Research Project
9463550
Abstract Respiratory syncytial virus (RSV), a viral agent that causes severe respiratory illness, infects a large percentage of infants and children worldwide by the age of three (E. Heylen et al, 2017). According to the CDC, RSV is responsible for over 50,000 hospitalizations and 2.1 million outpatient visits among children younger than 5 years as well as 180,000 hospitalizations and 14,000 deaths among the elderly in the US alone (E. K. Miller, et al. 2013). After more than 40 years of research, several RSV vaccine candidates are in the pipeline, but none have progressed through the final approval process. A major target for vaccine development has been guided by the successful prophylactic use of a neutralizing monoclonal antibody, palivizumab (SynergisR) which is directed against the fusion glycoprotein (F protein). The treatment is expensive, must be given every 3-6 months for maximum protection, and is currently limited to high-risk young pediatric patients (E. Heylen et al, 2017). Clinical studies with unmodified F protein stimulates some neutralizing antibodies, but also non-neutralizing antibodies. We hypothesize that the non-neutralizing antibodies interfere with the action of neutralizing antibodies and that their elimination may improve the protective immunity stimulated by rationally-designed F variants. Guided by our previous work with HIV, Influenza, HRV, and most recently with RSV, we analyzed structural and immunological data for the F protein RSV to identify and immune dampen non- neutralizing epitopes. In a preliminary study, we designed and produced a panel of immune refocused F antigens and showed that the most promising candidates retained binding to neutralizing antibodies while losing binding to non-neutralizing antibodies. We propose to examine these types of F variants in both pre- and post-fusion conformations for improved protection in a cotton rat challenge study.
