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.
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
16
Alternative antibiotic treatment failure therapy: Azithromycin 2 g orally in a single dose after treatment failure with both cephalosporin and quinolone antibiotics.
Mandatory antibiotic treatment failure therapy: Ceftriaxone 250 mg intramuscular in a single dose on patient request, at the onset of symptoms, or on the 5th study day after inoculation.
Mandatory antibiotic treatment failure therapy: Ciprofloxacin 500 mg orally in a single dose on patient request, at the onset of symptoms or on the 5th study day after inoculation.
0.4 mL of a suspension containing 10\^5 - 10\^6 CFU of wild-type (WT) Neisseria gonorrhoeae, in phosphate-buffered saline, delivered to the anterior urethra through a No.8 pediatric French catheter.
0.4 mL of a suspension containing 10\^5 - 10\^6 CFU of isogenic LptA mutant Neisseria gonorrhoeae, in phosphate-buffered saline, delivered to the anterior urethra through a No.8 pediatric French catheter.
University of North Carolina Health Care - Infectious Diseases
Chapel Hill, North Carolina, United States
The Proportion of Participants That Become Infected With Individual N. Gonorrhoeae Strains in Non-competitive Infections
Infection defined as reported symptoms of urethritis, including urethral discharge or dysuria, plus presence of gram-negative intracellular diplococci in a urethral swab smear. The proportion of infected participants by Day 5 with N. gonorrhoeae was assessed by group among participants with non-competitive infections. Participants could become infected and received treatment any day before or on day 5.
Time frame: Day of infection, any day between Day 1 and Day 5
The Proportion of Participants That Become Infected With Mixed Inoculum
Infection defined as reported symptoms of urethritis, including urethral discharge or dysuria, plus presence of gram-negative intracellular diplococci in a urethral swab smear. Participants could become infected and received treatment any day before or on day 5.
Time frame: Day of infection, any day between Day 1 and Day 5
The Proportion of Wild Type (WT) Organisms Recovered From Urine and Urethral Swab Specimens From Individual Subjects Infected With Mixed Inoculum
Infection defined as reported symptoms of urethritis, including urethral discharge or dysuria, plus presence of gram-negative intracellular diplococci in a urethral swab smear. Participants could become infected and received treatment any day before or on day 5.
Time frame: Baseline (Day 0) and the day of infection (any day between Day 1 and Day 5)
EGF Cytokine Levels in Peripheral Blood
EGF Cytokine levels in peripheral blood collected from subjects were measured at the screening visit, during experimental infection and at the follow-up visit. Only cytokines detected during the treatment visit upon experimental infection or day 5 in \> 50% of peripheral blood samples are included. Cytokine outcome values reported below the limit of quantitation are assigned 1/2 the lower limit of quantitation for calculation of mean values; limits of 95% confidence intervals are bounded by 1/2 the lower limit of quantitation and the upper limit of quantitation for each cytokine.
Time frame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
Eotaxin Cytokine Levels in Peripheral Blood
Eotaxin cytokine levels in peripheral blood collected from subjects were measured at the screening visit, during experimental infection and at the follow-up visit. Only cytokines detected during the treatment visit upon experimental infection or day 5 in \> 50% of peripheral blood samples are included. Cytokine outcome values reported below the limit of quantitation are assigned 1/2 the lower limit of quantitation for calculation of mean values; limits of 95% confidence intervals are bounded by 1/2 the lower limit of quantitation and the upper limit of quantitation for each cytokine.
Time frame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
G-CSF Cytokine Levels in Peripheral Blood
G-CSF Cytokine levels in peripheral blood collected from subjects were measured at the screening visit, during experimental infection and at the follow-up visit. Only cytokines detected during the treatment visit upon experimental infection or day 5 in \> 50% of peripheral blood samples are included. Cytokine outcome values reported below the limit of quantitation are assigned 1/2 the lower limit of quantitation for calculation of mean values; limits of 95% confidence intervals are bounded by 1/2 the lower limit of quantitation and the upper limit of quantitation for each cytokine.
