TuberculosisPhase 3MTBVACN3NCT04975178
Efficacy, Safety and Immunogenicity Evaluation of MTBVAC in Newborns in Sub-Saharan Africa
A Phase 3 study testing MTBVAC and BCG in people with Tuberculosis, run by Biofabri, S.L at 1 site in South Africa.
Trial 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. Read more about this study
- Who is it for?
- Ages 5 minutes to 7 daysHealthy volunteers can take part
- Conditions the study is for
- Tuberculosis
- What is being tested?
- MTBVAC and BCG
- Type of treatment
- Vaccines, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 7,120 participants
- Where
- 1 siteSouth Africa
- Study dates
- 17 Oct 2022to Feb 2029
- Phase
- Phase 3
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 5 minutes to 7 days
- All sexes
- Healthy volunteers accepted
- Child
Who may be able to join
- 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.
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- 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.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
South Africa1 site, 1 recruiting
- Recruiting
South African Tuberculosis Initiative, Brewelskloof Hospital
Worcester, Western Cape, 6850
Michele Tameris, MD, +27 23 346 5400, michele.tameris@uct.ac.za
About this study
Official title: 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.
Read the 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.
- Conditions
- Tuberculosis
- Being tested
- MTBVAC, BCG
- Medical subject headings
- Tuberculosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MTBVACBiological
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.
BCGBiological
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.
| Study group | Role | What they receive |
|---|---|---|
| MTBVAC | Experimental | 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. Receives: Biological: MTBVAC |
| BCG | Active comparator | 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. Receives: Biological: BCG |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: Minimum of 24 months to a maximum 80 months; or until study end in South Africa.
Secondary outcomes (1)
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
Measured: Minimum of 24 months to a maximum 80 months; or until study end in South Africa.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Jul 2021
- Study start17 Oct 2022
- Primary completionFeb 2029 (estimated)
- Study completionFeb 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (21)Papers the sponsor has linked to this study.
- Other trials for TuberculosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- 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.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 7,120 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Biofabri, S.L
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- 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
- Responsible party
- Sponsor
- Investigators
- Mark Hatherill, Principal investigator, University of Cape Town, Faculty of Health Sciences
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04975178
- Sponsor's protocol ID
- MTBVACN3
- Acronym
- MTBVACN3
- Status last verified
- Feb 2025
- First submitted
- 21 Jun 2021
- Last updated
- 10 Feb 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Tameris M, Mearns H, Penn-Nicholson A, Gregg Y, Bilek N, Mabwe S, Geldenhuys H, Shenje J, Luabeya AKK, Murillo I, Doce J, Aguilo N, Marinova D, Puentes E, Rodriguez E, Gonzalo-Asensio J, Fritzell B, Thole J, Martin C, Scriba TJ, Hatherill M; MTBVAC Clinical Trial Team. Live-attenuated Mycobacterium tuberculosis vaccine MTBVAC versus BCG in adults and neonates: a randomised controlled, double-blind dose-escalation trial. Lancet Respir Med. 2019 Sep;7(9):757-770. doi: 10.1016/S2213-2600(19)30251-6. Epub 2019 Aug 12.
PubMed 31416768Spertini F, Audran R, Chakour R, Karoui O, Steiner-Monard V, Thierry AC, Mayor CE, Rettby N, Jaton K, Vallotton L, Lazor-Blanchet C, Doce J, Puentes E, Marinova D, Aguilo N, Martin C. Safety of human immunisation with a live-attenuated Mycobacterium tuberculosis vaccine: a randomised, double-blind, controlled phase I trial. Lancet Respir Med. 2015 Dec;3(12):953-62. doi: 10.1016/S2213-2600(15)00435-X. Epub 2015 Nov 17.
PubMed 26598141Arbues A, Aguilo JI, Gonzalo-Asensio J, Marinova D, Uranga S, Puentes E, Fernandez C, Parra A, Cardona PJ, Vilaplana C, Ausina V, Williams A, Clark S, Malaga W, Guilhot C, Gicquel B, Martin C. Construction, characterization and preclinical evaluation of MTBVAC, the first live-attenuated M. tuberculosis-based vaccine to enter clinical trials. Vaccine. 2013 Oct 1;31(42):4867-73. doi: 10.1016/j.vaccine.2013.07.051. Epub 2013 Aug 17.
PubMed 23965219Aguilo N, Gonzalo-Asensio J, Alvarez-Arguedas S, Marinova D, Gomez AB, Uranga S, Spallek R, Singh M, Audran R, Spertini F, Martin C. Reactogenicity to major tuberculosis antigens absent in BCG is linked to improved protection against Mycobacterium tuberculosis. Nat Commun. 2017 Jul 14;8:16085. doi: 10.1038/ncomms16085.
