Respiratory Syncytial Virus (RSV), subgroups A and B, are responsible for serious respiratory tract disease in infants, and the elderly and immunocompromised persons. No vaccine is currently available and subunit approaches have so far failed. The investigators have utilized recently described "reverse genetic" techniques to construct a unique set of live, recombinant chimeric RSV vaccine candidates that express both subgroup A and subgroup B specific surface antigens. Two mutagenesis strategies which they have previously used to attenuate the wild type (WT) RSV A2 strain will be used to complete construction of chimeric virus vaccine candidates for preclinical testing. Using alanine scanning and cysteine replacement mutagenesis of the RSV L gene (RNA-dependent polymerase) the investigators have defined genetic loci that when altered produce a temperature sensitive replication phenotype. Deletion of non-essential genes (SH, M2-2, NS1, NS2) will be combined with the L gene ts mutations to produce genetically stable chimeric RS viruses that are non-pathogenic and have unique replication phenotypes. The overall goal of the Phase 1 SBIR grant is to select a chimeric RS virus that is safe, immunogenic and protects against WT RSV challenge. A Phase 2 SBIR grant will be used to complete preclinical testing in a subhuman primate model and to initiate human clinical trials. PROPOSED COMMERCIAL APPLICATION: The SBIR application should lead to generation of live attenuated RSV vaccines. RSV vaccine is needed to prevent disease caused by RSV infection.
