B cells imprinted by ancestral SARS-CoV-2 develop pan-sarbecovirus neutralization in immune recalls

A key question on ancestral SARS-CoV-2 immune imprinting is to what extent imprinted B cells can develop neutralizing breadth and potency in immune recalls. Here, we longitudinally tracked B cells recognizing wild-type spike in two individuals, who were sequentially infected by Omicron variants after receiving mRNA vaccines. Functional and genetic analysis of 632 monoclonal antibodies (mAbs) from those B cells reveals that mAbs cloned after second infection have dramatically enhanced neutralizing breadth and potency, which is attributed to recall and maturation of pre-existing memory B cells. Among the 11 mAbs that potently neutralize SARS-CoV-2 variants from wild-type to KP.3, 5 mAbs are classified into public clonotypes encoded by IGHV3-53 or IGHV3-66, whereas the rest belong to a rarely reported clonotype encoded by IGHV3-74. Notably, IGHV3-74 mAbs can also broadly neutralize other sarbecoviruses by targeting a novel epitope on receptor-binding domain of spike. These results support that ancestral SARS-CoV-2 immune imprinting can be harnessed in developing pan-SARS-CoV-2 and even pan-sarbecovirus vaccines. Summary Chen et al. demonstrate that B cells imprinted by ancestral SARS-CoV-2 have tremendous potential to develop neutralizing breadth and potency in repeated immune recalls driven by Omicron variants, implicating that ancestral SARS-CoV-2 immune imprinting can be harnessed in developing pan-SARS-CoV-2 and even pan-sarbecovirus vaccines.