Time frame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
Fractalkine Cytokine Levels in Peripheral Blood
Fractalkine Cytokine levels in peripheral blood collected from subjects were measured at the screening visit, during experimental infection and at the follow-up visit. Only cytokines detected during the treatment visit upon experimental infection or day 5 in \> 50% of peripheral blood samples are included. Cytokine outcome values reported below the limit of quantitation are assigned 1/2 the lower limit of quantitation for calculation of mean values; limits of 95% confidence intervals are bounded by 1/2 the lower limit of quantitation and the upper limit of quantitation for each cytokine.
Time frame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
GRO Cytokine Levels in Peripheral Blood
GRO Cytokine levels in peripheral blood collected from subjects were measured at the screening visit, during experimental infection and at the follow-up visit. Only cytokines detected during the treatment visit upon experimental infection or day 5 in \> 50% of peripheral blood samples are included. Cytokine outcome values reported below the limit of quantitation are assigned 1/2 the lower limit of quantitation for calculation of mean values; limits of 95% confidence intervals are bounded by 1/2 the lower limit of quantitation and the upper limit of quantitation for each cytokine.
Time frame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
IL-1RA Cytokine Levels in Peripheral Blood
IL-1RA Cytokine levels in peripheral blood collected from subjects were measured at the screening visit, during experimental infection and at the follow-up visit. Only cytokines detected during the treatment visit upon experimental infection or day 5 in \> 50% of peripheral blood samples are included. Cytokine outcome values reported below the limit of quantitation are assigned 1/2 the lower limit of quantitation for calculation of mean values; limits of 95% confidence intervals are bounded by 1/2 the lower limit of quantitation and the upper limit of quantitation for each cytokine.
Time frame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
IL-8 Cytokine Levels in Peripheral Blood
IL-8 Cytokine levels in peripheral blood collected from subjects were measured at the eligibility testing visit, during experimental infection and at the follow-up visit. Only cytokines detected during experimental infection in \> 50% of peripheral blood samples are included. Cytokine outcome values reported below the limit of quantitation are assigned 1/2 the lower limit of quantitation for calculation of mean values; limits of 95% confidence intervals are bounded by 1/2 the lower limit of quantitation and the upper limit of quantitation for each cytokine.
Time frame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
IP-10 Cytokine Levels in Peripheral Blood
IP-10 Cytokine levels in peripheral blood collected from subjects were measured at the screening visit, during experimental infection and at the follow-up visit. Only cytokines detected during the treatment visit upon experimental infection or day 5 in \> 50% of peripheral blood samples are included. Cytokine outcome values reported below the limit of quantitation are assigned 1/2 the lower limit of quantitation for calculation of mean values; limits of 95% confidence intervals are bounded by 1/2 the lower limit of quantitation and the upper limit of quantitation for each cytokine.
Time frame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
MCP-1 Cytokine Levels in Peripheral Blood
MCP-1 Cytokine levels in peripheral blood collected from subjects were measured at the eligibility testing visit, during experimental infection and at the follow-up visit. Only cytokines detected during experimental infection in \> 50% of peripheral blood samples are included. Cytokine outcome values reported below the limit of quantitation are assigned 1/2 the lower limit of quantitation for calculation of mean values; limits of 95% confidence intervals are bounded by 1/2 the lower limit of quantitation and the upper limit of quantitation for each cytokine.
Time frame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
MIP-1Beta Cytokine Levels in Peripheral Blood
MIP-1Beta Cytokine levels in peripheral blood collected from subjects were measured at the screening visit, during experimental infection and at the follow-up visit. Only cytokines detected during the treatment visit upon experimental infection or day 5 in \> 50% of peripheral blood samples are included. Cytokine outcome values reported below the limit of quantitation are assigned 1/2 the lower limit of quantitation for calculation of mean values; limits of 95% confidence intervals are bounded by 1/2 the lower limit of quantitation and the upper limit of quantitation for each cytokine.
Time frame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
VEGF Cytokine Levels in Peripheral Blood
VEGF Cytokine levels in peripheral blood collected from subjects were measured at the screening visit, during experimental infection and at the follow-up visit. Only cytokines detected during the treatment visit upon experimental infection or day 5 in \> 50% of peripheral blood samples are included. Cytokine outcome values reported below the limit of quantitation are assigned 1/2 the lower limit of quantitation for calculation of mean values; limits of 95% confidence intervals are bounded by 1/2 the lower limit of quantitation and the upper limit of quantitation for each cytokine.
