A broadly protective antibody targeting gammaherpesvirus gB.

Gammaherpesvirus is a subfamily of herpesvirus, distinct phylogenetically from alphaherpesvirus and betaherpesvirus and characterized by its oncogenic subtypes, including Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus1. It broadly infects humans and other vertebrates and causes various diseases and malignancies2,3. However, no specific antiviral agents are available for each subtype or the whole family. gB is a common fusion protein that is vital for herpesvirus infection and is an ideal target for broad vaccine development; however, a lack of structural and mechanistic understanding of gB hinders this effort4. Here we report the molecular basis of broad gB binding and cross-genus virus neutralization by an antibody, Fab5. This antibody confers effective protection against authentic virus challenges in immunocompetent mice, non-human primates and humanized mice with murine, rhesus and human gammaherpesvirus. Cryo-electron microscopy structures reveal that Fab5 targets a conserved and vulnerable epitope of gammaherpesvirus gB that is antigenically exposed in both pre-fusion and post-fusion states. This finding not only demonstrates that Fab5 is a cross-genus antibody that is broadly reactive to gammaherpesvirus infection and pathogenesis progression, but also offers insights into potential common mechanisms for herpesvirus infection and facilitates the development of broad-spectrum vaccines against gammaherpesviruses.