Urinary tract infections (UTI) remain among the most common bacterial infections. They are a frequent cause of morbidity and constitute a large public health cost to society. Recurrent UTIs constitute a serious health problem, especially to adult women and female children. These infections are caused primarily by E. coli which infect the bladder by an ascending route from the fecal flora. Even in patients without demonstrable vesicoureteral reflux or obstruction, a lower tract UTI may proceed to pyelonephritis. The overall goal of this research is to establish a safe, effective vaccine treatment against UTI. The current approach to treating women with recurrent UTIs is to prevent infection by long-term administration of low dose antibiotics. This treatment is largely successful, but extended use of antibiotics carries the risk of allergic reactions in patients and development of antibiotic resistant uropathogens. An alternative treatment approach is to boost a patient's innate resistance to UTI by immunization. Two European research groups have tested parenteral and oral immunization against UTI with some success. We have previously demonstrated in animal models that vaginal mucosal immunization with killed bacteria can lessen the severity or duration of an induced UTI. Our current investigations are now focused on applying this immunization method in women susceptible to recurrent UTIs. During the past 2 years we have successfully completed a Phase I clinical trial which demonstrated no adverse effects from vaginal mucosal immunization. A Phase II clinical trial to test vaccine efficacy has been initiated in the past 6 months. Review of the early data indicates a positive treatment effect in immunized subjects. This ongoing research is the only U.S. clinical trial of a vaccine against UTI. In this proposal we will: 1) complete the Phase II clinical trial of vaginal mucosal immunization using a killed whole-cell vaccine, 2) identify E. coli antigens that are most responsible for eliciting UTI- protective antibodies, and 3) develop an acellular, endotoxin-free vaccine for stimulating protective antibodies in the urogenital tract.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK030808-13
Application #
2138512
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1982-04-01
Project End
1997-08-31
Budget Start
1995-09-12
Budget End
1996-08-31
Support Year
13
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Surgery
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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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