Efficacy, Safety and Immunogenicity Evaluation of MTBVAC in Newborns in Sub-Saharan Africa (MTBVACN3)

October 6, 2023 updated by: Biofabri, S.L

Randomised, Double-Blind, Controlled Phase 3 Trial to Evaluate the Efficacy, Safety and Immunogenicity of MTBVAC in Healthy HIV Unexposed (HU) and HIV Exposed Uninfected (HEU) Newborns in Tuberculosis-Endemic Regions of Sub-Saharan Africa

The objective of this project is to demonstrate safety, immunogenicity and improved efficacy of the new live attenuated M. tuberculosis vaccine called MTBVAC in a Phase 3 efficacy trial in HIV-uninfected infants born to HIV-infected and HIV-uninfected mothers as compared to standard of care BCG vaccination. The proposal builds upon a group of TB vaccine development partners in Europe and sub-Saharan Africa established in a previous EDCTP-supported project. It creates an expanded consortium of clinical trial partners for the optimal implementation of a large infant efficacy trial of MTBVAC in high TB incidence settings. New capacity for efficacy trials in infants will be a valuable resource for the TB vaccine development community. The proposal will create a network of institutions in three TB endemic African countries with enhanced laboratory capacity to conduct TB vaccine immunology studies and to bio-bank samples to discover immune correlates of vaccine-mediated protection.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

A new effective tuberculosis (TB) vaccine is essential to achieve World Health Organization End TB goals and eliminate TB by 2050. The optimal long-term strategy would be a combination of serial mass campaigns in adults, coupled with universal newborn vaccination. Newborns are the only human population without prior mycobacterial exposure in TB endemic countries and we hypothesize that live attenuated mycobacterial vaccines will offer better protection to this naïve population compared to adults.

The objective of this project is to demonstrate safety, immunogenicity and improved efficacy of the new live attenuated M. tuberculosis vaccine called MTBVAC in a Phase 3 efficacy trial in HIV-uninfected infants born to HIV-infected and HIV-uninfected mothers as compared to standard of care BCG vaccination. The proposal builds upon a group of TB vaccine development partners in Europe and sub-Saharan Africa established in a previous EDCTP-supported project. It creates an expanded consortium of clinical trial partners for the optimal implementation of a large infant efficacy trial of MTBVAC in high TB incidence settings. New capacity for efficacy trials in infants will be a valuable resource for the TB vaccine development community. The proposal will create a network of institutions in three TB endemic African countries with enhanced laboratory capacity to conduct TB vaccine immunology studies and to bio-bank samples to discover immune correlates of vaccine-mediated protection.

MTBVAC is a novel TB vaccine candidate based on an attenuated M. tuberculosis clinical isolate of the Euro-American lineage. Attenuation is based on two independent, stable genetic deletions of the genes phoP and fadD26 coding for two major virulence factors, the transcription factor PhoP and the cell-wall lipids PDIM, respectively. The hypothesis is that MTBVAC will provide improved protection, as individuals latently infected with live M.tuberculosis have an 80% lower chance of developing TB, and as MTBVAC contains most of the genes deleted from BCG and presents a wider collection of antigens to the host immune system. Preclinical studies in different animal models indicated that MTBVAC is safe and is able to induce an improved protection compared to BCG.

Phase 1 studies showed that MTBVAC was safe and immunogenic in naïve adults and newborns, and evoked an immune response that exceeded the magnitude of BCG-induced immune responses. Larger dose-defining Phase 2a studies in newborns and in adults at extended dose-ranges to confirm these findings will be finalised in early 2021, and allow selection of a vaccine dose to progress into the proposed multi-centre efficacy trial in infants.

Study Type

Interventional

Enrollment (Estimated)

7120

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • South Africa
    • Western Cape
      • Worcester, Western Cape, South Africa, 6850
        • Recruiting
        • South African Tuberculosis Initiative, Brewelskloof Hospital
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

5 minutes to 1 week (Child)

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  • Male or female newborns within seven days of birth.
  • Written informed maternal consent, including permission to access maternal antenatal, postnatal, and infant medical records.
  • Infant participants and their caregivers available for trial follow-up and display the willingness and capacity to comply with trial procedures.
  • Newborns must be in good general health during pregnancy and delivery, as assessed by medical history and targeted physical examination.
  • Birth weight ≥ 2450 grams.
  • Apgar score at 5 minutes ≥ 7.
  • A maternal HIV test result (rapid test, enzyme-linked immunosorbent assay (ELISA), or Polymerase chain reaction (PCR)) taken within 30 days of delivery, or within seven days post-partum must be available and documented if HIV uninfected. If the mother is HIV infected, then she must be on antiretroviral (ARV) therapy as per in-country guidelines with a viral load of <50 copies/mL (within six months of labour).
  • Estimated gestational age ≥ 37 weeks.
  • Mother has not participated in a clinical trial within three months prior to the infant's birth.
  • Mother has never participated in a TB vaccine trial before.
  • Infant may not participate in any other clinical trials.

