A human neutralizing antibody targets the receptor-binding site of SARS-CoV-2

Shi, Rui; Shan, Chao; Duan, Xiaomin; Chen, Zhihai; Li, Peipei; Song, Jin‐Wen; Song, Tao; Bi, Xiaoshan; Han, Chao; Wu, Lingxia; Gao, Ge; Hu, Xue; Zhang, Yanan; Tong, Zhou; Huang, Weijin; Liu, William Jun; Wu, Guizhen; Zhang, Bo; Wang, Lan; Qi, Jianxun; Feng, Hui; Wang, Fu Sheng; Wang, Qihui; Gao, George F.; Yuan, Zhiming; Yan, Jinghua

doi:10.1038/s41586-020-2381-y

Cited by 1,344 publications

(1,516 citation statements)

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“…They could be used therapeutically, perhaps to prevent individuals from having to undergo intensive therapy, 13/34 but also prophylactically, to protect health workers or risk groups that do not respond to vaccination. Before clinical application, the risk of antibody-dependent enhancement of disease (ADE) has to be considered for COVID- 19. In contrast to antibodies against Ebola where ADCC is important for protection 22 , antibodies directed against the spike protein of SARS-CoV-2 may lead to ADE [56][57][58] .…”

Section: Discussionmentioning

confidence: 99%

“…Monoclonal human antibodies against SARS-CoV were also described to cross-react with SARS-CoV-2, some of them were able to neutralize SARS-CoV-2 15,16 . In other approaches monoclonal antibodies against SARS-CoV-2 were selected by rescreening memory B-cells from a SARS patient 17 , selected from COVID-19 patients by single 19 or using phage display 20,21 . Human recombinant antibodies were successfully used for the treatment of other viral diseases.The antibody mAb114 22 and the three antibody cocktail REGN-EB3 23 showed a good efficiency in clinical trials against Ebola virus 24 .…”

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confidence: 99%

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SARS-CoV-2 neutralizing human recombinant antibodies selected from pre-pandemic healthy donors binding at RBD-ACE2 interface

Bertoglio

Meier

Langreder

et al. 2020

Preprint

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COVID-19 is a severe acute respiratory disease caused by SARS-CoV-2, a novel betacoronavirus discovered in December 2019 and closely related to the SARS coronavirus (CoV). Both viruses use the human ACE2 receptor for cell entry, recognizing it with the Receptor Binding Domain (RBD) of the S1 subunit of the viral spike (S) protein.The S2 domain mediates viral fusion with the host cell membrane. Experience with SARS and MERS coronavirus has shown that potent monoclonal neutralizing antibodies against the RBD can inhibit the interaction with the virus cellular receptor (ACE2 for SARS) and block the virus cell entry. Assuming that a similar strategy would be successful against SARS-CoV-2, we used phage display to select from the human naïve universal antibody gene libraries HAL9/10 anti SARS2 spike antibodies capable of inhibiting interaction with ACE2. 309 unique fully human antibodies against S1 were identified. 17 showed more than 75% inhibition of spike binding to cells expressing ACE2, assessed by flow cytometry and several antibodies showed even an 50% inhibition at a molar ratio of the antibody to spike protein or RBD of 1:1. Furthermore, these antibodies neutralized active SARS-Cov-2 virus infection of VeroE6 cells. All 17 were all able to bind the isolated RBD, four of them with sub-nanomolar EC50. Epitope analysis of the antibodies revealed that six bind at the RBD-ACE2 interface and two on the opposite side of the domain. Universal libraries from healthy donors offer the advantage that antibodies can be generated quickly and independent from the availability of material from recovered patients in a pandemic situation. 4/34 Main textIn 2015 Menachery et al. wrote: "Our work suggests a potential risk of SARS-CoV reemergence from viruses currently circulating in bat populations." 1 . Four years later, a novel coronavirus causing a severe pneumonia was discovered and later named SARS-CoV-2. The outbreak started on a sea food market in Wuhan, Hubei province (China) at the end of 2019. The disease was named COVID-19 (coronavirus disease 2019) by the World Health Organization (WHO). Sequencing showed high identity to bat corona viruses (CoV, in particular RaTG13), beta-CoV virus causing human diseases like SARS and MERS and, to a lesser extent, the seasonal CoV hCoV-OC43 and HCov-HKU1 2,3 . The spike (S) protein of SARS-CoV-2, as well as SARS-CoV, binds to the human zinc peptidase angiotensin-converting enzyme 2 (ACE2) which is expressed on lung cells, heart, kidney and intestine cells and acts as receptor for virus entry. S protein consists of the N-terminal S1 subunit, which includes the receptor binding domain (RBD), and the Cterminal S2 subunit which is anchored to the viral membrane and is required for trimerization and fusion of the virus and host membrane 4-6 . The membrane bound host protease TMPRSS2 is responsible for S protein priming by cleavage of specific sites between S1 and S2. In addition to proteolytic activation of the S2' site, conformational changes and viral entry 7-10 .Antibodies against the...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

