4.7 Article

Structural insights into broadly neutralizing antibodies elicited by hybrid immunity against SARS-CoV-2

Journal

EMERGING MICROBES & INFECTIONS
Volume 12, Issue 1, Pages -

Publisher

TAYLOR & FRANCIS LTD
DOI: 10.1080/22221751.2022.2146538

Keywords

SARS-CoV-2; Omicron BA; 1 breakthrough infection; hybrid immunity; broadly neutralizing antibody; memory B cell; structural basis of antibody

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In this study, the diversity, potency, breadth, and structural insights of bNAbs derived from memory B cells of BNT162b2-vaccinated individuals after Omicron BA.1 breakthrough infection were determined. The infection activated diverse memory B cell clonotypes that generated potent class I/II and III bNAbs with new epitopes mapped to the receptor-binding domain (RBD). While the top eight bNAbs neutralized wildtype and BA.1 effectively, they displayed different IgH/IgL sequences and neutralization profiles against other variants of concern (VOCs). Two class III NAbs, P2D9 and P3E6, showed comparable potency against BA.4/BA.5, but structural analysis revealed distinct modes of action. P3E6 neutralized all tested variants through a unique bivalent interaction with two RBDs. These findings provide new insights into the hybrid immunity generated by BNT162b2-induced diverse memory B cells in response to Omicron breakthrough infection.
Increasing spread by SARS-CoV-2 Omicron variants challenges existing vaccines and broadly reactive neutralizing antibodies (bNAbs) against COVID-19. Here we determine the diversity, potency, breadth and structural insights of bNAbs derived from memory B cells of BNT162b2-vaccinee after homogeneous Omicron BA.1 breakthrough infection. The infection activates diverse memory B cell clonotypes for generating potent class I/II and III bNAbs with new epitopes mapped to the receptor-binding domain (RBD). The top eight bNAbs neutralize wildtype and BA.1 potently but display divergent IgH/IgL sequences and neuralization profiles against other variants of concern (VOCs). Two of them (P2D9 and P3E6) belonging to class III NAbs display comparable potency against BA.4/BA.5, although structural analysis reveals distinct modes of action. P3E6 neutralizes all variants tested through a unique bivalent interaction with two RBDs. Our findings provide new insights into hybrid immunity on BNT162b2-induced diverse memory B cells in response to Omicron breakthrough infection for generating diverse bNAbs with distinct structural basis.

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