Exclusion Criteria:

Receipt of BCG vaccination prior to enrolment.

  • Significant antenatal, intrapartum, or postpartum complications that may affect the health of the newborn.
  • Skin condition, bruising or birth mark at the intended injection site.
  • Maternal HIV test (rapid test, ELISA, or PCR) result not available.
  • HIV exposed Newborn's HIV PCR result positive or not available.
  • Maternal history of TB during pregnancy.
  • History of close/household contact with a TB patient, antenatal or postnatal, whether maternal, other family member or another household member who has not yet completed TB treatment.
  • Clinically suspected neonatal sepsis.
  • Any severe congenital malformation.
  • History or evidence of any systemic disease on examination, or any illness that in the opinion of the Investigator may interfere with the evaluation of the safety and immunogenicity of the vaccine. Neonatal jaundice not considered clinically significant is not an exclusion.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: BCG

BCG is a live attenuated M. bovis strain developed 100 years ago and is used as a preventive vaccine against tuberculosis. It is administered at birth.

One 0.05 mL reconstituted dose of BCG contains 2.5 x 105 CFU. The control vaccine will be the BCG vaccine available and recommended in South Africa at time of the trial.

BCG vaccine produced by AJ Biologics (formerly Staten Serum Institute) is the only BCG vaccine (Danish strain) currently licensed for routine use in South Africa. The recommended BCG injection volume for newborn infants (0.05 mL, after reconstitution with BCG diluent) contains approximately 2.5 x 105 CFU (range 1-4 x 105 CFU). BCG vaccine vials should be stored in the site pharmacy at 2-8ºC.
Biological: BCG
BCG is a live attenuated M. bovis strain developed 100 years ago and is used as a preventive vaccine against tuberculosis. It is administered at birth.
Experimental: MTBVAC

Both MTBVAC and BCG vaccines are administered by intradermal route in the left deltoid region. One 0.05 mL reconstituted dose of MTBVAC will be defined based on the phase IIa results.

MTBVAC is manufactured by Biofabri. MTBVAC is formulated (1.5 - 8.5 x104 CFU/dose, 1.5 - 8.5 x105 CFU/dose or 1.5 - 8.5 x106 CFU/dose (to be selected) and presented as a lyophilised pellet in 20 dose vials (0.05 mL/dose, after reconstitution with sterile water for injection). MTBVAC vaccine will be released and distributed by BIOFABRI, and imported to the sites following approval by the local regulatory authority. MTBVAC vaccine must be stored at +2°C to +8°C. Reconstituted MTBVAC vaccine must be stored at +2ºC to +8ºC and administered as soon as possible, within 4 hours of reconstitution. A single vaccine vial will be used for each participant.
Biological: MTBVAC
MTBVAC is a novel TB vaccine candidate based on an attenuated M. tuberculosis clinical isolate of the Euro-American lineage. Attenuation is based on two independent, stable genetic deletions of the genes phoP and fadD26 coding for two major virulence factors, the transcription factor PhoP and the cell-wall lipids PDIM, respectively. We hypothesize that MTBVAC will provide improved protection, as individuals latently infected with live M.tuberculosis have an 80% lower chance of developing TB, and as MTBVAC contains most of the genes deleted from BCG and presents a wider collection of antigens to the host immune system. Preclinical studies in different animal models indicated that MTBVAC is safe and is able to induce an improved protection compared to BCG.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
To demonstrate efficacy in terms of incidence of MTBVAC against TB disease in healthy HU and HEU newborns compared to BCG
Time Frame: Minimum of 24 months to a maximum 80 months; or until study end in South Africa.
Primary: Time from vaccination to diagnosis of first confirmed or unconfirmed TB disease, which might be right-censored due to loss to follow-up, death, or successful completion of the study without acquiring TB disease from day of vaccination. Secondary: Confirmed TB disease, which might be right-censored due to loss to follow-up, death, or successful completion of the study without acquiring TB from day of vaccination. Exploratory: i) Time from vaccination to diagnosis of first unconfirmed or unlikely TB disease, which might be right-censored due to loss to follow-up, death, or successful completion of the study without acquiring TB disease from day of vaccination. ii) Confirmed or unconfirmed TB, which might be right-censored due to loss to follow-up, death, or successful completion of the study without acquiring TB carried out with a washout period of 90 days after vaccination. iii) Confirmed TB disease; iv) Unconfirmed or unlikely TB disease (ver ii for iii and iv).
Minimum of 24 months to a maximum 80 months; or until study end in South Africa.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
To assess the safety and reactogenicity of MTBVAC in healthy HU and HEU newborns compared to BCG.
Time Frame: Minimum of 24 months to a maximum 80 months; or until study end in South Africa.
Incidence and severity of: Solicited AEs; Local solicited AEs (injection-site reactions): pain, erythema (redness), swelling, and induration (collected up to Day 10), and ulceration, drainage/discharge, and scarring (collected up to Day 56); Systemic solicited AEs: fever, irritability, vomiting, diarrhea, and skin rash (collected up to Day 10). Unsolicited AEs: MAAEs; Medically un-attended AEs. Solicited AEs with onset after Day 10: Local solicited AEs (injection-site reactions): pain, erythema (redness), swelling, and induration. Systemic solicited AEs: fever, irritability, vomiting, diarrhea, and skin rash. Solicited AEs with onset after Day 56: ulceration, drainage/discharge, and scarring; AESIs, SAEs
Minimum of 24 months to a maximum 80 months; or until study end in South Africa.

