Understanding and inducing immunity against rabies and Epstein Barr virus Class III fusion proteins

Viral fusion proteins are important targets for vaccine-induced neutralising antibody. Structure-guided design of such antigens in pre-fusion conformation has created leading vaccine candidates against viruses with Class I and II fusion proteins, such as respiratory syncytial virus and dengue virus. Use of pre-fusion stabilised Class III proteins for vaccination has not yet been reported, but these too are major vaccine targets for rabies virus and the herpesviruses (the gB proteins). I propose to build upon preliminary data demonstrating pre-fusion stabilisation of rabies glycoprotein. I will evaluate pre-fusion-stabilised immunogens for vaccines against rabies and a chosen herpesvirus, Epstein Barr virus (EBV). By isolating monoclonal antibodies against EBV gB, I will ascertain whether herpesvirus gB proteins contain pre-fusion-specific neutralising epitopes. In healthy EBV carriers, I will explore whether salivary EBV shedding can be used as a marker of immune control of virus reactivation, to dissect mechanisms of natural immunity, and to rapidly detect efficacy in future early-phase vaccine trials. A low-cost single-dose vaccine based on stabilised rabies glycoprotein could help reduce the 60,000 deaths due to rabies each year. An effective EBV vaccine could reduce the >100,000 deaths per year due to EBV-driven cancers and, many believe, could also prevent multiple sclerosis.