This is a Phase 1, interventional, non-randomized, experimental infection model study in healthy adult males (N=up to 25) between the ages of 18-35 at study enrollment. The study is designed to test the requirements of predicted N. gonorrhoeae virulence determinants for gonococcal infection in the male urethra through infection with engineered mutants of N. gonorrhoeae. We hypothesize that key virulence determinants involved in N. gonorrhoeae adherence and resistance to innate immunity are essential for infection in the male urethra. We predict that mutations abolishing expression of these virulence determinants will eliminate or significantly reduce gonococcal infectivity or the ability to induce inflammation in an infected individual, thus identifying potential vaccine candidates. For each mutant to be investigated under this protocol, initial trials will be conducted in which subjects receive a bacterial inoculum containing a mixture of equivalent numbers of two isogenic strains, differing in expression of one or more genes. A competitive advantage for one strain during urethral infection will be manifest by recovery of that strain in a statistically significantly higher proportion of isolates recovered from infected subjects than in the inoculum. Following infections with mixed inocula, infectivity of the mutant in single-strain infections will be compared to that of the wild-type in single-strain infections. In addition, the proportion of infected subjects that develop signs or symptoms of urethritis with mutant and wild- type inocula will be compared. The Mixed FA7527/FA1090 group (n = up to 25 ) will receive a bacterial inoculum containing a mixture of equivalent numbers of the isogenic mutant and WT strains. In single-strain infections, the Mutant FA7527 group (n = up to 8) will receive a bacterial inoculum containing only the isogenic mutant N. gonorrhoeae strain, and the Wild-type FA1090 group (n = up to 8) will receive a bacterial inoculum containing only the wild-type (WT) N. gonorrhoeae strain. All subjects will be examined daily for symptoms of infection and receive antibiotic treatment at the end of the inpatient portion of the trial. Study duration will be 1 year, and the duration for all participants will be about 3 weeks. The primary objective of the study is to compare the ability of different engineered mutants of Neisseria gonorrhoeae to cause a clinical infection (signs or symptoms of urethritis such as discomfort during urination, urethral discharge, etc.) in the male urethra. The study secondary objectives are to: (1) characterize host immune responses to infection by measuring cytokines and other mediators in specimens including serum, peripheral blood lymphocytes and urine obtained from subjects before, during and after experimental gonococcal infection, and (2) characterize bacterial gene expression during experimental infection.
This is a Phase 1, interventional, non-randomized, experimental infection model study in healthy adult males (N=up to 25) between the ages of 18-35 at study enrollment. The study is designed to test the requirements of predicted N. gonorrhoeae virulence determinants for gonococcal infection in the male urethra through infection with engineered mutants of N. gonorrhoeae. We predict that mutations abolishing expression of N. gonorrhoeae virulence determinants will eliminate or significantly reduce gonococcal infectivity or the ability to induce inflammation in an infected individual, thus identifying potential vaccine candidates. Study duration will be 1 year, and the duration for all participants will be about 3 weeks. The primary objective of the study is to compare the ability of different engineered mutants of Neisseria gonorrhoeae to cause a clinical infection (signs or symptoms of urethritis such as discomfort during urination, urethral discharge, etc.) in the male urethra.