4C-MenB Vaccine for Gonorrhea

Overseen By Arlene Sena-Soberano, MD, MPH

Age: 18 - 65

Sex: Male

Trial Phase: Phase 2

Sponsor: University of North Carolina, Chapel Hill

Must not be taking: Warfarin, Probenecid, Theophylline, others

Disqualifiers: Immunodeficiencies, Autoimmune disorders, Cancer, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

140 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a double-blind randomized controlled trial to test whether the group B meningitis vaccine 4 component Neisseria meningitidis serogroup B vaccine (BEXSEROTM) (4C-MenB), trade name Bexsero™), currently approved for use by the United States Food and Drug Administration (FDA) and recommended by the Centers for Disease Control and Prevention (CDC) for protection from Neisseria meningitidis infections, also protects from Neisseria gonorrhoeae infection using controlled human experimental infection to test protection. The information the investigator learn by doing this study may also help to develop a vaccine that protects individuals from having gonorrhea infection. The study population will consist of male participants \> 18 and \< 36 years old, living in central North Carolina, in general good health without a history of 4C-MenB vaccination. Approximately 120-140 participants will be enrolled. Participants will receive 2 doses of vaccine (2 doses of 4C-MenB or 2 comparator vaccines- seasonal influenza and tetanus/diptheria booster) as intramuscular injections, and then one intraurethral challenge with Neisseria gonorrhoeae. Following the challenge, participants will cross-over and receive two doses of vaccines not received prior to challenge (2 doses of 4CMenB or the 2 comparator vaccines- seasonal influenza and tetanus/diptheria booster) All participants receive all vaccinations by the end of the study and all vaccines used in this study are licensed and FDA-approved.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop all current medications, but certain medications are not allowed with the antibiotics used in the study. You should avoid medications like warfarin, probenecid, and some others listed in the trial details.

What data supports the effectiveness of the 4C-MenB vaccine (Bexsero) for treating gonorrhea?

Research suggests that the 4C-MenB vaccine, originally designed to protect against meningitis, might also offer some protection against gonorrhea. Studies have shown that similar vaccines can reduce the risk of gonorrhea, indicating potential effectiveness for 4C-MenB in this new use. ^{1 2 3 4 5}

Is the 4C-MenB (Bexsero) vaccine safe for humans?

The 4C-MenB (Bexsero) vaccine has been used safely in people aged 10-25 years, with safety data collected from reports in the Vaccine Adverse Event Reporting System (VAERS) between 2015 and 2018. It has been used in response to outbreaks and is recommended for those at increased risk of meningococcal disease. ^{6 7 8 9 10}

How is the 4C-MenB vaccine different from other treatments for gonorrhea?

The 4C-MenB vaccine, originally developed to protect against meningococcal disease, is unique because it contains multiple components that trigger an immune response, potentially offering protection against gonorrhea, a condition with limited vaccine options. This approach is novel as it repurposes a vaccine designed for a different bacterial infection to address gonorrhea. ^{6 7 8 10 11}

Research Team

Joseph A Duncan, MD, PhD

Principal Investigator

University of North Carolina, Chapel Hill

Eligibility Criteria

This trial is for healthy males aged 18-35 in central North Carolina who haven't been vaccinated against Neisseria meningitidis group B. Participants must consent to avoid sexual activity during certain phases, not have a history of severe reactions to antibiotics or vaccines, and be able to attend all study visits.

Inclusion Criteria

No history of prior Neisseria meningitidis serogroup B (MenB) vaccination

Denies current drug abuse that would interfere with study activities

I do not have a history of unusual bleeding.

Exclusion Criteria

Hemoglobin level < 11.0 g/dL or above ULN and deemed clinically significant by the study physician

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

Student or employee under the direct supervision of any of the study investigators

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Initial Vaccination

Participants receive two doses of vaccines (either BEXSERO™ or control vaccines) prior to the bacterial challenge phase

4 weeks

2 visits (in-person)

Neisseria gonorrhoeae Challenge

Participants receive a suspension containing N. gonorrhoeae and are monitored for development of urethritis

1-10 days

Daily visits (in-person)

Post-Challenge Vaccination

Participants receive two doses of vaccines not received prior to the challenge (either BEXSERO™ or control vaccines)

4 weeks

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• 4C-MenB

Trial Overview The trial tests if the FDA-approved Bexsero™ vaccine for meningitis B also prevents gonorrhea infection. It's a double-blind study where participants receive either the meningitis vaccine or other vaccines (flu and tetanus/diptheria), followed by an experimental challenge with gonorrhea bacteria.

Participant Groups

Group I: Experimental arm Experimental Treatment 7 Interventions

All participants receive two immunizations prior to the bacterial challenge phase and two immunizations after the challenge phase. Individuals assigned to the experimental arm receive the recommended two doses of BEXSERO™ prior to bacterial challenge and control vaccines (FLULAVAL™ and TDVAX™) in the post-challenge vaccination phase. For bacterial challenge, all participants receive a suspension containing 10\^6 colony-forming units of N. gonorrhoeae strain FA1090 delivered to the anterior urethra. Participants receive 100% effective antibiotic treatment for N. gonorrhoeae strain FA1090 infection 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 afterurethral inoculation with bacterial product, regardless of infection status.

