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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Tuberculosis

Intervention / Treatment
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* Biological: MTBVAC
* Biological: BCG


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 5 Minutes
Maximum Age: 7 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study is designed to include the following: Safety population (all study participants randomized to receive BCG or MTBVAC in a 1:1 fashion): All participants from the 4 South African sites (approx. 7000); all 120 participants from Madagascar & Senegal. Reactogenicity population: - First 1000 from the 4 South African sites and all 120 in Madagascar and Senegal. Immunogenicity population (subset of the safety population - total 460): - First 60 HU and 25 HEU participants from the South African sites (total 340) and all 120 from Madagascar & Senegal. Efficacy population (subset of the safety population - all participants from the South African sites): First 1000, including 240 HU and 100 HEU newborns. Additional 6000 (not part of reactogenicity & immunogenicity population). Senegal & Madagascar participants are excluded from the efficacy population. DSMB will periodically review cumulative safety and reactogenicity data.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MTBVAC<br>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<br>* 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.<br>|
| Active Comparator: BCG<br>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<br>* 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.<br>|

What is the study measuring?
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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 | 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. | 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. |