Urinary tract infections (UTI) remain a common clinical problem: they have especially high morbidity in children and may lead to severe pyelonephritis and bacteremia. Most UTI's have an ascending route from the E. coli in fecal and inroital flora. E. coli with virulence factors such as P-fimbriae may cause pyelonephritis even in """"""""non-obstructed"""""""" and non-refluxing patients. Following a UTI, there is a local and systemic immune response. In susceptible patients, this immune response has been shown to be diminished. Our previous research in rats has shown that vaginal immunization can augment the immune response which, in turn, results in faster resolution of induced UTI's. Because of safety and its local effects, the vaginal surface route may be optimal. In applying this hypothesis to primates, we have again shown that vaginal immunization causes local and systemic immune responses and hastens the resolution of an induced cystitis. In this proposal, we plan to continue developing a vaginal immunogen to protect cynomolgus monkeys against induced ascending UTI's. Because increasing the antigen dose in the immunizing regimen caused a decrease in immune responses and protection afforded, we believe it is necessary to more thoroughly examine vaccine doses and administration. In the first year we will develop an optimal immunizing schedule for E. coli strain 1677, with which we have had the most experience, and test the efficacy of that regimen. During the immunization and cystitis periods we will fully characterize the systemic and local immune responses by quantitation of immunoglobulin levels, monitoring the activity of helper and suppressor T cell, and determining antibody specificities by immunoblots. Experiments to be conducted in the second and third years will be designed to test an immunogen made from multiple E. coli strains. In the third year, we propose to initiate a Phase I clinical trial of the multi-strain vaginal immunogen in human subjects.
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