Abstract

Gammaherpesvirus is a subfamily of herpesvirus, distinct phylogenetically from alpha- and betaherpesvirus and featured by its oncogenic subtypes, including Epstein-Barr virus and Kaposi’s sarcoma-associated herpesvirus 1 . It broadly infects humans and other vertebrate animals and causes various diseases and malignancies 2,3 . However, no specific antiviral agents are available for each type or the whole family. gB is the common fusion protein vital for herpesvirus infection and an ideal target for broad vaccine development, while the lack of basis for gB as a universal antigen hinders such effort 4 . Here, we report the molecular basis for broad gB binding and cross-genus virus neutralization by an antibody Fab5 for the first time. This antibody confers effective protection against authentic virus challenges in immune-competent mice, non-human primates, and humanized mice with murine, rhesus, and human gammaherpesvirus. Cryo-EM structures revealed that Fab5 targeted a conservative and vulnerable epitope of gammaherpesvirus gB and antigenically exposed across pre- or post-fusion status. This finding not only demonstrates Fab5 as cross-genus antibody broadly reactive against gammaherpesvirus infection and pathogenesis progression, but offers insights into potential common mechanisms for herpesvirus infection and facilitates the development of broad-spectrum vaccines against the gammaherpesvirus.