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 malignancies^2,3. 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.