Identifying a Mutant Respiratory Syncytial Virus G Immunogen as a Vaccine Candidate

Respiratory syncytial virus (RSV) is the top cause of severe lower respiratory disease in infants and children and causes over 100,000 deaths in children worldwide each year. RSV is also a leading cause of respiratory disease in immunocompromisedand elderly populations. However, no FDA approved vaccine exists to protect against RSV infection. RSV contains two immunogenic proteins on its envelope, RSV F and RSV G, that have been the targets of vaccine developmental strategies. Most current efforts to create a vaccine against RSV focus on RSV F, and several candidates are in phase III clinical trials. The only current prophylaxis available for RSV is a monoclonal antibody against RSV F, yet it does not prevent infection. RSV G as a vaccine immunogen is linked to vaccine enhanced disease and is poorly immunogenic, however anti-RSV G antibodies have been shown to be protective in animal models of RSV disease and correlate with protection in humans. In this thesis, I present the history of an inactivated RSV vaccine that caused vaccine enhanced disease in children, a summary of studies using RSV G as a vaccine antigen, and an overview of the RSV G vaccine antigens currently in clinical trials. I present data showing that the structure-based design of an RSV G immunogen with a mutation in the central conserved domain is a promising vaccine candidate. Finally, I present studies to investigate RSV G binding and activation of the human chemokine receptor CX3CR1 on mammalian cells. Overall, these studies provide a foundation for the further development of the RSV G immunogen as a vaccine candidate to protect against RSV disease