Group II: Control arm Experimental Treatment 7 Interventions

All participants receive two immunizations prior to the bacterial challenge phase and two immunizations after the challenge phase. Individuals assigned to the control arm receive control vaccines that have no relevance to N. gonorrhoeae infection (FLULAVAL™ and TDVAX™) prior to bacterial challenge and then receive two doses of BEXSERO™ in the post-challenge vaccination phase. For bacterial challenge, all participants receive a suspension containing 10\^6 colony-forming units of N. gonorrhoeae strain FA1090 delivered to the anterior urethra. Participants receive 100% effective antibiotic treatment for N. gonorrhoeae strain FA1090 infection 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 afterurethral inoculation with bacterial product, regardless of infection status.

4C-MenB is already approved in European Union, United States for the following indications:

Approved in European Union as Bexsero for:

• Invasive meningococcal disease caused by serogroup B

Approved in United States as Bexsero for:

• Invasive meningococcal disease caused by serogroup B in adolescents and young adults aged 10 through 25 years

Who Is Running the Clinical Trial?

University of North Carolina, Chapel Hill

Lead Sponsor

Trials

1,588

Recruited

4,364,000+

National Institute of Allergy and Infectious Diseases (NIAID)

Collaborator

Trials

3,361

Recruited

5,516,000+

Findings from Research

The MenB-4C vaccine was found to be protective against gonorrhoea, with a complete vaccination series showing a 40% effectiveness and a partial series showing 26% effectiveness in individuals aged 16-23 years in two US cities.

Among 167,706 infections analyzed, complete vaccination significantly reduced the prevalence of gonorrhoea compared to no vaccination, suggesting that this vaccine could provide cross-protection against Neisseria gonorrhoeae and highlights the potential for developing effective gonococcal vaccines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of a serogroup B outer membrane vesicle meningococcal vaccine against gonorrhoea: a retrospective observational study. Abara, WE., Bernstein, KT., Lewis, FMT., et al.[2023]

The protein-based meningococcal group B vaccine Bexsero(®) may provide some protection against secondary infections, but its early effectiveness after a single dose is low, especially in young children who are at higher risk.

The estimated number needed to vaccinate (NNV) to prevent one secondary case is over 1000 in household settings, indicating that while Bexsero(®) could be useful in outbreaks, its practical application for individual cases may be limited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preventing secondary cases of invasive meningococcal capsular group B (MenB) disease using a recently-licensed, multi-component, protein-based vaccine (Bexsero(®)). Ladhani, SN., Cordery, R., Mandal, S., et al.[2022]

Vaccination of men who have sex with men (MSM) against gonorrhoea using the 4CMenB vaccine, particularly through a risk-based approach, is likely to be cost-effective and could avert a significant number of cases while saving healthcare costs over a 10-year period.

The study suggests that improving the efficacy of a gonorrhoea vaccine is more valuable than extending its duration of protection, highlighting the importance of focusing on vaccine effectiveness in future development efforts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Public health impact and cost-effectiveness of gonorrhoea vaccination: an integrated transmission-dynamic health-economic modelling analysis. Whittles, LK., Didelot, X., White, PJ.[2022]

In a study of 1051 men living with HIV, those who received two doses of the 4CMenB vaccine had a 44% lower risk of contracting gonorrhea compared to those who did not receive the vaccine, indicating its effectiveness in this population.

The study, which followed participants for an average of 3.8 years, suggests that the 4CMenB vaccine may provide significant protection against gonorrhea among men who have sex with men and have a history of sexually transmitted infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Meningococcus B Vaccination Effectiveness Against Neisseria gonorrhoeae Infection in People Living With HIV: A Case-Control Study. Raccagni, AR., Galli, L., Spagnuolo, V., et al.[2023]

The 4CMenB vaccine, primarily designed to protect against meningococcal infections, may also provide some level of protection against Neisseria gonorrhoeae, the bacteria responsible for gonorrhea, although more research is needed to confirm this.

Understanding the immune response to gonococcal infections is complex, as the mechanisms of protection against local infections (like gonorrhea) may differ from those against systemic infections (like meningitis), highlighting the need for further studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Insight into Prevention of Neisseria Gonorrhoeae: A Short Review. La Fauci, V., Lo Giudice, D., Squeri, R., et al.[2022]

The Meningococcal Antigen Typing System (MATS) accurately predicts the strain coverage of the 4CMenB vaccine, showing a significant association with serum bactericidal antibody assay results from a representative sample of MenB strains in England and Wales.