PubMed 28706226Andrews JR, Noubary F, Walensky RP, Cerda R, Losina E, Horsburgh CR. Risk of progression to active tuberculosis following reinfection with Mycobacterium tuberculosis. Clin Infect Dis. 2012 Mar;54(6):784-91. doi: 10.1093/cid/cir951. Epub 2012 Jan 19.
PubMed 22267721Camacho LR, Ensergueix D, Perez E, Gicquel B, Guilhot C. Identification of a virulence gene cluster of Mycobacterium tuberculosis by signature-tagged transposon mutagenesis. Mol Microbiol. 1999 Oct;34(2):257-67. doi: 10.1046/j.1365-2958.1999.01593.x.
PubMed 10564470Copin R, Coscolla M, Efstathiadis E, Gagneux S, Ernst JD. Impact of in vitro evolution on antigenic diversity of Mycobacterium bovis bacillus Calmette-Guerin (BCG). Vaccine. 2014 Oct 14;32(45):5998-6004. doi: 10.1016/j.vaccine.2014.07.113. Epub 2014 Sep 6.
PubMed 25211768Gonzalo-Asensio J, Marinova D, Martin C, Aguilo N. MTBVAC: Attenuating the Human Pathogen of Tuberculosis (TB) Toward a Promising Vaccine against the TB Epidemic. Front Immunol. 2017 Dec 15;8:1803. doi: 10.3389/fimmu.2017.01803. eCollection 2017.
PubMed 29326700Gonzalo-Asensio J, Mostowy S, Harders-Westerveen J, Huygen K, Hernandez-Pando R, Thole J, Behr M, Gicquel B, Martin C. PhoP: a missing piece in the intricate puzzle of Mycobacterium tuberculosis virulence. PLoS One. 2008;3(10):e3496. doi: 10.1371/journal.pone.0003496. Epub 2008 Oct 23.
PubMed 18946503Graham SM, Ahmed T, Amanullah F, Browning R, Cardenas V, Casenghi M, Cuevas LE, Gale M, Gie RP, Grzemska M, Handelsman E, Hatherill M, Hesseling AC, Jean-Philippe P, Kampmann B, Kabra SK, Lienhardt C, Lighter-Fisher J, Madhi S, Makhene M, Marais BJ, McNeeley DF, Menzies H, Mitchell C, Modi S, Mofenson L, Musoke P, Nachman S, Powell C, Rigaud M, Rouzier V, Starke JR, Swaminathan S, Wingfield C. Evaluation of tuberculosis diagnostics in children: 1. Proposed clinical case definitions for classification of intrathoracic tuberculosis disease. Consensus from an expert panel. J Infect Dis. 2012 May 15;205 Suppl 2(Suppl 2):S199-208. doi: 10.1093/infdis/jis008. Epub 2012 Mar 22.
PubMed 22448023Kamath AT, Fruth U, Brennan MJ, Dobbelaer R, Hubrechts P, Ho MM, Mayner RE, Thole J, Walker KB, Liu M, Lambert PH; AERAS Global TB Vaccine Foundation; World Health Organization. New live mycobacterial vaccines: the Geneva consensus on essential steps towards clinical development. Vaccine. 2005 May 31;23(29):3753-61. doi: 10.1016/j.vaccine.2005.03.001. Epub 2005 Mar 24.
PubMed 15893612Knight GM, Griffiths UK, Sumner T, Laurence YV, Gheorghe A, Vassall A, Glaziou P, White RG. Impact and cost-effectiveness of new tuberculosis vaccines in low- and middle-income countries. Proc Natl Acad Sci U S A. 2014 Oct 28;111(43):15520-5. doi: 10.1073/pnas.1404386111. Epub 2014 Oct 6.
PubMed 25288770Marais S, Thwaites G, Schoeman JF, Torok ME, Misra UK, Prasad K, Donald PR, Wilkinson RJ, Marais BJ. Tuberculous meningitis: a uniform case definition for use in clinical research. Lancet Infect Dis. 2010 Nov;10(11):803-12. doi: 10.1016/S1473-3099(10)70138-9. Epub 2010 Sep 6.
PubMed 20822958Scriba TJ, Kaufmann SH, Henri Lambert P, Sanicas M, Martin C, Neyrolles O. Vaccination Against Tuberculosis With Whole-Cell Mycobacterial Vaccines. J Infect Dis. 2016 Sep 1;214(5):659-64. doi: 10.1093/infdis/jiw228. Epub 2016 May 30.