Time frame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
EGF Cytokine Levels in Urine
EGF Cytokine levels in urine collected from subjects were measured at the screening visit, during experimental infection and at the follow-up visit. Only cytokines detected during the treatment visit upon experimental infection or day 5 in \> 50% of both the urine and peripheral blood samples are included. Cytokine outcome values reported below the limit of quantitation are assigned 1/2 the lower limit of quantitation for calculation of mean values; limits of 95% confidence intervals are bounded by 1/2 the lower limit of quantitation and the upper limit of quantitation for each cytokine. Only the cytokines measured in both the urine and peripheral blood samples are included. Cytokine outcome values reported below the limit of detection are excluded.
Time frame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
Eotaxin Cytokine Levels in Urine
Eotaxin Cytokine levels in urine collected from subjects were measured at the screening visit, during experimental infection and at the follow-up visit. Only cytokines detected during the treatment visit upon experimental infection or day 5 in \> 50% of both the urine and peripheral blood samples are included. Cytokine outcome values reported below the limit of quantitation are assigned 1/2 the lower limit of quantitation for calculation of mean values; limits of 95% confidence intervals are bounded by 1/2 the lower limit of quantitation and the upper limit of quantitation for each cytokine. Only the cytokines measured in both the urine and peripheral blood samples are included. Cytokine outcome values reported below the limit of detection are excluded.
Time frame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
G-CSF Cytokine Levels in Urine
G-CSF Cytokine levels in urine collected from subjects were measured at the screening visit, during experimental infection and at the follow-up visit. Only cytokines detected during the treatment visit upon experimental infection or day 5 in \> 50% of both the urine and peripheral blood samples are included. Cytokine outcome values reported below the limit of quantitation are assigned 1/2 the lower limit of quantitation for calculation of mean values; limits of 95% confidence intervals are bounded by 1/2 the lower limit of quantitation and the upper limit of quantitation for each cytokine. Only the cytokines measured in both the urine and peripheral blood samples are included. Cytokine outcome values reported below the limit of detection are excluded.
Time frame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
Fractalkine Cytokine Levels in Urine
Fractalkine Cytokine levels in urine collected from subjects were measured at the screening visit, during experimental infection and at the follow-up visit. Only cytokines detected during the treatment visit upon experimental infection or day 5 in \> 50% of both the urine and peripheral blood samples are included. Cytokine outcome values reported below the limit of quantitation are assigned 1/2 the lower limit of quantitation for calculation of mean values; limits of 95% confidence intervals are bounded by 1/2 the lower limit of quantitation and the upper limit of quantitation for each cytokine. Only the cytokines measured in both the urine and peripheral blood samples are included. Cytokine outcome values reported below the limit of detection are excluded.
Time frame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
GRO Cytokine Levels in Urine
GRO Cytokine levels in urine collected from subjects were measured at the screening visit, during experimental infection and at the follow-up visit. Only cytokines detected during the treatment visit upon experimental infection or day 5 in \> 50% of both the urine and peripheral blood samples are included. Cytokine outcome values reported below the limit of quantitation are assigned 1/2 the lower limit of quantitation for calculation of mean values; limits of 95% confidence intervals are bounded by 1/2 the lower limit of quantitation and the upper limit of quantitation for each cytokine. Only the cytokines measured in both the urine and peripheral blood samples are included. Cytokine outcome values reported below the limit of detection are excluded.
Time frame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
IL-1RA Cytokine Levels in Urine
IL-1RA Cytokine levels in urine collected from subjects were measured at the screening visit, during experimental infection and at the follow-up visit. Only cytokines detected during the treatment visit upon experimental infection or day 5 in \> 50% of both the urine and peripheral blood samples are included. Cytokine outcome values reported below the limit of quantitation are assigned 1/2 the lower limit of quantitation for calculation of mean values; limits of 95% confidence intervals are bounded by 1/2 the lower limit of quantitation and the upper limit of quantitation for each cytokine. Only the cytokines measured in both the urine and peripheral blood samples are included. Cytokine outcome values reported below the limit of detection are excluded.
