A potent and protective human neutralizing antibody targeting a key vulnerable site of Epstein-Barr Virus

Abstract Epstein-Barr virus (EBV) is associated with a range of epithelial and B cell malignancies as well as autoimmune disorders, for which there are still no specific treatments or effective vaccines. Here, we isolated EBV gH/gL-specific antibodies from an EBV-infected individual. One antibody, 1D8, efficiently neutralized EBV infection of two major target cell types, B cells and epithelial cells. In humanized mice, 1D8 provided strong protection against a high-dose EBV challenge by substantially reducing viral loads and associated tumor burden. Crystal structure analysis revealed that 1D8 binds to a key vulnerable interface between the D-I/D-II domains of the viral gH/gL protein, especially the D-II of the gH, thereby interfering with the gH/gL-mediated membrane fusion and binding to target cells. Overall, we identified a potent neutralizing antibody as a promising candidate for prophylactic and therapeutic interventions against EBV infection. The key vulnerable site also provides insights into the EBV vaccines design.