Clinical trial NCT06446752: BIYELA - Bexsero Immunisation in Young Women in Africa
Official title: A Phase 3 Randomized, Observer-Blind, Placebo-Controlled Study to Assess Efficacy of Meningococcal Group B (rMenB+OMV NZ (Bexsero)) in Preventing Gonococcal Infection Among South African Cis-Gender Women
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Gonorrhea
Gonorrhea of Pharynx
Gonorrhea of Anus
Gonorrhea of Cervix
Keywords: sexually transmitted infections
STI
Gonorrhea
Lead sponsor: University of Washington
Sponsor class: OTHER
Collaborators: name: Bill and Melinda Gates Foundation
name: University of Witwatersrand, South Africa
First posted: 2024-06-06
Enrollment: 1100
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 1:1 randomization to Bexsero vaccine or placebo injection, to be administered as two intramuscular (IM) doses, two months apart (at Enrollment/Visit 1 and Month 2/Visit 3). Assessment for safety events at one month following the IM doses (Visit 2 and Visit 4), followed by 5 in-clinic follow-up visits for safety, clinical, and laboratory assessments.
Primary purpose: PREVENTION

Brief summary: This proposed 2-arm randomized evaluation of two doses of 4CMenB vaccine versus placebo at Enrollment and Month 2 is designed as a proof-of-concept study to inform potential use for dual meningococcal B and gonococcal prevention, and to inform Neisseria gonorrheae vaccine development.

Detailed description: The World Health Organization (WHO) estimates that the global incidence of gonorrhea in 2020 was 82 million (CI: 48-130 million) among 15 to 49-year-olds, reflecting global incidence rates of 19/1000 women and 23/1000 men in that age group. Most gonococcal infections occur in LMICs. High rates of curable sexually transmitted infections (STIs) have been observed in pre-exposure prophylaxis (PrEP) demonstration projects conducted in adolescent girls and young women (AGYW) from eastern and southern Africa, with prevalences of Chlamydia trachomatis (CT) infection ranging from 24-30%, Neisseria gonorrheae (NG) infection from 7-10%, and syphilis seropositivity from 1-5%.

The consequences of bacterial STIs on AGYW's sexual and reproductive health can be substantial with long-term clinical repercussions: pelvic inflammatory disease (PID), chronic pelvic pain, tubal infertility, pregnancy complications, fetal and neonatal death, and increased susceptibility to HIV. Effective STI prevention interventions are needed to protect individuals, to prevent secondary transmission to partners, and to reduce the risk of long-term reproductive health consequences, particularly for women and their infants. STI prevention interventions could be integrated into PrEP programs, given the high prevalence and incidence of STIs in PrEP populations and the feasibility of providing integrated services in PrEP programs.

N.gonorrhoeae has been identified as a priority pathogen for the development of new vaccines and therapeutics given the current limited therapeutic options in the context of high rates of antimicrobial resistance. A vaccine for NG could mitigate the growing threat of antimicrobial resistance in NG, reduce the high NG prevalence and incidence among African women, and reduce the risk of reproductive morbidity from undiagnosed and untreated NG infection. Women have an increased risk of HIV due to bacterial STIs, both through direct mechanisms such as increased susceptibility due to genital inflammation, and indirectly through infertility, which is associated with increased condom-less sex as part of efforts to become pregnant. There are few other preventative bacterial STI interventions for women on the short-term horizon; unfortunately doxycycline post-exposure prophylaxis for STI prevention (doxy-PEP) was not effective for prevention of CT or NG among 449 Kenyan cis-gender women ages 18 to 30 who were taking HIV PrEP. This lack of efficacy appears to be in part due to adherence; doxycycline was detected in only 29% of 200 hair samples collected at follow-up visits from 50 randomly selected women in the doxy-PEP arm.

Gonorrhea may be vaccine-preventable. Several meningococcal outer membrane vesicle (OMV) proteins have \>90% sequence homology with gonococcal OMV proteins. The meningococcal 4CMenB (Bexsero) vaccine (rMenB+OMV NZ), that targets serogroup B N. meningitidis, is a licensed OMV vaccine that contains protein antigens commonly expressed on the surface of both N. meningitidis and N. gonorrhoeae. It induces bactericidal antibodies that mediate killing of the majority of epidemiologically relevant serogroup B N. meningitidis strains. Gonococcal proteins share a high level of identity with several antigens contained in the Bexsero rMenB+OMV NZ vaccine and vaccination with Bexsero induces antibodies in humans that recognize gonococcal proteins 22, 26, 27, 23, 24, 28. In addition to OMV, the vaccine includes three purified recombinant N. meningitidis serogroup B protein antigens (rMenB), two which are fused with accessory antigens: 1) neisserial heparin binding antigen (NHBA), fused with the accessory protein genome-derived neisserial antigen (GNA) 1030, 2) factor H-binding protein (fHbp), fused to GNA2091, and 3) neisserial adhesin A (NadA), presented as a single antigen. NHBA is present in virtually all N. gonorrhoeae strains and its nucleotide and amino acid sequences are highly conserved (96.9% sequence identity in N. gonorrhoeae strains, with 71.3% identity to the Bexsero antigens). Gonococcal fHbp is similar to meningococcal variant 3, which is included in the vaccine, but is not surface exposed and therefore is not expected to contribute to protection. Both GNA2091 and GNA1030 accessory antigens are highly conserved; although their potential contribution to protection is unknown, they could provide an added effect. NadA is absent in gonococcal strains. In a humanized mouse model, 4CMenB immunized mice had antibodies that showed functional activity against NG, clearance of NG was accelerated and bacterial load reduced, serum immunoglobin G (IgG) and IgG cross-reacted with NG OMV and there was a four-fold increase in serum bactericidal50 titres all suggestive of 4CMenB activity against NG28.

