Walter J. Hopkins

Vaginal Mucosal Immunization for Recurrent Urinary Tract Infection: Phase II Clinical Trial

PURPOSE Decreased local immunity to uropathogenic bacteria may be a factor predisposing women to recurrent urinary tract infections. Our phase I study demonstrated the safety of a multi-strain vaccine administered as a vaginal suppository. A phase II study was conducted to determine vaccine efficacy. MATERIALS AND METHODS A total of 91 women susceptible to recurrent urinary tract infections was entered into the study and the courses were analyzed in a randomized, double-blind, placebo controlled trial of vaginal mucosal immunization. Subjects received 3 vaginal suppositories at weekly intervals. Depending on the treatment group each suppository contained 1 of 2 vaccine doses or suppository material only. Each patient was followed for 5 months to record infection episodes, and obtain urine, vaginal irrigates and serum to measure immunological responses. RESULTS Immunogen treated women who were off antibiotic prophylaxis throughout the study had a significant delay in interval to reinfection during the first 8 weeks compared to women receiving placebo. Mean interval until reinfection was delayed from 8.7 weeks for placebo treated to 13 weeks for vaccine treated women. Immunological responses in serum, urine and vaginal fluid were variable. No serious adverse effects were observed. CONCLUSIONS These data demonstrate that vaginal mucosal immunization can enhance resistance to urinary tract infections in susceptible patients.

Vaginal mucosal immunization for recurrent urinary tract infection : Extended phase II clinical trial

Many women remain susceptible to ascending urinary tract infections (UTIs) despite the absence of a demonstrable anatomic abnormality [1]. Repeated treatment with antibiotics is often necessary for these women but may lead to adverse reactions and infection with antibiotic-resistant organisms [2]. On the basis of concepts of mucosal immunity in the genitourinary tract [3-5], we have been working to develop an effective mucosally applied vaginal immunogen to help prevent ascending UTIs. After a trial in nonhuman primates, we carried out and reported two previous clinical trials in susceptible women [6-8]. We are now reporting on a clinical trial to extend the time period of protection through use of the same multivalent vaginal immunogen and through immunogen boosts given at 4week intervals.

Acute acrolein-induced cystitis in mice

To develop a method of direct intravesical administration of acrolein and evaluate the severity of cystitis in response to increasing doses of acrolein in female C57BL/6N (C57) mice, with further studies to compare the severity of acute acrolein‐induced cystitis among C57, C3H/HeJ (HeJ), and C3H/OuJ (OuJ) strains of mice, as chemical cystitis produced by the systemic administration of cyclophosphamide is thought to result from renal excretion of hepatic metabolites, particularly acrolein.

Immunization Against Urinary Tract Infection with a Multi-Valent Vaginal Vaccine

Systemic and local immune responses are thought to play an important role in susceptibility to urinary tract infection. In an attempt to boost local immunity, a vaccine was administered parenterally or vaginally to two mouse strains. Both routes of immunization increased the number of splenic antibody-forming cells against the bacterial strains in the vaccine. Following vaginal or parenteral immunization and subsequent induction of cystitis with live E. coli, immunized animals had fewer viable bladder E. coli than non-immunized animals.

Vaginal immunization against induced cystitis in monkeys.

Cynomolgus monkeys received either vaginal immunization with formalin-killed E. coli or vaginal instillation of excipient without the bacteria. At 2, 7, 14 and 21 days after induction of a urinary tract infection with live E. coli, immunized monkeys showed enhanced clearance of bacteriuria compared to non-immunized controls. Immunized monkeys also showed increased levels of urinary anti-E. coli IgA and IgG after the immunizing and infecting procedures. Induction of heightened local immunity by vaginal immunization may lessen host susceptibility to urinary tract infections.

Congenital Immunodeficiencies in Mice Increase Susceptibility to Urinary Tract Infection

Severe combined immunodeficient (SCID), T cell deficient, and immunocompetent mice were challenged intravesically with viable uropathogenic Escherichia coli. In comparison to immunocompetent controls, SCID mice had significantly greater numbers of viable E. coli in their bladders and kidneys 7 days after inoculation. Splenic anti-E. coli antibody-forming cells (AFC) were virtually absent in SCID mice at 7.0 days after infection. Adoptive transfer of spleen cells from E. coli-immunized immunocompetent mice to SCID mice enhanced their resistance to urinary tract infection (UTI), as evidenced by lower bacterial counts in bladder and kidneys following an induced infection. Congenitally T cell deficient nude mice and immunocompetent heterozygous controls had equivalent bladder and kidney infection levels at 2 and 7 days after UTI. Immunocompetency thus appears to play a significant role in resistance to E. coli UTI in this animal model. Since mice deficient only in T cells did not show increased UTI susceptibility, T cell-independent antibody responses may be an important immunologic defense mechanism.

Vaginal Immunization of Monkeys against Urinary Tract Infection with a Multi-Strain Vaccine

Cynomolgus monkeys were treated with a vaccine containing 10 heat-killed uropathogenic bacteria including 6 Escherichia coli strains. The multi-strain vaccine was administered either as a vaginal surface immunogen or intramuscularly. Following an induced E. coli cystitis, bladder infections were significantly reduced compared with controls at 1 and 2 weeks (intramuscular route) or 1 week (vaginal route) after UTI. This vaccine has been shown to be efficacious against cystitis in humans when given parenterally and has now proved efficacious in nonhuman primates by the vaginal mucosal route.

A Comparative Study of Major Histocompatibility Complex and Red Blood Cell Antigen Phenotypes as Risk Factors for Recurrent Urinary Tract Infections in Women

Recurrent urinary tract infections (RUTI) are a significant health problem for many women, and host characteristics that increase susceptibility are not completely defined. This study evaluated data from 99 patients to examine further the question of a possible association between major histocompatibility complex (MHC) or red blood cell (RBC) antigen phenotype and predisposition to RUTIs. MHC class I and II, ABO, and Lewis RBC phenotypes were determined serologically. The MHC class II phenotypes of 55 subjects were also determined by DNA polymerase chain reaction techniques. There were no significant differences in the proportions of HLA-A or -B antigen types between patients and controls, nor in the frequencies of serologically or DNA-defined HLA-DR or -DQ phenotypes. Patient ABO and Lewis RBC phenotypes were not statistically different than those for controls. Thus, the overall risk for women to develop RUTIs does not appear to be associated with any single HLA, ABO, or Lewis phenotype.

Decreased immunologic responsiveness following intensified vaginal immunization against urinary tract infection.

In an attempt to further increase the protective effect of vaginal immunization against urinary tract infections in Cynomolgus monkeys, the immunogen of killed E. coli was given more times, in larger amounts, and with the adjuvant MDP. Instead of increasing the protective effect, no protective effect on induced cystitis was observed. In addition, rises in urinary and serum immunoglobulins previously observed after vaginal immunization and induced cystitis were lessened. These observations appear to correspond with the classical concepts of immunologic unresponsiveness.

Urinary glycosaminoglycan levels following induced cystitis in monkeys.

Urinary glycosaminoglycan (GAG) levels were measured by the Whiteman assay in five monkeys following induction of an E. coli urinary tract infection. Urinary GAG levels rose as the infection developed and returned to baseline levels as the infection resolved. Elevated urinary GAG levels may be a marker for the tissue injury incurred by such infections and may offer insight into their pathophysiology.