SARS-CoV-2 neutralizing human recombinant antibodies selected from pre-pandemic healthy donors binding at RBD-ACE2 interface

Bertoglio

Meier

Langreder

et al. 2020

Preprint

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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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“…Over the course of just a few months, Coronavirus Disease 2019 (COVID- 19) developed into a global pandemic, causing over 370,000 deaths by beginning of June 2020 1 . Etiological investigation and gene sequencing identified a novel RNA coronavirus, provisionally named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 2, 3 .…”

Section: Introductionmentioning

confidence: 99%

Ultra-sensitive nanozyme-based chemiluminescence paper test for rapid diagnosis of SARS-CoV-2 infection

Liú

Han

et al. 2020

Preprint

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The recently emerged coronavirus disease COVID-19 has now evolved into a global pandemic. Early detection is crucial for its effective control. Nucleic acid testing for viral pathogen and serological testing for host antibodies are playing important roles in current COVID-19 diagnosis. However, while nucleic acid testing is complicated, facility-restricted and time-consuming, antibody testing may result in high rates of false-negative diagnoses, especially during the early stages of viral infection. Thus, a more rapid and reliable test for both early COVID-19 diagnosis and whole-population screening is urgently needed. Here, we developed a novel nanozyme-based chemiluminescence paper assay for rapid and high-sensitive testing of SARS-CoV-2 spike antigen. Our paper test uses a newly established peroxidase-mimic Co-Fe@hemin nanozyme instead of natural HRP that catalytically amplifies the chemiluminescent signal, allowing for target concentrations to be as low as 0.1 ng/ml. Furthermore, our nanozyme-based chemiluminescence test exhibits a linear range that is 32-fold wider compared to ELISA tests. Importantly, testing is completed in less than 16 min, compared to 1-2 h required for ELISA or nucleic acid tests. Critically, signal detection is feasible using a smartphone camera. Ingredients for our test are simple and readily available, rendering overall cost considerably lower than those used in current diagnoses. In conclusion, our novel test provides a high-sensitive, point-of-care testing (POCT) approach for SARS-CoV-2 antigen detection, which should greatly increase current early screening capacities for suspected infections, and considerably lower demand for national healthcare resources.

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A human neutralizing antibody targets the receptor-binding site of SARS-CoV-2

Cited by 1,344 publications

References 32 publications

SARS-CoV-2 neutralizing human recombinant antibodies selected from pre-pandemic healthy donors binding at RBD-ACE2 interface

SARS-CoV-2 neutralizing human recombinant antibodies selected from pre-pandemic healthy donors binding at RBD-ACE2 interface

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

Ultra-sensitive nanozyme-based chemiluminescence paper test for rapid diagnosis of SARS-CoV-2 infection

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