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Tertiary objective: To assess immunogenicity of MTBVAC in healthy HU and HEU newborns.
Time Frame: Minimum of 24 months to a maximum 80 months; or until study end in South Africa.
• Frequencies and co-expression patterns of CD4 and CD8 T cells expressing IFNγ, TNF, IL-2, IL-17, and/or IL-22 induced by MTBVAC or BCG vaccination detected by WB-ICS after in vitro stimulation with MTBVAC, BCG, or a megapool of mycobacterial peptides.
Minimum of 24 months to a maximum 80 months; or until study end in South Africa.
Exploratory objective: To assess immunogenicity of MTBVAC in healthy HU and HEU newborns.
Time Frame: Minimum of 24 months to a maximum 80 months; or until study end in South Africa.
Qualitative (positive or negative) and quantitative (TB Ag-Nil IFNγ concentration) QFT-Gold Plus assay results (QFT conversion will be defined as a positive test without a prior positive test; QFT reversion will be defined as a negative test following a positive test).
Minimum of 24 months to a maximum 80 months; or until study end in South Africa.
Exploratory objective: To biobank samples for (future) biomarker studies to identify immunological correlates of vaccine-induced protection and biomarkers of risk for TB disease
Time Frame: Minimum of 24 months to a maximum 80 months; or until study end in South Africa.

• The following samples will be collected and biobanked for future studies to investigate the immune correlates of TB infection:

  • PBMC
  • Plasma
  • Paxgene The analyses will be described in a separate document.
Minimum of 24 months to a maximum 80 months; or until study end in South Africa.
Exploratory objective: To assess the non-specific effects of MTBVAC in healthy HU and HEU newborns compared to BCG.
Time Frame: Minimum of 24 months to a maximum 80 months; or until study end in South Africa.

Primary

• SAEs (hospitalization, death) due to non-TB infectious diseases classified as MedDRA SOC Infections and infestations occurring from Days 0 to 42.

Secondary

  • MAAEs due to non-TB infectious diseases classified as MedDRA SOC Infections and infestations occurring from Days 0 to 42.
  • SAEs (hospitalization, death) due to non-TB infectious diseases classified as MedDRA SOC Infections and infestations occurring from Day 42 to EoSe.
  • MAAEs due to non-TB infectious diseases classified as MedDRA SOC Infections and infestations occurring from Day 42 to EoSe.
  • SAEs (hospitalization, death) occurring from Days 0 to 42 (or receipt of another vaccine type).
  • MAAEs occurring from Days 0 to 42 (or receipt of another vaccine type).
  • SAEs (hospitalization, death) from Day 42 to EoSe.
  • MAAEs from Day 42 to EoSe.
Minimum of 24 months to a maximum 80 months; or until study end in South Africa.
Exploratory objective: To assess TB case definitions determined by study-specific TB investigations compared to non-study solicited TB investigations in South Africa
Time Frame: Minimum of 24 months to a maximum 80 months; or until study end in South Africa.
  • Time from vaccination to diagnosis of first confirmed or unconfirmed TB disease, which might be right-censored due to loss to follow-up, death, or successful completion of the study without acquiring TB disease from the day of the vaccination.
  • Time from vaccination to diagnosis of first confirmed TB disease, which might be right-censored due to loss to follow-up, death, or successful completion of the study without acquiring TB disease from the day of the vaccination.
Minimum of 24 months to a maximum 80 months; or until study end in South Africa.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Biofabri, S.L

Collaborators

University of Stellenbosch
University of Cape Town
TuBerculosis Vaccine Initiative
Universidad de Zaragoza
University of KwaZulu
Institut Pasteur de Madagascar
Biomedical Research Center EPLS
Wits Health Consortium (Pty) Ltd

Investigators

  • Principal Investigator: Mark Hatherill, University of Cape Town, Faculty of Health Sciences

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 23, 2022

Primary Completion (Estimated)

June 1, 2028

Study Completion (Estimated)

September 1, 2029

Study Registration Dates

First Submitted

June 21, 2021

First Submitted That Met QC Criteria

July 14, 2021

First Posted (Actual)

July 23, 2021

Study Record Updates

Last Update Posted (Actual)

October 10, 2023

Last Update Submitted That Met QC Criteria

October 6, 2023

Last Verified

October 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • MTBVACN3

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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