The studies done in this Project will carefully interdigitate the findings of Projects 1 and 2 into appropriate animal model systems to test candidate vaccine strains. The objectives are as follows: First, genetically engineered mutants from Project 1 will be tested initially in mice and subsequently in guinea pigs to determine their capacity to replicate in the CNS, peripheral tissue, to establish latency, to cause recurrent lesions in guinea pigs, to reactivate upon explantation from ganglia, and to protect these animal species from challenge with virulent viruses. These studies will aid in the design of prototype vaccines strains based on the results of studies in Projects 1 and 3. Second, once candidate vaccine strains become identified, extensive challenge studies in mice and guinea pigs will be done utilizing different routes of immunization and challenge. Successful challenge will be further correlated with systemic and mucosal immune responses. Third, attempts to enhance systemic and mucosal immunity by novel and careful employment of interleukins in feasibility experiments will be initiated. These experiments will utilize IL-4, IL-5, and/or IL-6 before immunization to determine its effects on immune response. If immunity can be enhanced without evidence of adverse effects, an attempt will be made to evaluate recombinant viruses carrying IL genes under various promoters. The knowledge gained from these studies will provide a basis for more detailed animal safety and immunogenicity studies in anticipation of human trials.
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