W177 - Repeated Exposure to SARS-CoV-2 Antigens Induces Exceptionally Broad and Potent Neutralizing Immunity to Major Sarbecoviruses in Humans Including SARS-CoV-1

Linqi Zhang – Tsinghua university; Xin Xie – T; Ziqing Yang – Tsinghua university; Qi Zhang – Tsinghua university

Abstract Text: Human antibody response to SARS-CoV-2 has become increasingly complex due to emerging variants and spread across the world, resulting in multiple waves of breakthrough infections with distinct antibody potency and breadth. Here, we identified two individuals stood out in their exceptional plasma neutralization to a diverse panel of sarbecoviruses including major SARS-CoV-2 variants, SARS-CoV-1, and ACE-2-using bat and pangolin coronaviruses. Looking into their immunization and infection history has revealed rather unusual episodes of antigen exposure, involving multiple intramuscular vaccination with inactivated virus, adenovirus-based, mRNA as well as intranasal vaccination with adenovirus-based vaccine, and intranasal infection/breakthrough infection with wildtype and/or Omicron BF.7.
To study the molecular basis of their antibody potency and breadth, we have isolated a total of 963 monoclonal antibodies from the two individuals. Of which, 254 antibodies exhibit neutralization activity to the infecting wildtype and BF.7 subvariant. Among these, many demonstrated exceptionally broad and potent neutralizing activity against a diverse panel of coronaviruses including SARS-CoV-1, all SARS-CoV-2 variants tested including the most recent Omicron subvariant EG.5.1, JD.1.1 and JN.1, as well as ACE-2-using bat and pangolin coronaviruses, resembling that of corresponding plasma samples. Crystal and cryo-EM structural analysis revealed some unique features of antibody epitope and recognition. Taken together, we have identified two individuals with remarkable antibody breadth and potency against wide range of human and animal coronaviruses. The discovery of these broad and potent monoclonal antibodies serves as the first and important step to inform the development of next-generation vaccine against diverse human coronaviruses and beyond.