A distinctive IGHV3-66 SARS-CoV-2 neutralizing antibody elicited by primary infection with an Omicron variant

SARS-CoV-2 Omicron sub-variants continuously evolve under the pressure of neutralizing antibodies (nAbs), eliminating numerous potential elite monoclonal nAbs. The IGHV3-53/3-66 public nAbs have great potential for neutralizing SARS-CoV-2. However, it has been unclear whether a primary Omicron infection could also induce IGHV3-53/3-66 nAbs. In this study, we report an IGHV3-66-encoding monoclonal nAb, ConBA-998, that was elicited by primary infection with BA.1. ConBA-998 is an Omicron-dependent nAb with high binding affinity that triggers the shedding of the S1 subunit from the spike protein. The cryo-electron microscopy (cryo-EM) structure revealed the interactions between ConBA-998 and the Omicron BA.1 spike protein. ConBA-998 has a distinctive binding mode to receptor-binding domain (RBD) that differs from canonical IGHV3-53/3-66 nAbs. Overall, our findings indicate that Omicron may elicit unique specific nAbs distinct from those induced by pre-Omicron variants, providing further insights into SARS-CoV-2 variant-specific antibody responses.