Longitudinal profiling of B cells primed by mRNA vaccine and recalled by Omicron variants uncovers antibodies broadly neutralizing sarbecoviruses

Regarding to the impact of ancestral SARS-CoV-2 immune imprinting on antibody responses to emerging variants, to what extent memory B cells elicited by wild-type (WT) spike can develop neutralizing breadth and potency in immune recalls is a key question. Here, we longitudinally tracked B cells recognizing WT spike in two individuals of mRNA vaccine, from convalescence of breakthrough infection to acute phase of reinfection. Comprehensive characterization of 632 monoclonal antibodies (mAbs) from those B cells reveals that mAbs cloned after reinfection have dramatically enhanced neutralizing breadth and potency, including 11 mAbs that potently neutralize all tested SARS-CoV-2 variants from WT to KP.3. Among the 11 mAbs, 5 mAbs are classified into public clonotypes encoded by IGHV3-53 or IGHV3-66, whereas the rest belong to a rare clonotype encoded by IGHV3-74. Notably, IGHV3-74 mAbs can even neutralize SARS-CoV-1 with a minimum IC50 of 0.055 μg/ml. Structural and functional analysis further suggests that IGHV3-74 mAbs target a novel epitope on receptor-binding domain, and the best mAb, termed KXD352, is highly resilient to variations on this epitope. Overall, this study demonstrates that both public and rare antibody clonotypes primed by prototype mRNA vaccine can achieve extraordinary neutralizing breadth and potency in repeated Omicron infections.