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 RSV infection have revealed 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 to G protein induced in the acute response to RSV vaccination or natural infection inhibit G protein CX3C-CX3CR1 interaction; however, it is unclear if anti-G protein antibody responses protect from disease pathogenesis. The long-term goal of our research is to determine the regions in RSV G protein that induce a protective antibody response which block G protein CX3C-CX3CR1 interaction to provide the foundation for the development of safe and efficacious RSV vaccine candidates. Our central hypothesis is that modifications to the G protein which eliminate the CX3C motif may improve vaccine safety while induction of antibodies that block this interaction may improve vaccine efficacy. The proposal will take advantage of a well-defined CX3C chemokine binding and leukocyte migration assay, panels of anti-G protein monoclonal antibodies, panels of G protein peptides and polypeptides, and well-defined mouse model. Using these reagents we will examine the following specific aims: 1) Determine regions in the G protein that induce antibodies which block G protein CX3C binding to CX3CR1; 2) Determine the ability of antibodies that block G protein CX3C binding to CX3CR1 to inhibit the pulmonary inflammatory response associated with RSV infection, or formalin- inactivated (FI-RSV) vaccine enhanced disease; 3) Determine the association between antibodies that block G protein binding to CX3CR1 and leukocyte migration and severity of RSV disease in humans. The proposed research is innovative because it will identify regions in the RSV G protein that induce antibodies which block RSV disease, and provide critical information on humoral responses associated with inhibiting RSV G protein CX3C-CX3CR1 interaction to prevent disease.