Research Project
9202914
Abstract Respiratory Syncytial Virus (RSV) is a human pathogen that is the predominant cause of acute lower respiratory tract infection in children. In the United States, nearly all children are infected with RSV by the age of three. RSV is a major cause of serious respiratory illness requiring hospitalization in children with symptoms ranging from severe pneumonia and bronchiolitis to milder infections. Furthermore, the inflammation associated with repeated RSV infections, especially in children, is associated with chronic lung-related pathology. Since infection by RSV does not elicit natural immunity to subsequent infections, significant morbidity and mortality are also associated with RSV infection of the elderly. There is no current FDA licensed vaccine for RSV infection and the only approved prophylactic treatment is the RSV neutralizing mAb Synagis. Recently, other strongly neutralizing antibodies against RSV were identified directed against novel epitopes in the RSV F-protein. Due to the limited prophylactic options there remains a critical need for the development of a RSV vaccine that can specifically generate neutralizing antibody responses in a platform that is efficacious in both children and the elderly. This vaccine ideally could be produced and purified in a cost effective and scalable manner, and that would the need for cold chain storage. We have developed a novel technology based on bacteriophage MS2 virus-like-particles (VLPs) that allow for the immunogenic display of heterologous peptide epitopes. We have constructed MS2 VLPs to display high- complexity, random sequence peptide libraries, which can be subjected to affinity-selection on known RSV neutralizing antibodies. This enables the discovery of epitope mimics (linear, conformational or non-peptide) recognized by selecting antibodies, and to display those epitope mimics on the surface of highly immunogenic VLP particles. Immunization with the selected VLPs then elicits antibodies whose activities mimic those of the selecting antibody. This novel technology provides the means to find new vaccine candidates that focus the immune response only on the most efficacious epitopes, which is critical in the case of RSV, where non- neutralizing antibodies have been shown to enhance disease. The objective of this proposal is to produce RSV VLP-based vaccine candidates displaying peptide epitope mimics of neutralizing RSV mAbs directed to the pre-fusion form of F-protein. The immunogenicity of the candidates will be tested using ELISA and in vitro neutralization assays. Immunogenic VLPs will be analyzed for efficacy and safety using a highly relevant cotton rat model of RSV infection.
