Highly conserved conformational “Jing” epitopes overcome SARS-CoV-2 Omicron antigenic drift and shift 3411

Abstract Description Background The continuously emerged SARS-CoV-2 immune escape variants have resulted in new global COVID-19 waves due to antigenic drift and shift. Understanding evolving human memory B cell responses elicited by breakthrough infections is necessary for vaccine development. Methods We delineated the B cell receptor repertoire and conducted the pseudovirus-based assay for recovered neutralizing antibodies (NAb) screening. We then analyzed the cryo-EM structures of top broadly NAbs (bnAb) and evaluated in vivo efficacy in hamster model. Results By investigating human B cell immunity with prior SARS-CoV-2 and/or SARS-CoV-1 infections, we discovered a panel of bnAbs. One individual with SARS-CoV-2 BA.5 breakthrough infection generated two lead bnAbs, which neutralized all Omicron subvariants tested including JN.1 and KP.2 with IC50 values less than 10 ng/mL, representing ultrapotent receptor binding domain (RBD)-specific class I bnAbs. Despite viral antigenic drift and shift, these lead bnAbs revealed highly conserved conformational “Jing” epitopes for ultrapotent ACE2 blockade, preventing hamster contact transmission. We also discovered new bnAbs that neutralized both SARS-CoV-2 and SARS-CoV-1, providing evidence of additional “Jing” epitopes. Conclusion Our findings demonstrated that “Jing” epitopes exist as a mode of action to cope with antigenic drift and shift during SARS-CoV-2 breakthrough infections. These epitopes may serve as useful targets for bnAbs and vaccine development. Funding Sources This study was supported by the Hong Kong Research Grants Council Collaborative Research Fund (C7156-20G, C1134-20G and C5110-20G); the Health@InnoHK, Innovation and Technology Commission; the Hong Kong Theme-Based Research Scheme (T11-706/18-N, T11-702/24-N and T12-703/23-N); Wellcome Trust P86433; the Hong Kong Health and Medical Research Fund (COVID1903010-Project 4, COVID190123 and 20190572). Topic Categories Viral Immunology (VIR)