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

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.

Automated summary

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.