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 UTIs have an ascending route from the E. coli in fecal and introital flora. Depending on the type of surface proteins (fimbriae) on the E. coli, the infection may be limited to cystitis; whereas other E. coli strains (P-fimbriated) are likely to cause pyelonephritis. Following certain types of human and experimental UTI, there is an increase in locally secreted immunoglobulins, especially secretory IgA. This immune response can be augmented by immunization. Our previous research in rats has presented evidence that immunization against UTI is best achieved by instillation of antigens onto a contiguous mucosal surface, the vagina. Vaginal immunization against UTI induces an IgA and IgG immune response in the bladder as measured by an ELISA assay, causes decreased bacterial adherence to bladder epithelium, results in faster resolution of an induced UTI, and decreases damage to the bladder epithelium as visualize by scanning electron microscopy. In this proposal, we plan to extend this vaginal immunizing program to assess whether we can protect cynomolgus monkeys against induced ascending UTI. Following induction of cystitis or pyelonephritis with E. coli strains (including some with P-fimbriae), immunized monkeys will be compared to non-immunized controls with regard to urinary bacterial counts, duration of bacteriuria, elevations of C-reactive protein, local secretion of antibodies, urinary and vaginal mucin levels, and other measures to assess the severity of the infection. In this way, we hope to define the optimal regimen to follow for vaginal immunization against UTIs in primates with the eventual goal of having an effective and safe immunizing regimen against UTIs in humans.

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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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University of Wisconsin Madison
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Hopkins, Walter J; Elkahwaji, Johny; Beierle, Lori M et al. (2007) Vaginal mucosal vaccine for recurrent urinary tract infections in women: results of a phase 2 clinical trial. J Urol 177:1349-53;quiz 1591
Uehling, David T; Hopkins, Walter J; Elkahwaji, Johny E et al. (2003) Phase 2 clinical trial of a vaginal mucosal vaccine for urinary tract infections. J Urol 170:867-9
Morin, Michelle D; Hopkins, Walter J (2002) Identification of virulence genes in uropathogenic Escherichia coli by multiplex polymerase chain reaction and their association with infectivity in mice. Urology 60:537-41
Uehling, D T; Hopkins, W J; Beierle, L M et al. (2001) Vaginal mucosal immunization for recurrent urinary tract infection: extended phase II clinical trial. J Infect Dis 183 Suppl 1:S81-3
Jones-Carson, J; Balish, E; Uehling, D T (1999) Susceptibility of immunodeficient gene-knockout mice to urinary tract infection. J Urol 161:338-41
Hopkins, W J; Heisey, D M; Uehling, D T (1999) Association of human leucocyte antigen phenotype with vaccine efficacy in patients receiving vaginal mucosal immunization for recurrent urinary tract infection. Vaccine 17:169-71
Hopkins, W J; Uehling, D T; Wargowski, D S (1999) Evaluation of a familial predisposition to recurrent urinary tract infections in women. Am J Med Genet 83:422-4
Hopkins, W J; Heisey, D M; Lorentzen, D F et al. (1998) A comparative study of major histocompatibility complex and red blood cell antigen phenotypes as risk factors for recurrent urinary tract infections in women. J Infect Dis 177:1296-301
Uehling, D T; Hopkins, W J; Balish, E et al. (1997) Vaginal mucosal immunization for recurrent urinary tract infection: phase II clinical trial. J Urol 157:2049-52
Hopkins, W; Gendron-Fitzpatrick, A; McCarthy, D O et al. (1996) Lipopolysaccharide-responder and nonresponder C3H mouse strains are equally susceptible to an induced Escherichia coli urinary tract infection. Infect Immun 64:1369-72

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