Time frame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
IL-8 Cytokine Levels in Urine
IL-8 Cytokine levels in urine collected from subjects were measured at the screening visit, during experimental infection and at the follow-up visit. Only cytokines detected during the treatment visit upon experimental infection or day 5 in \> 50% of both the urine and peripheral blood samples are included. Cytokine outcome values reported below the limit of quantitation are assigned 1/2 the lower limit of quantitation for calculation of mean values; limits of 95% confidence intervals are bounded by 1/2 the lower limit of quantitation and the upper limit of quantitation for each cytokine. Only the cytokines measured in both the urine and peripheral blood samples are included. Cytokine outcome values reported below the limit of detection are excluded.
Time frame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
IP-10 Cytokine Levels in Urine
IP-10 Cytokine levels in urine collected from subjects were measured at the screening visit, during experimental infection and at the follow-up visit. Only cytokines detected during the treatment visit upon experimental infection or day 5 in \> 50% of both the urine and peripheral blood samples are included. Cytokine outcome values reported below the limit of quantitation are assigned 1/2 the lower limit of quantitation for calculation of mean values; limits of 95% confidence intervals are bounded by 1/2 the lower limit of quantitation and the upper limit of quantitation for each cytokine. Only the cytokines measured in both the urine and peripheral blood samples are included. Cytokine outcome values reported below the limit of detection are excluded.
Time frame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
MCP-1 Cytokine Levels in Urine
MCP-1 Cytokine levels in urine collected from subjects were measured at the screening visit, during experimental infection and at the follow-up visit. Only cytokines detected during the treatment visit upon experimental infection or day 5 in \> 50% of both the urine and peripheral blood samples are included. Cytokine outcome values reported below the limit of quantitation are assigned 1/2 the lower limit of quantitation for calculation of mean values; limits of 95% confidence intervals are bounded by 1/2 the lower limit of quantitation and the upper limit of quantitation for each cytokine. Only the cytokines measured in both the urine and peripheral blood samples are included. Cytokine outcome values reported below the limit of detection are excluded.
Time frame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
MIP-1Beta Cytokine Levels in Urine
MIP-1Beta Cytokine levels in urine collected from subjects were measured at the screening visit, during experimental infection and at the follow-up visit. Only cytokines detected during the treatment visit upon experimental infection or day 5 in \> 50% of both the urine and peripheral blood samples are included. Cytokine outcome values reported below the limit of quantitation are assigned 1/2 the lower limit of quantitation for calculation of mean values; limits of 95% confidence intervals are bounded by 1/2 the lower limit of quantitation and the upper limit of quantitation for each cytokine. Only the cytokines measured in both the urine and peripheral blood samples are included. Cytokine outcome values reported below the limit of detection are excluded.
Time frame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
VEGF Cytokine Levels in Urine
VEGF Cytokine levels in urine collected from subjects were measured at the screening visit, during experimental infection and at the follow-up visit. Only cytokines detected during the treatment visit upon experimental infection or day 5 in \> 50% of both the urine and peripheral blood samples are included. Cytokine outcome values reported below the limit of quantitation are assigned 1/2 the lower limit of quantitation for calculation of mean values; limits of 95% confidence intervals are bounded by 1/2 the lower limit of quantitation and the upper limit of quantitation for each cytokine. Only the cytokines measured in both the urine and peripheral blood samples are included. Cytokine outcome values reported below the limit of detection are excluded.
Time frame: Screening Visit (Day -30 to Day -1), Treatment Visit (Day 1 to Day 5), and Follow-Up Visit (3 to 7 days following Treatment Visit)
Pattern of Gonococcal Gene Expression in Urine Sediment
RNA-seq is the standard method for measuring bacterial gene expression.
Time frame: Day 1 through Day 5
Quantity of Gonococcal Gene Expression in Urine Sediment
RNA-seq is the standard method for measuring bacterial gene expression.
Time frame: Day 1 through Day 5
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.