.; Sharaf, Naima G.; Hoffman, Pauline R.; Koranda, Nicholas; Gristick, Harry B.; Gaebler, Christian; Muecksch, Frauke; Lorenzi, Julio C. C.; Finkin, Shlomo; Hägglöf, Thomas; Hurley, Arlene; Millard, Katrina G.; Weisblum, Yiska; Schmidt, Fabian; Hatziioannou, Théodora; Bieniasz, Paul D.; Caskey, Marina; Robbiani, Davide F.; Nussenzweig, Michel C.; Björkman, Pamela J.

doi:10.1016/j.cell.2020.06.025

Cited by 762 publications

(819 citation statements)

References 102 publications

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“…Overall, our findings support the importance of bivalent binding for SARS-CoV-2 neutralizing antibodies, and especially for cross-neutralization of SARS-CoV. Such a contribution of bivalent IgG (avidity) to SARS-CoV-2 neutralization has also been suggested in a recent study that compared binding of polyclonal IgGs and Fabs [24].…”

Section: Mainsupporting

confidence: 87%

Cross-neutralization of a SARS-CoV-2 antibody to a functionally conserved site is mediated by avidity

Liu

Yuan

et al. 2020

Preprint

112

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Most antibodies isolated from COVID-19 patients are specific to SARS-CoV-2. COVA1-16 is a relatively rare antibody that also cross-neutralizes SARS-CoV. Here we determined a crystal structure of COVA1-16 Fab with the SARS-CoV-2 RBD, and a negative-stain EM reconstruction with the spike glycoprotein trimer, to elucidate the structural basis of its cross-reactivity. COVA1-16 binds a highly conserved epitope on the SARS-CoV-2 RBD, mainly through a long CDR H3, and competes with ACE2 binding due to steric hindrance rather than epitope overlap. COVA1-16 binds to a flexible up conformation of the RBD on the spike and relies on antibody avidity for neutralization. These findings, along with structural and functional rationale for the epitope conservation, provide a blueprint for development of more universal SARS-like coronavirus vaccines and therapies.

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Section: Mainsupporting

confidence: 87%

Cross-neutralization of a SARS-CoV-2 antibody to a functionally conserved site is mediated by avidity

Liu

Yuan

et al. 2020

Preprint

112

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“…There is an urgent need for broadly effective therapeutics to treat SARS-CoV-2 infections during the ongoing COVID-19 pandemic (1, 2). Antibodies isolated from convalescent patient sera and recombinant antibodies cloned from the B-cells of recovered patients have been effective in past and recent pandemics, and much of the ongoing drug development effort is based on these approaches (3)(4)(5)(6)(7)(8). However, strategies for antibody development necessarily follow widespread viral spread and infection, which costs precious time in a rapidly developing pandemic.…”

mentioning

confidence: 99%

“…Protein engineering approaches to identify binders to viral entry proteins offer a rapid alternative, without the prerequisite for an infected population. In the first step of a SARS-CoV-1 or CoV-2 infection, the receptor binding domain (RBD) of the trimeric spike protein on the surface of the virus binds to the membrane-bound receptor angiotensin-converting enzyme II (ACE2) to enter human cells (3,4,8). Most neutralizing antibodies to SARS-CoV-1 and CoV-2 block viral entry by binding to the ACE2 binding site on the RBD.…”

mentioning

confidence: 99%

Engineered ACE2 receptor traps potently neutralize SARS-CoV-2

Glasgow

Limonta

et al. 2020

Preprint

145

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An essential mechanism for SARS-CoV-1 and -2 infection begins with the viral spike protein binding to the human receptor protein angiotensin-converting enzyme II (ACE2). Here we describe a stepwise engineering approach to generate a set of affinity optimized, enzymatically inactivated ACE2 variants that potently block SARS-CoV-2 infection of cells. These optimized receptor traps tightly bind the receptor binding domain (RBD) of the viral spike protein and prevent entry into host cells. We first computationally designed the ACE2-RBD interface using a two-stage flexible protein backbone design process that improved affinity for the RBD by up to 12-fold. These designed receptor variants were affinity matured an additional 14-fold by random mutagenesis and selection using yeast surface display. The highest affinity variant contained seven amino acid changes and bound to the RBD 170-fold more tightly than wild-type ACE2. With the addition of the natural ACE2 collectrin domain and fusion to a human Fc domain for increased stabilization and avidity, the most optimal ACE2 receptor traps neutralized SARS-CoV-2 pseudotyped lentivirus and authentic SARS-CoV-2 virus with half-maximal inhibitory concentrations (IC50) in the tens of ng/ml range. Engineered ACE2 receptor traps offer a promising route to fighting infections by SARS-CoV-2 and other ACE2-utilizing coronaviruses, with the key advantage that viral resistance would also likely impair viral entry. Moreover, such traps can be pre-designed for viruses with known entry receptors for faster therapeutic response without the need for neutralizing antibodies isolated or generated from convalescent patients.

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“…The PD-graph is consistent with the patterns of insertions and deletions we previously noted within the E-protein that mark the flaviviruses FV (4) according to species and disease specificity. With regard to the latter, hemorrhagic Yellow Fever (YF) virus (node 26) lies near the 4 DENV serotypes (nodes [19][20][21][22], which can cause hemorrhagic disease with fatal consequences in children.…”

Section: The Pd-graphs Correlates With Vector and Host Competencementioning

confidence: 99%

“…and epitopes recognized by neutralizing antibodies isolated from survivors(21)(22)(23) to the SARS-CoV-1 virus that caused many deaths in a brief epidemic that ended in Asia in 2003(24). It is more distantly related to the lethal Middle East respiratory syndrome coronavirus (MERS) (25).…”

mentioning

confidence: 99%

D-graph clusters flaviviruses and β-coronaviruses according to their hosts, disease type and human cell receptors

Braun¹,

Schein

Braun

2020

Preprint

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Motivation: There is a need for rapid and easy to use, alignment free methods to cluster large groups of protein sequence data. Commonly used phylogenetic trees based on alignments can be used to visualize only a limited number of protein sequences. DGraph, introduced here, is a dynamic programming application developed to generate 2D-maps based on similarity scores for sequences. The program automatically calculates and graphically displays property distance (PD) scores based on physico-chemical property (PCP) similarities from an unaligned list of FASTA files. Such PD-graphs show the interrelatedness of the sequences, whereby clusters can reveal deeper connectivities. Results: PD-Graphs generated for flavivirus (FV), enterovirus (EV), and coronavirus (CoV) sequences from complete polyproteins or individual proteins are consistent with biological data on vector types, hosts, cellular receptors and disease phenotypes. PD-graphs separate the tick- from the mosquito-borne FV, clusters viruses that infect bats, camels, seabirds and humans separately and the clusters correlate with disease phenotype. The PD method segregates the β-CoV spike proteins of SARS, SARS-CoV-2, and MERS sequences from other human pathogenic CoV, with clustering consistent with cellular receptor usage. The graphs also suggest evolutionary relationships that may be difficult to determine with conventional bootstrapping methods that require postulating an ancestral sequence.

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Structures of Human Antibodies Bound to SARS-CoV-2 Spike Reveal Common Epitopes and Recurrent Features of Antibodies

Cited by 762 publications

References 102 publications

Cross-neutralization of a SARS-CoV-2 antibody to a functionally conserved site is mediated by avidity

Cross-neutralization of a SARS-CoV-2 antibody to a functionally conserved site is mediated by avidity

Engineered ACE2 receptor traps potently neutralize SARS-CoV-2

D-graph clusters flaviviruses and β-coronaviruses according to their hosts, disease type and human cell receptors

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