Model-guided design of a stabilized pre-fusion class III viral fusogen, rabies virus glycoprotein

ended

This proposal aims to stabilize the pre-fusion form of rabies virus glycoprotein (RVG), the most structurally-tractable clinically-relevant class III fusogen by combining computational biology, immunology, and structural biology. Rabies virus is fatal; it kills 55,000 people each year and costs billions to control it in animals. Current human rabies vaccines are cumbersome to use and prohibitively costly, thus there is demand for a new generation of rabies vaccines. Enveloped viruses’ fusion glycoproteins are important subunit vaccine candidates. Structure-guided stabilization of class I fusogens has been a major advance in vaccinology. Many major human pathogens have class III fusogens (notably, all herpesviruses and rabies virus): several post-fusion structures have been reported, but their antigenically critical pre-fusion forms have not been stabilized. A high-quality homology model of RVG will guide design of mutations to stabilise the trimeric pre-fusion protein. Designed mutants will be transiently expressed in mammalian cells, selected for stability, and characterized immunologically. Lead candidates will be used as immunogens in mouse models and in structural studies. These data will guide design of improved rabies vaccines, and provide insights into RVG’s interaction with neutralizing antibodies and host receptors. Certain structural elements are conserved across class III fusogens, and so the approach may lead towards stabilization of herpesvirus fusogens. The fellowship will be based between two departments at a world-class host institution. Together, they will offer the Researcher an unusual combination of exposure to both cutting-edge molecular biochemistry and Europe’s leading academic centre for translational vaccine development. This unique training will equip the Researcher with a truly discipline-spanning skill set and position her to make a leading contribution to the development of novel antiviral interventions and public health.