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:10.1101/2020.05.28.121533

Cited by 224 publications

(369 citation statements)

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“…5A-B), which thus constrains its length. Consistently, among RBD-targeting antibodies currently reported ( 17–28 ), those encoded by IGHV3-53 have a significantly shorter CDR H3 compared to those encoded by other IGHV genes (p-value = 6e-8, Mann-Whitney U test) (Fig. 5C).…”

Section: Mainsupporting

confidence: 83%

“…2A-C). This conclusion was also arrived in a recent study that also reported SARS-CoV-2 RBD-targeting antibodies that are encoded by either IGHV3-53 or IGHV3-66 tend to have a short CDR H3 ( 28 ). In fact, IGHV3-53 and IGHV3-66 antibodies in general have slightly shorter than average CDR H3’s (by around one residue), but do appear to have a few much shorter CDR H3’s (<10 amino acids) than average in the baseline antibody repertoire ( 30 ).…”

Section: Mainsupporting

confidence: 63%

“…Therefore, RBD-targeting antibodies could neutralize SARS-CoV-2 by blocking ACE2 binding. A number of antibodies that target the RBD of SARS-CoV-2 have now been discovered in very recent studies ( 13–28 ). We compiled a list of 294 SARS-CoV-2 RBD-targeting antibodies where information on IGHV gene usage is available ( 17–28 ) (Table S2), and found that IGHV3-53 is the most frequently used IGHV gene among such antibodies (Fig.…”

Section: Mainmentioning

confidence: 99%

“… (A) The distribution of IGHV gene usage is shown for a total of 294 RBD-targeting antibodies ( 17–28 ). (B-F) Crystal structures of (B) CC12.1 in complex with SARS-CoV-2 RBD, (C) CC12.3 with SARS-CoV-2 RBD, (D) human ACE2 with SARS-CoV-2 RBD (PDB 6M0J) ( 12 ), (E) SARS-CoV-2 RBD with CC12.1 and CR3022, and (F) SARS-CoV-2 RBD with CC12.3 and CR3022.…”

Section: Mainmentioning

confidence: 99%

“…(B) Same as panel A, except that CC12.3 (pink) is shown. (C) The lengths of CDR H3 in RBD-targeting antibodies that were previously isolated ( 17–28 ) are analyzed. The distribution of CDR H3 lengths in RBD-targeting IGHV3-53 antibodies and those in non-IGHV3-53-encoded antibodies are compared.…”

Section: Mainmentioning

confidence: 99%

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Structural basis of a public antibody response to SARS-CoV-2

Yuan

Liu

et al. 2020

Preprint

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26Molecular-level understanding of human neutralizing antibody responses to SARS-CoV-27 2 could accelerate vaccine design and facilitate drug discovery. We analyzed 294 28 SARS-CoV-2 antibodies and found that IGHV3-53 is the most frequently used IGHV 29 gene for targeting the receptor binding domain (RBD) of the spike (S) protein. We 30 determined crystal structures of two IGHV3-53 neutralizing antibodies +/-Fab CR3022 31 ranging from 2.33 to 3.11 Å resolution. The germline-encoded residues of IGHV3-53 32 dominate binding to the ACE2 binding site epitope with no overlap with the CR3022 33 epitope. Moreover, IGHV3-53 is used in combination with a very short CDR H3 and 34 different light chains. Overall, IGHV3-53 represents a versatile public VH in neutralizing 35 SARS-CoV-2 antibodies, where their specific germline features and minimal affinity 36 maturation provide important insights for vaccine design and assessing outcomes.37 3 MAIN 38The ongoing COVID-19 pandemic, which is caused by severe acute respiratory 39 syndrome coronavirus 2 (SARS-CoV-2), is far from an end (1). The increasing global 40 health and socioeconomic damage require urgent development of an effective COVID-41 19 vaccine. While multiple vaccine candidates have entered clinical trials (2), the 42 molecular features that contribute to an effective antibody response are not clear. Over 43 the past decade, the concept of a public antibody response (also known as multidonor 44 class antibodies) to specified microbial pathogens has emerged. A public antibody 45 response describes antibodies that have shared genetic elements and modes of 46 recognition, and can be observed in multiple individuals against a given antigen. Such 47 responses to microbial pathogens have been observed against influenza (3), dengue (4), 48 malaria (5), and HIV (6). Identification of public antibody responses and characterization 49 of the molecular interactions with cognate antigen can provide insight into the 50 fundamental understanding of the immune repertoire and its ability to quickly respond to 51 novel microbial pathogens, as well as facilitate rational vaccine design against these 52 pathogens (7, 8). 54The spike (S) protein is the major surface antigen of SARS-CoV-2. The S protein utilizes 55 its receptor-binding domain (RBD) to engage the host receptor ACE2 for viral entry (9-56 12). Therefore, RBD-targeting antibodies could neutralize SARS-CoV-2 by blocking 57 ACE2 binding. A number of antibodies that target the RBD of SARS-CoV-2 have now 58 been discovered in very recent studies (13-28). We compiled a list of 294 SARS-CoV-2 59RBD-targeting antibodies where information on IGHV gene usage is available (17-28) 60 (Table S2), and found that IGHV3-53 is the most frequently used IGHV gene among 61 such antibodies ( Fig. 1A). Of 294 RBD-targeting antibodies, 10% are encoded by 62 IGHV3-53, as compared to only 0.5% to 2.6% in the repertoire of naïve healthy 63 4 individuals (29) with a mean of 1.8% (30). The prevalence of IGHV3-53 in the antibody 64 response in SARS-Co...

