Respiratory syncytial virus (RSV) is the most important cause of severe lower respiratory tract illness in infants and the elderly. Currently, no safe and efficacious RSV vaccine exists. Advances in our understanding of immunity and disease pathogenesis associated with infection have shown that RSV G protein contains a CX3C chemokine motif that interacts with the CX3CR1 chemokine receptor, modifies the activities of CX3CL1, and affects aspects of immunity and disease pathogenesis. Antibodies directed to the CX3C motif inhibit G protein CX3C-CX3CR1 interaction and reduce disease pathogenesis. The long- term goal of our research is to develop a novel nanocapsule vaccine engineered to carry a RSV G protein polypeptide that we have previously shown to induce neutralizing and disease protective antibody. The nanocapsule technology is attractive for vaccine development as it targets professional antigen- presenting cells which we have shown to improve the immunogenicity of both T cell and antibody target epitopes. The proposal will take advantage of well-defined assays and a mouse model to: (1) Identify the optimal CX3C motif vaccine antigen sequence based on G polypeptide vaccination of mice and evaluation of G protein CX3C-CX3CR1 blocking antibody responses, (2) Construct nanocapsule vaccine candidates with the appropriate G polypeptide and demonstrate immunogenicity and protection in a mouse model, (3) Use optimized, efficacious nanocapsule vaccines to further understand the disease modifying effect of antibodies that block G protein CX3C-CX3CR1 interaction and disease pathogenesis, 4) Evaluate parameters of safety and duration of vaccine efficacy in the memory response to (G peptide nanocapsule vaccination and RSV challenge, and (5) Evaluate the safety and efficacy of G peptide nanocapsule vaccine in the context of pre-existing RSV immunity. The proposed research is innovative because it will identify regions in the RSV G protein that induce antibodies which neutralize infection and block RSV disease, incorporate the optimal polypeptide in an novel nanocapsule-based vaccine candidate that targets antigen-presenting cells, and will provide long-term protection against RSV strains. Respiratory syncytial virus is the most important cause of sever lower respiratory tract illness in infants and the elderly. Currently, no safe and efficacious RSV vaccine exists. The long-term goal of our research is to develop a novel nanocapsule vaccine engineered to carry a RSV G protein polypeptide that we have previously shown to induce neutralizing and disease protective antibody.