PubMed 27247343Stucki D, Brites D, Jeljeli L, Coscolla M, Liu Q, Trauner A, Fenner L, Rutaihwa L, Borrell S, Luo T, Gao Q, Kato-Maeda M, Ballif M, Egger M, Macedo R, Mardassi H, Moreno M, Tudo Vilanova G, Fyfe J, Globan M, Thomas J, Jamieson F, Guthrie JL, Asante-Poku A, Yeboah-Manu D, Wampande E, Ssengooba W, Joloba M, Henry Boom W, Basu I, Bower J, Saraiva M, Vaconcellos SEG, Suffys P, Koch A, Wilkinson R, Gail-Bekker L, Malla B, Ley SD, Beck HP, de Jong BC, Toit K, Sanchez-Padilla E, Bonnet M, Gil-Brusola A, Frank M, Penlap Beng VN, Eisenach K, Alani I, Wangui Ndung'u P, Revathi G, Gehre F, Akter S, Ntoumi F, Stewart-Isherwood L, Ntinginya NE, Rachow A, Hoelscher M, Cirillo DM, Skenders G, Hoffner S, Bakonyte D, Stakenas P, Diel R, Crudu V, Moldovan O, Al-Hajoj S, Otero L, Barletta F, Jane Carter E, Diero L, Supply P, Comas I, Niemann S, Gagneux S. Mycobacterium tuberculosis lineage 4 comprises globally distributed and geographically restricted sublineages. Nat Genet. 2016 Dec;48(12):1535-1543. doi: 10.1038/ng.3704. Epub 2016 Oct 31.
PubMed 27798628
Study at a glance
From the registry record, last updated by the sponsor on 10 Feb 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT04975178
- Acronym / sponsor ID
- MTBVACN3 / MTBVACN3
- Conditions
- Tuberculosis
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 7,120 participants (estimated)
- Lead sponsor
- Biofabri, S.LIndustry (pharma, biotech, devices)
- Collaborators
- 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
- Study start
- 17 Oct 2022 (actual)
- Primary completion
- Feb 2029 (estimated)
- Study completion
- Feb 2029 (estimated)
- First posted
- 23 Jul 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- 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.
| Arm | Type | Receives |
|---|---|---|
| MTBVAC | Experimental | Biological: MTBVACBoth 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. |
| BCG | Active comparator | Biological: BCGBCG 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. |
Who may qualify
- Ages
- 5 minutes to 7 days
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child
Key inclusion criteria (11 listed)
- 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.
Key exclusion criteria (10 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MTBVACMTBVAC 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. | Biological | MTBVAC |
| BCGBCG 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. | Biological | BCG |
Primary outcome
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).
1 secondary outcome
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.
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Feb 2025.
- Background: PubMed 31416768Tameris M, Mearns H, Penn-Nicholson A, Gregg Y, Bilek N, Mabwe S, Geldenhuys H, Shenje J, Luabeya AKK, Murillo I, Doce J, Aguilo N, Marinova D, Puentes E, Rodriguez E, Gonzalo-Asensio J, Fritzell B, Thole J, Martin C, Scriba TJ, Hatherill M; MTBVAC Clinical Trial Team. Live-attenuated Mycobacterium tuberculosis vaccine MTBVAC versus BCG in adults and neonates: a randomised controlled, double-blind dose-escalation trial. Lancet Respir Med. 2019 Sep;7(9):757-770. doi: 10.1016/S2213-2600(19)30251-6. Epub 2019 Aug 12.
- Background: PubMed 26598141Spertini F, Audran R, Chakour R, Karoui O, Steiner-Monard V, Thierry AC, Mayor CE, Rettby N, Jaton K, Vallotton L, Lazor-Blanchet C, Doce J, Puentes E, Marinova D, Aguilo N, Martin C. Safety of human immunisation with a live-attenuated Mycobacterium tuberculosis vaccine: a randomised, double-blind, controlled phase I trial. Lancet Respir Med. 2015 Dec;3(12):953-62. doi: 10.1016/S2213-2600(15)00435-X. Epub 2015 Nov 17.
- Background: PubMed 23965219Arbues A, Aguilo JI, Gonzalo-Asensio J, Marinova D, Uranga S, Puentes E, Fernandez C, Parra A, Cardona PJ, Vilaplana C, Ausina V, Williams A, Clark S, Malaga W, Guilhot C, Gicquel B, Martin C. Construction, characterization and preclinical evaluation of MTBVAC, the first live-attenuated M. tuberculosis-based vaccine to enter clinical trials. Vaccine. 2013 Oct 1;31(42):4867-73. doi: 10.1016/j.vaccine.2013.07.051. Epub 2013 Aug 17.
- Background: PubMed 28706226Aguilo N, Gonzalo-Asensio J, Alvarez-Arguedas S, Marinova D, Gomez AB, Uranga S, Spallek R, Singh M, Audran R, Spertini F, Martin C. Reactogenicity to major tuberculosis antigens absent in BCG is linked to improved protection against Mycobacterium tuberculosis. Nat Commun. 2017 Jul 14;8:16085. doi: 10.1038/ncomms16085.
