Ocular HSV-1 infection is a major cause of corneal scarring and blindness in the United States. The main goal of this study is to develop a subunit vaccine that prevents initial HSV-1 infection and completely eliminates eye disease and latency. In our preliminary results we have shown that a cocktail of 7 recombinantly expressed HSV-1 glycoproteins (gB, gC, gD, gE, gG, gH, gI), but no individual glycoprotein completely eliminated eye disease and the establishment of latency following HSV-1 ocular challenge. This high level of protection correlated with neutralizing antibody, CTL, and local ocular IL-2 and/or TNF-alpha. Our detailed specific aims to further elucidate the biological and immunological mechanisms by which a vaccine can protect against eye disease and latency include: 1. Optimize our glycoprotein mixture to provide the most efficient protection against primary ocular HSV-1 challenge in the mouse, especially against the establishment of latency. Mice vaccinated with various HSV-1 glycoprotein cocktails will be challenged ocularly with HSV-1. Vaccine effectiveness will be based on decreased establishment of latency, decreased eye disease, decreased virus replication in the eye and spread to the trigeminal ganglia and brain, and increased survival. This will allow us to determine the optimal combination of glycoproteins for maximum efficacy. 2. Test the hypothesis that in vaccinated mice both CD4+ and CD8+ T-cell immune responses are required for optimal efficacy against ocular HSV-1 challenge. We will determine the ability of different vaccines, including the optical vaccine determined empirically in specific aim 1, to protect CD4 and C8 """"""""knockout"""""""" mice against ocular challenge. Vaccine experiments with passive antibody transfer will also be done. These studies should reveal the type or combination of types of immune response that provide the most efficacious protection. 3. Confirm the hypothesis that local IL-2 and/or TNF-alpha are important in protection against eye disease following ocular HSV-1 challenge. Using selected vaccines we will confirm our preliminary correlation between local IL-2 and/or local TNF-alpha responses, and optimal protection against eye disease and latency. Depletion experiments with anti-IL-2 and anti-TNF-alpha monoclonal antibodies will be done to provide further evidence for the importance of IL-2 and/or TNF-alpha.
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