BIYELA - Bexsero Immunisation in Young Women in Africa

Gonorrhea Clinical Trial

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06446752
• Other study ID #: STUDY00019050
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: June 2024
• Est. completion date: August 2026

Study information

• Verified date: June 2024
• Source: University of Washington
• Contact: Meighan Krows
• Phone: 206-520-3833
• Email: meigs[@]uw.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 1100
• Est. completion date: August 2026
• Est. primary completion date: May 31, 2026
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years to 45 Years

Eligibility

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

Related Conditions & MeSH terms

• Gonorrhea
• Gonorrhea of Pharynx

Intervention

Biological:
• Bexsero
Administered as an IM injection by 0.5-mL single-dose syringe at enrollment (Visit 1) and 2 months post-enrollment (Visit 3).
• Placebo
Administered as an IM injection by 0.5-mL single-dose syringe at enrollment (Visit 1) and 2 months post-enrollment (Visit 3).

Locations

Country	Name	City	State
South Africa	Desmond Tutu Health Foundation - Emavundleni Research Centre	Cape Town
South Africa	Desmond Tutu Health Foundation - Masiphumulele Site	Cape Town
South Africa	Khayelitsha Vuka Research Clinic	Cape Town
South Africa	Wits RHI Ward 21 Clinical Research Site	Johannesburg
South Africa	Center for Community Based Research (CCBR)	Pietermaritzburg

Sponsors (3)

Lead Sponsor	Collaborator
University of Washington	Bill and Melinda Gates Foundation, University of Witwatersrand, South Africa

Country where clinical trial is conducted

South Africa, 

References & Publications (19)

Amornkul PN, Vandenhoudt H, Nasokho P, Odhiambo F, Mwaengo D, Hightower A, Buve A, Misore A, Vulule J, Vitek C, Glynn J, Greenberg A, Slutsker L, De Cock KM. HIV prevalence and associated risk factors among individuals aged 13-34 years in Rural Western Ke — View Citation

Celum C, Hosek S, Tsholwana M, Kassim S, Mukaka S, Dye BJ, Pathak S, Mgodi N, Bekker LG, Donnell DJ, Wilson E, Yuha K, Anderson PL, Agyei Y, Noble H, Rose SM, Baeten JM, Fogel JM, Adeyeye A, Wiesner L, Rooney J, Delany-Moretlwe S. PrEP uptake, persistence — View Citation

Celum CL, Bukusi EA, Bekker LG, Delany-Moretlwe S, Kidoguchi L, Omollo V, Rousseau E, Travill D, Morton JF, Mogaka F, O'Malley G, Barnabee G, van der Straten A, Donnell D, Parikh UM, Kudrick L, Anderson PL, Haberer JE, Wu L, Heffron R, Johnson R, Morrison — View Citation

Celum CL, Gill K, Morton JF, Stein G, Myers L, Thomas KK, McConnell M, van der Straten A, Baeten JM, Duyver M, Mendel E, Naidoo K, Dallimore J, Wiesner L, Bekker LG. Incentives conditioned on tenofovir levels to support PrEP adherence among young South Af — View Citation

Hadad R, Jacobsson S, Pizza M, Rappuoli R, Fredlund H, Olcen P, Unemo M. Novel meningococcal 4CMenB vaccine antigens - prevalence and polymorphisms of the encoding genes in Neisseria gonorrhoeae. APMIS. 2012 Sep;120(9):750-60. doi: 10.1111/j.1600-0463.201 — View Citation

Kakaire O, Byamugisha JK, Tumwesigye NM, Gamzell-Danielsson K. Prevalence and factors associated with sexually transmitted infections among HIV positive women opting for intrauterine contraception. PLoS One. 2015 Apr 10;10(4):e0122400. doi: 10.1371/journa — View Citation

Kennedy CE, Haberlen SA, Narasimhan M. Integration of sexually transmitted infection (STI) services into HIV care and treatment services for women living with HIV: a systematic review. BMJ Open. 2017 Jun 21;7(6):e015310. doi: 10.1136/bmjopen-2016-015310. — View Citation

Masese L, Baeten JM, Richardson BA, Bukusi E, John-Stewart G, Graham SM, Shafi J, Kiarie J, Overbaugh J, McClelland RS. Changes in the contribution of genital tract infections to HIV acquisition among Kenyan high-risk women from 1993 to 2012. AIDS. 2015 J — View Citation

