Human neutralizing antibodies elicited by SARS-CoV-2 infection

Abstract

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a global health emergency that is in urgent need of intervention 1-3. The entry of SARS-CoV-2 into its target cells depends on binding between the receptor-binding domain (RBD) of the viral spike protein and its cellular receptor, angiotensin-converting enzyme 2 (ACE2) 2,4-6. Here we report the isolation and characterization of 206 RBD-specific monoclonal antibodies derived from single B cells from 8 individuals infected with SARS-CoV-2. We identified antibodies that potently neutralize SARS-CoV-2; this activity correlates with competition with ACE2 for binding to RBD. Unexpectedly, the anti-SARS-CoV-2 antibodies and the infected plasma did not cross-react with the RBDs of SARS-CoV or Middle East respiratory syndrome-related coronavirus (MERS-CoV), although there was substantial plasma cross-reactivity to their trimeric spike proteins. Analysis of the crystal structure of RBD-bound antibody revealed that steric hindrance inhibits viral engagement with ACE2, thereby blocking viral entry. These findings suggest that anti-RBD antibodies are largely viral-species-specific inhibitors. The antibodies identified here may be candidates for development of clinical interventions against SARS-CoV-2. The rapid international transmission of SARS-CoV-2 poses a serious global health emergency with no available treatments or vaccine 1-3. SARS-CoV-2 shares substantial genetic and functional similarity with other human betacoronaviruses, including SARS-CoV and MERS-CoV 2,4-8. SARS-CoV-2 uses an envelope homotrimeric spike glycoprotein to interact with the cellular receptor ACE2 2,5,6,8. Binding with ACE2 triggers a cell membrane fusion cascade that results in viral entry. This suggests that disruption of the RBD-ACE2 interaction would block SARS-CoV-2 cell entry. The high-resolution structure of SARS-CoV-2 RBD bound to the N-terminal peptidase domain of ACE2 has recently been determined 6-8. The ACE2-binding mechanism is nearly identical between SARS-CoV-2 and SARS-CoV RBDs 7-10. Animal studies on RBD-based vaccines against SARS-CoV and MERS-CoV have shown strong polyclonal antibody responses that inhibit viral entry 11,12. These findings suggest that anti-RBD antibodies should effectively block SARS-CoV-2 entry. In this study, we report on RBD-specific monoclonal antibodies obtained from individuals infected with SARS-CoV-2. Plasma antibody response against SARS-CoV-2 We collected cross-sectional and longitudinal blood samples from eight patients infected with SARS-CoV-2, who were infected during the early outbreak in Shenzhen (Supplementary Table 1). Samples were named according to patient ID and A, B, or C depending on when they were collected. Six patients (P1 to P4, P8 and P16) had recently travelled to Wuhan and the others (P5 and P22) had direct contact with people who had recently been in Wuhan. P1 to P5 comprise a family cluster, including the first documented case of human-to-human transmission...

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

“…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).…”

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

“…Firstly, other CLP-based vaccines have shown to be safe and highly immunogenic in humans. In fact, the marketed Human Papillomavirus (HPV) vaccines, based on HPV L1 CLP, induce extremely potent and durable antibody responses otherwise only seen after vaccination with live-attenuated viral vaccines [42][43][44] proportion of neutralizing compared to binding antibodies [9][10][11][12][13][14][15] . In fact, the unidirectional antigen display enabled by the Tag/Catcher-AP205 platform has previously been exploited to selectively favor induction of antibodies targeting desired epitopes 62 .…”

“…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.…”

Longitudinal proteomic profiling reveals increased early inflammation and sustained apoptosis proteins in severe COVID-19

“…Third, most patients reportedly develop antibodies to nucleocapsid (N) and Spike (S) proteins 14, 15, 16 , including to RBD, a receptor-binding domain of the S protein, that is essential for virus entry into host cells via the ACE2 receptor 17 . Antibodies to the N protein, which protects viral RNA, are apparently prevalent in patients with SARS-CoV and SARS-CoV-2 infections 18,19 , and can comprise a relatively sensitive early biomarker for infection 20,21 .…”