Efficacy of Immunization With 4C-MenB in Preventing Experimental Urethral Infection With Neisseria Gonorrhoeae

The study is a single-site, double-blind randomized controlled trial to test whether vaccination with 4C-MenB, BEXSERO™ (approved for protection against invasive disease with group B Neisseria meningitidis), according to the FDA-approved schedule , provides protection from urethral infection with Neisseria gonorrhoeae in the controlled human male gonococcal infection model. The study will be conducted in 3 phases: 1) initial vaccination phase, 2) Neisseria gonorrhoeae challenge phase, and 3) post-challenge vaccination phase.

The study intervention is vaccination with two doses of BEXSERO™ and two commercially available FDA-approved vaccines that do not have relevance to Neisseria gonorrhoeae: quadrivalent influenza (FLULAVAL™) and tetanus/diphtheria (TDVAX™). At enrollment, participants are randomized in a 1:1 ratio to the control vaccine arm or the experimental vaccine arm. All participants receive two immunizations prior to the bacterial challenge phase and two immunizations in the post-challenge phase. Individuals assigned to the experimental arm receive two doses of BEXSERO™ prior to Neisseria gonorrhoeae challenge and control vaccines in the post-challenge vaccination phase. Participants assigned to the control arm receive FLULAVAL™ and TDVAX™ prior to challenge and BEXSERO™ in the post-challenge vaccination phase. Primary and secondary outcomes are determined following bacterial challenge. This study design provides clinical equipoise, because all participants receive the known benefits associated with administration of BEXSERO™ for protection against meningococcal disease.

For bacterial challenge, all participants receive a suspension containing 10^6 colony-forming units of Neisseria gonorrhoeae strain FA1090 delivered to the anterior urethra. This dose has been shown to produce symptomatic gonococcal urethritis in 80-90% of unvaccinated, exposed participants within 5 days after bacterial inoculation. Participants are followed with daily visits to assess for development of urethritis and presence of Neisseria gonorrhoeae in their urine. Participants receive 100% effective antibiotic treatment when (1) requested by the participant regardless of signs, symptoms or positive cultures, (2) urethral discharge is observed by the examining clinician or reported by the participant, or (3) 10 days after urethral inoculation with bacterial product, regardless of infection status.

Inclusion criteria

Participants must meet all the inclusion criteria to participate in the study.

• Assigned male at birth and now ≥ 18 and < 36 years old
• No history of prior Neisseria meningitidis serogroup B (MenB) vaccination
• Able and willing to be located easily by providing street address and telephone number (land line and/or cell phone number)
• Willingness to provide written informed consent
• Informed consent obtained and signed
• Able and willing to attend all study visits
• Able and willing to abstain from all sexual activity involving contact with the participant's penis, urine, or semen and a person other than the participant during experimental gonococcal infection phase until the follow-up test for gonorrhea is negative
• Able and willing to abstain from scheduled immunizations other than those provided through the study, between enrollment and completion of Ng challenge.
• No clinically significant abnormalities on physical exam
• Urinalysis: leukocyte esterase and WBC values within normal limits
• 50% complement hemolytic activity (CH50) within normal limits (WNL)
• Negative HIV and syphilis test results at the screening visit
• Denies history of bleeding diathesis
• Denies history of seizures (due to reports of seizures with ciprofloxacin), history of childhood febrile seizure acceptable
• Denies history of cancer, except basal cell carcinoma of the skin >5 years ago
• Denies current drug abuse that would interfere with study activities
• Denies history of penile, urethral, prostate, testis and associated structures surgery (varicocele repair, vasectomy, and vasectomy repair are acceptable if greater than 1 year prior to enrollment)

Exclusion criteria

Participants meeting any of the exclusion criteria at initial screening and screening prior to Ng challenge will be excluded from study participation. If the results of Complete blood count (CBC), serum alanine transaminase (ALT), serum creatinine, or urinalysis obtained at initial screening are outside acceptable limits, and the clinician judges the deviation unlikely to be clinically relevant, one-time repeat screening is permitted. Acceptable laboratory values are presented in Appendix B.15

• Student or employee under the direct supervision of any of the study investigators
• Any known immunodeficiencies, including complement deficiency, antibody deficiency, chronic granulomatous disease or HIV infection
• A history of prior confirmed N. meningitidis infection
• Hemophilia or other bleeding diatheses.
• Autoimmune disorders; mild autoimmune disorders, such as eczema, are not exclusionary and will be determined by the study physician.
• Unstable psychiatric condition (defined as receiving either <3 months of the same medication (and dose) or a decompensating event during the previous 3 months) or psychiatric condition that, in the opinion of the investigator, will compromise the participant's ability to comply with protocol requirements
• Known anatomic abnormality of the urethra or urethral meatus (granular hypospadias is not exclusionary if the study physician believes that the urethral location will not interfere with inoculation catheter insertion)
• Any immunization in 28 days prior to enrollment
• Self-reported treatment for cancer within the past year
• Receipt of anticoagulants (aspirin or nonsteroidal anti-inflammatory drugs (NSAIDS) are acceptable) within 14 days prior to study entry.
• Use of any systemic immunomodulatory treatment, systemic corticosteroids, (inhaled and topical corticosteroids acceptable), investigational products, interleukins, interferons, growth factors, or intravenous immunoglobulin (IVIG) within 45 days prior to study entry.
• Have donated blood or blood products within 28 days before study vaccination, plan to donate blood at any time during the study and up to 28 days after the last blood draw.
• Allergy to penicillin, cephalosporins or ciprofloxacin or to lidocaine or any component of 4C-MenB vaccine or control vaccines (flu, Influenza vaccine (FLULAVALTM) and Td, TDVAXTM), including latex (confirmed delayed contact hypersensitivity to latex is not exclusionary)
• Treatment with medications that are contraindicated with cefixime, ceftriaxone or ciprofloxacin and that cannot be withheld for the single doses given in this study
• Serum creatinine level > 1.1X upper limit of normal (ULN) and deemed clinically significant by the study physician
• Serum ALT level > 1.25X ULN and deemed clinically significant by the study physician
• WBC count < 2.5 or > 15.0 x109/L and deemed clinically significant by the study physician
• Absolute neutrophil count (ANC) < 1.0 x 109/L and deemed clinically significant by the study physician
• Hemoglobin level < 11.0 g/dL or above ULN and deemed clinically significant by the study physician
• Urinalysis: Qualitative protein level ≥ 1+ or Red blood cell (RBC) count≥ 6/hpf
• Any condition in the opinion of the investigator that would interfere with the proper conduct of the trial.

Medications not permitted with cefixime or ceftriaxone:

Warfarin Probenecid Aspirin Diuretics such as furosemide Aminoglycoside antibiotics Chloramphenicol

Medications not permitted with ciprofloxacin:

Tizanidine Theophylline Warfarin Glyburide Cyclosporine Probenecid Phenytoin Methotrexate Antacids, multivitamins, and other dietary supplements containing magnesium, calcium, aluminum, iron or zinc Caffeine-containing medications Sucralfate or didanosine chewable or buffered tablets