Naidoo S, Wand H, Abbai NS, Ramjee G. High prevalence and incidence of sexually transmitted infections among women living in Kwazulu-Natal, South Africa. AIDS Res Ther. 2014 Sep 15;11:31. doi: 10.1186/1742-6405-11-31. eCollection 2014. — View Citation

Ong JJ, Baggaley RC, Wi TE, Tucker JD, Fu H, Smith MK, Rafael S, Anglade V, Falconer J, Ofori-Asenso R, Terris-Prestholt F, Hodges-Mameletzis I, Mayaud P. Global Epidemiologic Characteristics of Sexually Transmitted Infections Among Individuals Using Pree — View Citation

Ong JJ, Fu H, Baggaley RC, Wi TE, Tucker JD, Smith MK, Rafael S, Falconer J, Terris-Prestholt F, Mameletzis I, Mayaud P. Missed opportunities for sexually transmitted infections testing for HIV pre-exposure prophylaxis users: a systematic review. J Int AI — View Citation

Paavonen J, Eggert-Kruse W. Chlamydia trachomatis: impact on human reproduction. Hum Reprod Update. 1999 Sep-Oct;5(5):433-47. doi: 10.1093/humupd/5.5.433. — View Citation

Petousis-Harris H, Radcliff FJ. Exploitation of Neisseria meningitidis Group B OMV Vaccines Against N. gonorrhoeae to Inform the Development and Deployment of Effective Gonorrhea Vaccines. Front Immunol. 2019 Apr 9;10:683. doi: 10.3389/fimmu.2019.00683. e — View Citation

Semchenko EA, Tan A, Borrow R, Seib KL. The Serogroup B Meningococcal Vaccine Bexsero Elicits Antibodies to Neisseria gonorrhoeae. Clin Infect Dis. 2019 Sep 13;69(7):1101-1111. doi: 10.1093/cid/ciy1061. — View Citation

Steen R, Wi TE, Kamali A, Ndowa F. Control of sexually transmitted infections and prevention of HIV transmission: mending a fractured paradigm. Bull World Health Organ. 2009 Nov;87(11):858-65. doi: 10.2471/blt.08.059212. — View Citation

Stephens AJ, Aubuchon M, Schust DJ. Antichlamydial antibodies, human fertility, and pregnancy wastage. Infect Dis Obstet Gynecol. 2011;2011:525182. doi: 10.1155/2011/525182. Epub 2011 Sep 22. — View Citation

Stewart J, Bukusi E, Sesay FA, Oware K, Donnell D, Soge OO, Celum C, Odoyo J, Kwena ZA, Scoville CW, Violette LR, Morrison S, Simoni J, McClelland RS, Barnabas R, Gandhi M, Baeten JM. Doxycycline post-exposure prophylaxis for prevention of sexually transm — View Citation

Tacconelli E, Carrara E, Savoldi A, Harbarth S, Mendelson M, Monnet DL, Pulcini C, Kahlmeter G, Kluytmans J, Carmeli Y, Ouellette M, Outterson K, Patel J, Cavaleri M, Cox EM, Houchens CR, Grayson ML, Hansen P, Singh N, Theuretzbacher U, Magrini N; WHO Pat — View Citation

Ville Y, Leruez M, Glowaczower E, Robertson JN, Ward ME. The role of Chlamydia trachomatis and Neisseria gonorrhoeae in the aetiology of ectopic pregnancy in Gabon. Br J Obstet Gynaecol. 1991 Dec;98(12):1260-6. doi: 10.1111/j.1471-0528.1991.tb15399.x. — View Citation

* Note: There are 19 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Assess efficacy of Bexsero in prevention of cervical and/or anorectal gonococcal infection	18 months
Secondary	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	To assess efficacy of Bexsero in prevention of cervical and/or anorectal gonococcal infection by pre-specified subgroups, including HIV status, anatomical site (cervical compared to anorectal), and presence or absence of chlamydia	18 months
Secondary	First diagnosis of pharyngeal gonorrhea occurring > 1 month after the second vaccination with study product through to study end, by study arm	To estimate the efficacy of Bexsero in prevention of pharyngeal gonococcal infection	18 months
Secondary	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	To assess the durability of protection	18 months
Secondary	To ascertain the safety of Bexsero	Proportion of participants with at least one serious adverse event (SAE), adverse event of special interest (AESI) or other reportable AE (adverse event)	18 months

External Links

•   Global progress report on HIV, viral hepatitis and sexually transmitted infections, 2021