This application was designed to continue evaluation of the host-parasite interaction in the pathogenesis of pyelonephritis. Our knowledge has led us to a method to design an effective vaccine to prevent recurrent upper urinary tract infections and the end stage renal disease which may follow. Since patients with recurrent urinary tract infections tend to be non- secretors, meaning they lack A, B, O blood group antigens in their secretions, we will evaluate secretor status in the monkey as we have recently found that some individual monkeys are secretors, while others are non-secretors. Bacterial factors to be evaluated will follow study of clinical bacterial isolates from different settings using restriction fragment length polymorphism patterns. By so doing it should allow substantiation of the hypothesis that nephropathogenic E. coli belong to a restricted number of clones. This being the case, they should also have a restricted number of serologically different P fimbriae which should allow us to evaluate a multivalent P fimbriae vaccine in our experimental animal. Other bacterial virulence factors to be studied include porins and the specific P fimbriae tip protein responsible for bacterial adherence. The structure of this protein has been determined using molecular genetics and in the consortium portion of this grant, synthetic vaccines will be based upon structural analysis of this tip protein. The vaccine will utilize porins, as well as the superantigen tetanus toxoid as a carrier. The vaccines will be tested together with different relevant E. coli serotypes, and specific O antigen oligosaCcharide-protein conjugates since recent studies have shown that such a conjugant protects against renal scarring. By the knowledge thus gained with these vaccine candidates in the nonhuman primate, it is planned to design a vaccine(s) to be tested in phase one clinical trials in human volunteers.
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