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

Abstract

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...

Structures of potent and convergent neutralizing antibodies bound to the SARS-CoV-2 spike unveil a unique epitope responsible for exceptional potency

“…The most potent one, BD-368-2, exhibited high therapeutic and prophylactic efficacy in hACE2-transgenic mice infected by SARS-CoV-2 (Bao et al, 2020). We also revealed the wide existence of a convergent, public, or stereotypic antibody response to SARS-CoV-2 by VH3-53/VH3-66 derived NAbs, which was confirmed and highlighted in several recent studies (Barnes et al, 2020;Hansen et al, 2020;Kim et al, 2020;Robbiani et al, 2020;Rogers et al, 2020;Yuan et al, 2020a). The VH3-53/VH3-66 convergent NAbs share highly conserved VDJ sequences and could be found in different individuals in distinct populations, similar to what has been observed in HIV, Influenza, and Hepatitis C viruses (Ekiert et al, 2009;Gorny et al, 2009;Marasca et al, 2001).…”

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

“…While antibodies that target the ACE2-binding site, such as BD23 [7], CB6 [23] [40], and CC12.3 [40], do not show cross-neutralization activity to SARS-CoV, the conserved epitopes further from the ACE2-binding site seem to be more able to support cross-neutralization [13,18,26]. It is also interesting that these so far rare cross-neutralizing antibodies, including COVA1-16, often seem to bind to epitopes that are not readily accessible in the pre-fusion native structure [17,26].…”

“…Structures were solved by molecular replacement using PHASER [49]. The models for molecular replacement of RBD and COVA1-16 were from PDB 6XC4 [40], 4IMK [50] and 2Q20 [51]. Iterative model building and refinement were carried out in COOT [52] and PHENIX [53], respectively.…”

A Novel Neutralizing Antibody Targeting Receptor Binding Domain of SARS-CoV-2

“…These observations indicate that the epitope of CT-P59 are unique from those of other antibodies [14][15][16][17][18][19] ( Fig. 2c).…”

“…4a). We found that the majority of the ACE2 blocking antibodies-including CB6 16 , B38 17 , CV30 18 , CC 12.1 19 , CC 12.3 19 and REGN10933 14 -adopt a similar orientation when bound to RBD. Each of these antibodies belong to the immunoglobulin heavy chain variable region genes (IGHV) 3 germline that is the most frequently used IGHV gene among the known SARS-CoV-2 neutralizing antibodies 22 .…”