- Background: PubMed 22267721Andrews JR, Noubary F, Walensky RP, Cerda R, Losina E, Horsburgh CR. Risk of progression to active tuberculosis following reinfection with Mycobacterium tuberculosis. Clin Infect Dis. 2012 Mar;54(6):784-91. doi: 10.1093/cid/cir951. Epub 2012 Jan 19.
- Background: PubMed 10564470Camacho LR, Ensergueix D, Perez E, Gicquel B, Guilhot C. Identification of a virulence gene cluster of Mycobacterium tuberculosis by signature-tagged transposon mutagenesis. Mol Microbiol. 1999 Oct;34(2):257-67. doi: 10.1046/j.1365-2958.1999.01593.x.
- Background: PubMed 25211768Copin R, Coscolla M, Efstathiadis E, Gagneux S, Ernst JD. Impact of in vitro evolution on antigenic diversity of Mycobacterium bovis bacillus Calmette-Guerin (BCG). Vaccine. 2014 Oct 14;32(45):5998-6004. doi: 10.1016/j.vaccine.2014.07.113. Epub 2014 Sep 6.
- Background: PubMed 29326700Gonzalo-Asensio J, Marinova D, Martin C, Aguilo N. MTBVAC: Attenuating the Human Pathogen of Tuberculosis (TB) Toward a Promising Vaccine against the TB Epidemic. Front Immunol. 2017 Dec 15;8:1803. doi: 10.3389/fimmu.2017.01803. eCollection 2017.
- Background: PubMed 18946503Gonzalo-Asensio J, Mostowy S, Harders-Westerveen J, Huygen K, Hernandez-Pando R, Thole J, Behr M, Gicquel B, Martin C. PhoP: a missing piece in the intricate puzzle of Mycobacterium tuberculosis virulence. PLoS One. 2008;3(10):e3496. doi: 10.1371/journal.pone.0003496. Epub 2008 Oct 23.
- Background: PubMed 22448023Graham SM, Ahmed T, Amanullah F, Browning R, Cardenas V, Casenghi M, Cuevas LE, Gale M, Gie RP, Grzemska M, Handelsman E, Hatherill M, Hesseling AC, Jean-Philippe P, Kampmann B, Kabra SK, Lienhardt C, Lighter-Fisher J, Madhi S, Makhene M, Marais BJ, McNeeley DF, Menzies H, Mitchell C, Modi S, Mofenson L, Musoke P, Nachman S, Powell C, Rigaud M, Rouzier V, Starke JR, Swaminathan S, Wingfield C. Evaluation of tuberculosis diagnostics in children: 1. Proposed clinical case definitions for classification of intrathoracic tuberculosis disease. Consensus from an expert panel. J Infect Dis. 2012 May 15;205 Suppl 2(Suppl 2):S199-208. doi: 10.1093/infdis/jis008. Epub 2012 Mar 22.
- Background: PubMed 15893612Kamath AT, Fruth U, Brennan MJ, Dobbelaer R, Hubrechts P, Ho MM, Mayner RE, Thole J, Walker KB, Liu M, Lambert PH; AERAS Global TB Vaccine Foundation; World Health Organization. New live mycobacterial vaccines: the Geneva consensus on essential steps towards clinical development. Vaccine. 2005 May 31;23(29):3753-61. doi: 10.1016/j.vaccine.2005.03.001. Epub 2005 Mar 24.
- Background: PubMed 25288770Knight GM, Griffiths UK, Sumner T, Laurence YV, Gheorghe A, Vassall A, Glaziou P, White RG. Impact and cost-effectiveness of new tuberculosis vaccines in low- and middle-income countries. Proc Natl Acad Sci U S A. 2014 Oct 28;111(43):15520-5. doi: 10.1073/pnas.1404386111. Epub 2014 Oct 6.
- WHO, Global Tuberculosis Report 2022. \[Online\] https://www.who.int/publications /i/item/9789240061729 \[accessed on 27 June 2023\].Link provided by the sponsor.
- WHO preferred products characteristics for TB vaccines 2018. \[Online\] https://apps.who.int/iris/ bitstream/handle/10665/273089/ WHO-IVB-18.06-eng.pdf?ua=1 \[accessed on 05 May 2021\].Link provided by the sponsor.
- Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017. \[Online\] https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables \[Accessed on 05 May 2021\].Link provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Mark Hatherill principal investigator
University of Cape Town, Faculty of Health Sciences
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing MTBVAC and BCG in people with Tuberculosis, run by Biofabri, S.L at 1 site in South Africa.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 10 Feb 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in South Africa. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Ingrid Murillo Jelsbak (+34 986 33 04 00 ext. 307, ingrid.murillo@biofabri.es), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04975178, which also lists 21 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Feb 2025.