Eligibility criteria: Inclusion Criteria:

* Individuals born female aged 18-45 years of age inclusive on the day of screening
* In good health as determined by past medical history, medication use, and targeted physical examination,

  1. If not living with HIV, negative HIV test conducted at screening
  2. If living with HIV, on an antiretroviral regimen for ≥3 months, with an undetectable HIV RNA of \<200 copies/ml and/or a CD4 count \>300 cells/cmm within 12 months of screening
* If of reproductive potential,

  1. Willing to not become pregnant during vaccination period and
  2. Have a negative pregnancy test prior to each vaccination and
  3. Willing to use a reliable method of contraception until month 3 (i.e., after the second vaccination visit)
  4. Not breastfeeding
* Sexually active in the past 3 months, defined as vaginal or anal sex
* At risk for gonorrhea based on sexual behaviour characteristics including

  1. Previous PrEP use in the past 12 months, or
  2. Past history of STIs in the past 12 months, or
  3. 2 or more partners in the past 12 months
* Has provided signed informed consent, and is willing and likely to comply with the trial procedures and follow-up visit requirements
* Has a negative gonorrhea and chlamydia nucleic acid amplification test (NAAT) in the 14 days prior to the Enrollment Visit

Exclusion Criteria:

* Contra-indications to Bexsero
* Previous receipt of a Meningococcal Group B vaccine
* Receipt of antibiotics active against N. gonorrhoeae in the 14 days prior to the Enrollment Visit, including oral or parenteral antibiotics\*

  * Participants with NG and/or CT detected at screening may re-screen after receiving appropriate antibiotic treatment
* Planned long-term (\> 4 weeks) antibiotic use for prophylaxis or treatment for acne or other bacterial condition(s)
* Use or planned use of a live vaccine within +/- 30 days, an inactive vaccine within +/- 14 days, or an influenza vaccine within +/- 7 days from receipt of study product. Authorized or approved, inactivated COVID-19 vaccines may be given more than 7 days +/- receipt of study product for all study participants
* Use of any investigational drug or vaccine within 30 days prior to enrollment, or planned/anticipated use during study participation
* Currently receiving immunosuppressive agent or systemic corticosteroids (dose \>5 mg/day of prednisone) for \>14 consecutive days within 90 days prior to enrollment. Topical or inhaled steroids are allowed. Topical steroids cannot be applied to study product injection site
* Has received antineoplastic (chemotherapy) or radiotherapy within 90 days prior to enrollment
* Has received immunoglobulins and/or any blood products within 180 days prior to enrollment
* Progressive, unstable, or uncontrolled disease including but not limited to cardiac, hepatic, renal, immunological, neurological or psychiatric conditions
* Has a condition which in the opinion of the investigator is not suitable for intramuscular vaccination, blood draws, or participation in the trial
* Pregnant or breastfeeding at enrollment

Primary outcomes:
measure: First diagnosis of gonorrhea at cervical or anorectal sites occurring greater than or equal to 1 month after the second vaccination with study product through to the study end
timeFrame: 18 months
Secondary outcomes:
measure: First diagnosis of gonorrhea at cervical or anorectal sites occurring >1 month after the second vaccination with study product through to study end, by specified subgroups
timeFrame: 18 months
measure: First diagnosis of pharyngeal gonorrhea occurring > 1 month after the second vaccination with study product through to study end, by study arm
timeFrame: 18 months
measure: Cumlative GC incidence in the first 9 months after receipt of the second dose of vaccine compared to cumlative GC incidence in the 10-16 months after receipt of the second dose
timeFrame: 18 months
measure: To ascertain the safety of Bexsero
timeFrame: 18 months
Other outcomes:
Locations:
city: Cape Town
country: South Africa
facility: Desmond Tutu Health Foundation - Emavundleni Research Centre
city: Cape Town
country: South Africa
facility: Desmond Tutu Health Foundation - Masiphumulele Site
city: Cape Town
country: South Africa
facility: Khayelitsha Vuka Research Clinic
city: Johannesburg
country: South Africa
facility: Wits RHI Ward 21 Clinical Research Site
city: Pietermaritzburg
country: South Africa
facility: Center for Community Based Research (CCBR)
Study officials:
affiliation: University of Washington
name: Connie Celum, MD, MPH
role: PRINCIPAL_INVESTIGATOR
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