Tuberculosis
Conditions
Brief summary
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
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.
Interventions
BIOLOGICALMTBVAC
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.
BIOLOGICALBCG
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.
Sponsors
TuBerculosis Vaccine Initiative
University of Cape Town
Institut Pasteur de Madagascar
Biomedical Research Center EPLS
Universidad de Zaragoza
University of Stellenbosch
University of KwaZulu
Wits Health Consortium (Pty) Ltd
Biofabri, S.L
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
MTBVAC and BCG vaccine will be prepared, and allocation concealed by the site pharmacist. All other site staff will be blinded to vaccine allocation, throughout the follow-up period. Data pertaining to the MTBVAC vaccine and to BCG control will be collected in an observer-blinded manner. Blinding will be maintained throughout the vaccination and follow-up portions of the vaccine trial. No set of individual codes will be held at Biofabri's Headquarters. Biofabri's Headquarters will be able to access the individual randomization code from the SATVI Pharmacy randomization register. The code will be broken by the Site's Pharmacist (Study Contact for Emergency Code Break) only in the case of medical events that the investigator/physician in charge of the participant feels cannot be treated without knowing the identity of the study vaccine(s). The Site's Pharmacist is responsible for unblinding the treatment assignment in accordance with specified time frames for expedited reporting of SAEs.
Intervention model description
The study is designed to include the following: 1. 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. 2. Reactogenicity population: \- First 1000 from the 4 South African sites and all 120 in Madagascar and Senegal. 3. 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. 4. 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.
Eligibility
Sex/Gender
ALL
Age
5 Minutes to 7 Days
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To demonstrate efficacy in terms of incidence of MTBVAC against TB disease in healthy HU and HEU newborns compared to BCG | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To assess the safety and reactogenicity of MTBVAC in healthy HU and HEU newborns compared to BCG. | 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 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Exploratory objective: To biobank samples for (future) biomarker studies to identify immunological correlates of vaccine-induced protection and biomarkers of risk for TB disease | 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. |
| Tertiary objective: To assess immunogenicity of MTBVAC in healthy HU and HEU newborns. | 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. |
| Exploratory objective: To assess TB case definitions determined by study-specific TB investigations compared to non-study solicited TB investigations in South Africa | 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. |
| Exploratory objective: To assess the non-specific effects of MTBVAC in healthy HU and HEU newborns compared to BCG. | 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. |
| Exploratory objective: To assess immunogenicity of MTBVAC in healthy HU and HEU newborns. | 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). |
Countries
South Africa
Contacts
Primary ContactIngrid Murillo Jelsbak
Backup ContactAndrea García Silva
Outcome results
None listed