MATS predicted a 70% strain coverage, which was confirmed by an 88% killing rate in the hSBA assay, demonstrating that MATS is a reliable tool for assessing the vaccine's effectiveness in infants and adolescents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bactericidal antibody against a representative epidemiological meningococcal serogroup B panel confirms that MATS underestimates 4CMenB vaccine strain coverage. Frosi, G., Biolchi, A., Lo Sapio, M., et al.[2019]

A review of 1,867 adverse event reports following the administration of the MenB-4C vaccine showed that 96% of these reports were classified as non-serious, indicating a favorable safety profile for the vaccine.

The most common adverse events reported were injection site pain, fever, and headache, which align with the expected safety outcomes from clinical studies, suggesting no new safety concerns have emerged since the vaccine's approval.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety surveillance of meningococcal group B vaccine (Bexsero®), Vaccine Adverse Event Reporting System, 2015-2018. Perez-Vilar, S., Dores, GM., Marquez, PL., et al.[2023]

The MenB-4C vaccine (Bexsero®) effectively induces serum bactericidal antibodies (SBA) against Neisserial Heparin binding antigen (NHba), with depletion of anti-NHba antibodies resulting in a significant decrease in SBA titers by 43-79%, indicating its important role in vaccine efficacy.

While anti-NHba antibodies contribute to SBA, some strains expressing high levels of NHba may still evade the immune response, highlighting the need for further understanding of the vaccine's limitations against certain bacterial strains.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of anti-NHba antibody in bactericidal activity elicited by the meningococcal serogroup B vaccine, MenB-4C. Partridge, E., Lujan, E., Giuntini, S., et al.[2018]

The MenB-4C vaccine was administered to 16,974 individuals, with a low incidence of serious adverse events (SAEs), including only one case of anaphylaxis, indicating that the vaccine is generally safe.

Most adverse events reported were mild, such as arm pain and fever, and consistent with previous studies, supporting the vaccine's use during meningococcal outbreaks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of a meningococcal group B vaccine used in response to two university outbreaks. Duffy, J., Johnsen, P., Ferris, M., et al.[2022]

The introduction of the Bexsero® meningococcal B vaccine into Spain's routine vaccination schedule could prevent 54% of invasive meningococcal disease cases and deaths with a 3+1 dosage, but it is currently not cost-effective at the existing price, with an incremental cost-utility ratio (ICUR) of 351,389 €/QALY.

For the vaccine to be considered cost-effective, the price would need to be reduced to 1.45 € for the 3+1 dosage or 3.37 € for the 2+1 dosage, indicating that pricing plays a crucial role in vaccine policy decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Economic evaluation of the introduction of 4CMenB (Bexsero®) in the national vaccine schedule in Spain]. Ruiz-Montero, R., Epstein, D., Guzmán Herrador, B., et al.[2021]

The multicomponent meningococcal serogroup B vaccine (4CMenB) effectively generates protective antibody responses in infants, adolescents, and adults, with the majority of participants achieving seroprotective levels after the recommended doses in clinical trials.

While the vaccine is generally well-tolerated, infants experienced more systemic side effects, such as fever, when 4CMenB was given alongside routine vaccinations, indicating a need for monitoring during coadministration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicomponent meningococcal serogroup B vaccine (4CMenB; Bexsero(®)): a review of its use in primary and booster vaccination. Carter, NJ.[2016]

References

1. United States pubmed.ncbi.nlm.nih.gov

Effectiveness of a serogroup B outer membrane vesicle meningococcal vaccine against gonorrhoea: a retrospective observational study. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Preventing secondary cases of invasive meningococcal capsular group B (MenB) disease using a recently-licensed, multi-component, protein-based vaccine (Bexsero(®)). [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Public health impact and cost-effectiveness of gonorrhoea vaccination: an integrated transmission-dynamic health-economic modelling analysis. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Meningococcus B Vaccination Effectiveness Against Neisseria gonorrhoeae Infection in People Living With HIV: A Case-Control Study. [2023]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Insight into Prevention of Neisseria Gonorrhoeae: A Short Review. [2022]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Bactericidal antibody against a representative epidemiological meningococcal serogroup B panel confirms that MATS underestimates 4CMenB vaccine strain coverage. [2019]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Safety surveillance of meningococcal group B vaccine (Bexsero®), Vaccine Adverse Event Reporting System, 2015-2018. [2023]

8. Netherlands pubmed.ncbi.nlm.nih.gov

The role of anti-NHba antibody in bactericidal activity elicited by the meningococcal serogroup B vaccine, MenB-4C. [2018]

9. United States pubmed.ncbi.nlm.nih.gov

Safety of a meningococcal group B vaccine used in response to two university outbreaks. [2022]

10. Spain pubmed.ncbi.nlm.nih.gov

[Economic evaluation of the introduction of 4CMenB (Bexsero®) in the national vaccine schedule in Spain]. [2021]

11. New Zealand pubmed.ncbi.nlm.nih.gov

Multicomponent meningococcal serogroup B vaccine (4CMenB; Bexsero(®)): a review of its use in primary and booster vaccination. [2016]