A potent neutralizing human antibody reveals the N-terminal domain of the Spike protein of SARS-CoV-2 as a site of vulnerability

Chi, Xiangyang; Yan, Renhong; Zhang, Jun; Zhang, Guanying; Zhang, Yuanyuan; Meng, Hao; Zhang, Zhe; Fan, Pengfei; Ya, Dong; Yang, Yating; Chen, Zhengshan; Guo, Yingying; Zhang, Jinlong; Li, Yaning; Song, Xiaohong; Chen, Yi; Xia, Lu; Fu, Ling; Hou, Lihua; Xu, Junjie; Yu, Changming; Li, Jianmin; Zhou, Qiang; Chen, Wei

doi:10.1101/2020.05.08.083964

Cited by 63 publications

(73 citation statements)

References 33 publications

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“…were over-represented . Other studies have also reported anti-SARS-CoV-2 mAbs derived from these genes (Brouwer et al, 2020;Cao et al, 2020;Chi et al, 2020;Ju et al, 2020;Rogers et al, 2020;Seydoux et al, 2020;Wu et al, 2020c;Zost et al, 2020).…”

Section: A Cryo-em Structure Of a Monoclonal Fab-s Protein Complex Rementioning

confidence: 95%

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

223

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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Section: A Cryo-em Structure Of a Monoclonal Fab-s Protein Complex Rementioning

confidence: 95%

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

223

339

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“…In fact, besides IGHV3-53, the only other IGHV gene that contains an NY motif in CDR H1 and an SGGS motif in CDR H2 is IGHV3-66, which is a closely-related IGHV gene to IGHV3-53 ( 32 ). As compared to IGHV3-53, IGHV3-66 has a lower occurrence frequency in the repertoire of healthy individuals (0.3% to 1.7%) ( 29 ), which may explain why IGHV3-66 is less prevalent than IGHV3-53, but yet is still quite commonly observed ( 19–22, 24, 26 ) in antibodies in SARS-CoV-2 patients (Fig. 1A).…”

Section: Mainmentioning

confidence: 99%

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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“…3). Interestingly, a recent study identi ed a potent neutralizing human antibody that binds to the N-terminal domain of SARS-CoV-2 S 36 . Although this antibody does not bind to the RBD or block its interaction with ACE2, its neutralizing activity was much higher than that of antibodies targeting the RBD 36 .…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, a recent study identi ed a potent neutralizing human antibody that binds to the N-terminal domain of SARS-CoV-2 S 36 . Although this antibody does not bind to the RBD or block its interaction with ACE2, its neutralizing activity was much higher than that of antibodies targeting the RBD 36 . This report highlights the importance of the N-terminal domain of SARS-CoV-2 S during viral infection and may support the important role of AXL during infection of the human pulmonary and bronchial systems.…”

Section: Discussionmentioning

confidence: 99%

AXL Promotes SARS-CoV-2 Infection of Pulmonary and Bronchial Epithelial Cells

Wang

Qiu

Hou

et al. 2020

Preprint

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The current coronavirus disease 2019 (COVID-19) pandemic presents a global public health challenge. The viral pathogen responsible, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), binds to a host receptor ACE2 through its spike (S) glycoprotein, which mediates membrane fusion and virus entry. Although the role of ACE2 as a receptor for SARS-CoV-2 is clear, studies have shown that ACE2 expression across different human tissues is extremely low, especially in pulmonary and bronchial cells. Thus, other host receptors and/or co-receptors that promote the entry of SARS-CoV-2 into cells of the respiratory system might exist. In this study, we have identified tyrosine-protein kinase receptor UFO (AXL), specifically interacts with SARS-CoV-2 S on the host cell membrane. When overexpressed in cells that do not highly express either AXL or ACE2, AXL promotes virus entry as efficiently as ACE2. Strikingly, deleting AXL, but not ACE2, significantly reduces infection of pulmonary cells by the SARS-CoV-2 virus pseudotype. Soluble human recombinant AXL, but not ACE2, blocks SARS-CoV-2 virus pseudotype infection in pulmonary cells. Taken together, our findings suggest AXL may play an important role in promoting SARS-CoV-2 infection of the human respiratory system and is a potential target in future clinical intervention strategies.

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A potent neutralizing human antibody reveals the N-terminal domain of the Spike protein of SARS-CoV-2 as a site of vulnerability

Cited by 63 publications

References 33 publications

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

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

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

AXL Promotes SARS-CoV-2 Infection of Pulmonary and Bronchial Epithelial Cells

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