The bacterium that causes syphilis, Treponema pallidum subsp. pallidum, disseminates widely throughout an infected host to infect every organ and tissue. Previous studies conducted in the Cameron laboratory have identified a surface-exposed T. pallidum adhesin, designated Tp0751, which mediates attachment to endothelial cells and, as such, plays an important role in the process of T. pallidum dissemination. In initial studies, immunization of rabbits with this treponemal adhesin induced an immune response that provided significant protection against T. pallidum dissemination. The long-term objective of the studies contained in this proposal is to expand on these prior promising protection results and develop an enhanced vaccinogen that fully protects immunized animals against disseminated T. pallidum infection. To accomplish this objective, the following specific aims are proposed: (1) determine the protective region(s) of the Tp0751 immunogen; (2) optimize the Tp0751 vaccinogen formulation; (3) optimize the delivery of the Tp0751 vaccinogen; and (4) test the heterologous protective capacity and duration of achieved protection of the optimal Tp0751 and Tpr vaccine formulation and delivery system. We anticipate these investigations will generate a syphilis candidate vaccine that exhibits protection against disseminated infection and, when combined with the optimized Tpr vaccinogen from Scientific Project 2, will provide complete protection against syphilis.