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Section: Mainsupporting

confidence: 83%

Section: Mainsupporting

confidence: 63%

Section: Mainmentioning

confidence: 99%

Section: Mainmentioning

confidence: 99%

Section: Mainmentioning

confidence: 99%

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Structural basis of a public antibody response to SARS-CoV-2

Yuan

Liu

et al. 2020

Preprint

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A surrogate cell‐based SARS‐CoV‐2 spike blocking assay

et al. 2021

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To monitor infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and successful vaccination against coronavirus disease 2019 (COVID-19), the kinetics of neutralizing or blocking anti-SARS-CoV-2 antibody titers need to be assessed. Here, we report the development of a quick and inexpensive surrogate SARS-CoV-2 blocking assay (SUBA) using immobilized recombinant human angiotensin-converting enzyme 2 (hACE2) and human cells expressing the native form of surface SARS-CoV-2 spike protein. Spike protein-expressing cells bound to hACE2 in the absence or presence of blocking antibodies were quantified by measuring the optical density of cell-associated crystal violet in a spectrophotometer. The advantages are that SUBA is a fast and inexpensive assay, which does not require biosafety level 2-or 3-approved laboratories. Most importantly, SUBA detects blocking antibodies against the native trimeric cell-bound SARS-CoV-2 spike protein and can be rapidly adjusted to quickly pre-screen already approved therapeutic antibodies or sera from vaccinated individuals for their ACE2 blocking activities against any emerging SARS-CoV-2 variants.

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Monoclonal antibodies capable of binding SARS-CoV-2 spike protein receptor-binding motif specifically prevent GM-CSF induction

Qiang

Zhu

et al. 2021

Journal of Leukocyte Biology

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A severe acute respiratory syndrome (SARS)-like coronavirus 2 (SARS-CoV-2) has recently caused a pandemic COVID-19 disease that infected approximately 94 million and killed more than 2,000,000 people worldwide. Like the SARS-CoV, SARS-CoV-2 also employs a receptor-binding motif (RBM) of its envelope spike protein for binding the host angiotensin-converting enzyme 2 (ACE2) to gain viral entry. Currently, extensive efforts are being made to produce vaccines against a surface fragment of a SARS-CoV-2, such as the spike protein, in order to boost protective antibodies that can inhibit virus-ACE2 interaction to prevent viral entry. It was previously unknown how spike protein-targeting antibodies would affect innate inflammatory responses to SARS-CoV-2 infections. Here we generated a highly purified recombinant protein corresponding to the RBM of SARS-CoV-2, and used it to screen for cross-reactive monoclonal antibodies (mAbs). We found two RBM-binding mAbs that competitively inhibited its interaction with human ACE2, and specifically blocked the RBM-induced GM-CSF secretion in both human peripheral blood mononuclear cells and murine macrophage cultures. Our findings have suggested a possible strategy to prevent SARS-CoV-2-elicited "cytokine storm," and revealed a potentially anti-inflammatory and protective mechanism for SARS-CoV-2 spike-based vaccines.

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

Cited by 224 publications

References 93 publications

Structural basis of a public antibody response to SARS-CoV-2

Structural basis of a public antibody response to SARS-CoV-2

A surrogate cell‐based SARS‐CoV‐2 spike blocking assay

Monoclonal antibodies capable of binding SARS-CoV-2 spike protein receptor-binding motif specifically prevent GM-CSF induction

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