Rapid isolation of potent SARS-CoV-2 neutralizing antibodies and protection in a small animal model

Rogers, Thomas F.; Zhao, Fangzhu; Huang, Deli; Beutler, Nathan; Burns, Alison; He, Wanting; Limbo, Oliver; Smith, Chloe N.; Song, Ge; Woehl, Jordan L.; Yang, Linlin; Abbott, Robert G.; Callaghan, Sean; Garcia, Elijah; Hurtado, Jonathan; Parren, Mara; Peng, Linghang; Ricketts, James; Ricciardi, Michael J.; Rawlings, Stephen A.; Smith, Davey M; Nemazee, David; Teijaro, John R.; Voss, James E.; Andrabi, Raiees; Briney, Bryan; Landais, Elise; Sok, Devin; Jardine, Joseph G.; Burton, Dennis R.

doi:10.1101/2020.05.11.088674

Cited by 88 publications

(171 citation statements)

References 15 publications

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“…Of 294 RBD-targeting antibodies, 10% are encoded by IGHV3-53, as compared to only 0.5% to 2.6% in the repertoire of naïve healthy individuals ( 29 ) with a mean of 1.8% ( 30 ). The prevalence of IGHV3-53 in the antibody response in SARS-CoV-2 patients has also been recognized in some recent antibody studies ( 20, 22, 27 ). These observations indicate that IGHV3-53 represents a frequent and public antibody response to the SARS-CoV-2 RBD.…”

Section: Mainmentioning

confidence: 66%

“…To understand the molecular features that endow IGHV3-53 with the ability to act as a public antibody, we determined crystal structures of two IGHV3-53 neutralizing antibodies, namely CC12.1 and CC12.3, in complex with the SARS CoV-2 RBD and also in the presence of the SARS-CoV1/2 cross-reactive Fab CR3022 ( 17 ). CC12.1 and CC12.3 were previously isolated from a SARS-CoV-2-infected patient and shown to be SARS-CoV-2 RBD-specific ( 27 ). Although CC12.1 and CC12.3 are both encoded by IGHV3-53, CC12.1 utilizes IGHJ6, IGKV1-9, and IGKJ3, whereas CC12.3 utilizes IGHJ4, IGKV3-20, and IGKJ1.…”

Section: Mainmentioning

confidence: 99%

“…Many of the epitope residues are not conserved between SARS-CoV-2 and SARS-CoV (Fig. 2E), explaining their lack of cross-reactivity ( 27 ). The buried surface area (BSA) from the heavy-chain interaction is quite similar in CC12.1 (723 Å 2 ), CC12.3 (698 Å 2 ), and B38 (713 Å 2 ).…”

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: Mainmentioning

confidence: 66%

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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“…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: 96%

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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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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“…The SARS-CoV spike proteins are known targets of protective immunity, eliciting both neutralizing antibodies and T-cell responses upon natural infection 8 . Consequently, the spike protein is a primary target for SARS-CoV-2 vaccine development, with emphasis on the receptor-binding domain (RBD), which appears to be the target for most neutralizing antibodies [9][10][11][12][13][14][15] . The urgent need of an effective SARS-CoV-2 vaccine, to contain the worldwide pandemic and prevent new viral outbreaks, has led to a global effort involving a wide range of vaccine technologies.…”

Section: Introductionmentioning

confidence: 99%

Capsid-like particles decorated with the SARS2-CoV-2 receptor-binding domain elicit strong virus neutralization activity

Fougeroux¹,

Goksøyr

Idorn

et al. 2020

Preprint

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The rapid development of a SARS-CoV-2 vaccine is a global priority. Here, we developed two capsid-like particle (CLP)-based vaccines displaying the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. RBD antigens were displayed on AP205 CLPs through a novel split-protein Tag/Catcher ensuring unidirectional and high-density display of RBD. Both soluble recombinant RBD, and RBD displayed on CLPs bound the ACE2 receptor with nanomolar affinity. Mice were vaccinated with soluble RBD or CLP-displayed RBD, formulated in Squalene-Water-Emulsion. The RBD-CLP vaccines induced higher levels of serum anti-RBD antibodies, than the soluble RBD vaccines. Remarkably, one injection with our lead RBD-CLP vaccine in mice elicited virus neutralization antibody titers comparable to those found in patients which had recovered from Covid-19. Following booster vaccinations, the virus neutralization titers exceeded those measured after natural infection, at serum dilutions above 1:10.000. Thus, the RBD-CLP vaccine is highly promising candidates for preventing COVID-19 disease.

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Rapid isolation of potent SARS-CoV-2 neutralizing antibodies and protection in a small animal model

Cited by 88 publications

References 15 publications

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

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

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

Capsid-like particles decorated with the SARS2-CoV-2 receptor-binding domain elicit strong virus neutralization activity

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