Role of F Protein Conformation in RSV Vaccine Efficacy



 DESCRIPTION (provided by applicant): Most acute viral respiratory disease in infants and young children is due to respiratory syncytial virus (RSV). This virus also causes serious disease in elderly and immunocompromised populations and is a significant cause of morbidity in healthy adult populations. Despite the substantial disease burden due to this virus worldwide, there are no vaccines available. Several problems have impeded RSV vaccine development. First is safety. An early formalin-inactivated vaccine (FI-RSV), which stimulated weak and unbalanced immune responses, predisposed infants to more severe disease upon natural exposure to live virus. A second problem is the failure of many vaccine candidates to stimulate protective immune responses. A third problem is the failure of natural infection as well as vaccine candidates to stimulate long-lived, protective memory responses. All these problems are ultimately due to a lack of understanding of mechanisms involved in stimulation of protective as well as durable anti-RSV immune responses. This proposal will test the hypothesis that different conformational forms of RSV F protein impact the properties of anti-RSV immune responses. The goal is to define conformations of RSV F protein, expressed on virus-like particles, that stimulate high titer neutralizing antibodies and protective, long-lived and memory immune responses and to understand the mechanisms responsible for generation of these responses. To test the hypothesis, four aims are proposed. Specific Aim 1: to characterize the RSV F protein binding properties of antibodies stimulated in mice and in cotton rats by VLPs containing stabilized pre-fusion or stabilized post-fusion F protein. Specific Aim 2: to clarify th role of anti-G antibodies in the neutralization titers induced in mice and cotton rats by VLPs containing the pre-fusion form of the RSV F protein and VLPs containing the post-fusion form. Specific Aim 3: to characterize immune responses to VLPs containing pre- and post-fusion forms of F in RSV experienced mice and cotton rats as models for maternal immunization. Specific Aim 4: to determine if VLPs containing the pre-fusion and the post-fusion F proteins induce RSV F protein specific long-lived bone marrow associated plasma cells (LLPC) and memory B cells in both mice and cotton rats.