A broadly neutralizing antibody protects Syrian hamsters against SARS-CoV-2 Omicron challenge

Abstract

The strikingly high transmissibility and antibody evasion of SARS-CoV-2 Omicron variants have posed great challenges to the efficacy of current vaccines and antibody immunotherapy. Here, we screen 34 BNT162b2-vaccinees and isolate a public broadly neutralizing antibody ZCB11 derived from the IGHV1-58 family. ZCB11 targets viral receptor-binding domain specifically and neutralizes all SARS-CoV-2 variants of concern, especially with great potency against authentic Omicron and Delta variants. Pseudovirus-based mapping of 57 naturally occurred spike mutations or deletions reveals that S371L results in 11-fold neutralization resistance, but it is rescued by compensating mutations in Omicron variants. Cryo-EM analysis demonstrates that ZCB11 heavy chain predominantly interacts with Omicron spike trimer with receptor-binding domain in up conformation blocking ACE2 binding. In addition, prophylactic or therapeutic ZCB11 administration protects lung infection against Omicron viral challenge in golden Syrian hamsters. These results suggest that vaccine-induced ZCB11 is a promising broadly neutralizing antibody for biomedical interventions against pandemic SARS-CoV-2.

Antigenic characterization of the SARS-CoV-2 Omicron subvariant BA.2.75

“…Another mutation proximal to residue 446 of the spike could knock out the current arsenal of therapeutic monoclonals. Although numerous mAbs have been isolated and shown to neutralize the new Omicron subvariants [13][14][15][16][17][18][19][20]22,23 , their development pathway to prove clinical efficacy has become rather daunting with the availability of effective vaccines and antiviral drugs.…”

“…We next assessed the neutralization resistance of BA.2.75 to a panel of 23 mAbs directed to known neutralizing epitopes on the viral spike. Among these, 21 target the four epitope classes in the RBD 5 , including REGN10987 (imdevimab) 6 , REGN10933 (casirivimab) 6 , COV2-2196 (tixagevimab) 7 , COV2-2130 (cilgavimab) 7 , LY-CoV555 (bamlanivimab) 8 , CB6 (etesevimab) 9 , Brii-196 (amubarvimab) 10 , Brii-198 (romlusevimab) 10 , S309 (sotrovimab) 11 , LY-CoV1404 (bebtelovimab) 12 , CAB-A17 13 , ZCB11 14 , Omi-3 15 , Omi-18 15 , XGv282 16 , XGv347 16 , S2E12 17 , A19-46.1 18 , 35B5 19 , and JMB2002 20 , as well as 10-40 21 from our group. The other two mAbs, C1717 22 and S3H3 23 , target NTD-SD2 and SD1, respectively.…”

“…The other two mAbs, C1717 22 and S3H3 23 , target NTD-SD2 and SD1, respectively. Many of the recently isolated mAbs were chosen because they could neutralize earlier Omicron subvariants [13][14][15][16][17][18][19][20]22,23 .…”

Cell and Animal Models for SARS-CoV-2 Research

“…Regarding Omicron variant, Zou et al showed that prophylactic and therapeutic vaccine-induced ZCB11 administration protects from lung infection in golden Syrian hamsters. Interestingly, ZCB11 also protected animals against the circulating Omicron BA.1 and Delta variants [ 213 ].…”

“…Regarding Omicron variant, Zou et al showed that prophylactic and therapeutic vaccine-induced ZCB11 administration protects from lung infection in golden Syrian hamsters. Interestingly, ZCB11 also protected animals against the circulating Omicron BA.1 and Delta variants [213]. Bertzbach et al established Chinese hamsters as a suitable supplemental model for SARS-CoV-2 study, showing pronounced clinical symptoms.…”