Dose-Defining Safety and Immunogenicity Study of MTBVAC in South African Neonates

Study Overview
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Brief Summary
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A Phase 2a dose-defining study of MTBVAC to evaluate the safety, reactogenicity, immunogenicity, and potential for IGRA conversion and reversion, of MTBVAC in South African newborns. Ninety-nine HIV unexposed, BCG naïve newborns will be randomized to receive either BCG 2.5 x 105 CFU (n=24) or MTBVAC at one of three dose levels (n=75). Allocation will be double blind. Enrolment will be sequential into 3 cohorts of increasing MTBVAC dose (Cohort 1: n=25 MTBVAC 2.5 x 10E+04 and n=8 BCG; Cohort 2: n=25 MTBVAC 2.5 x 10E+05 and n=8 BCG; Cohort 3: n=25 MTBVAC 2.5 x 10E+06 and n=8 BCG). Dose escalation will be staggered to allow gradual evaluation of safety; final selection of the dose for Cohort 3 will be based on all available safety and immunogenicity data.

Detailed Description
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new effective tuberculosis (TB) vaccine is essential to achieve World Health Organization (WHO) 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 as such, live attenuated mycobacterial vaccines may offer better protection to this naïve population compared to adults. MTBVAC is a novel TB vaccine candidate generated by genetically attenuating an M. tuberculosis clinical isolate of the EuroAmerican lineage. MTBVAC is based on two independent, stable genetic deletions of the genes coding for two major virulence factors, phoP coding for the transcription factor PhoP and fadD26 coding for the synthesis of PDIM. Since MTBVAC contains most of the genes deleted from BCG, it presents a wider collection of mycobacterial antigens to the host immune system. Safety and immunogenicity of MTBVAC has been demonstrated in BCG naive adults; and MTBVAC appears safe in a small ongoing Phase 1b study in South African newborns. Definitive demonstration of safety and immunogenicity at the optimal MTBVAC dose is key to progression into multi-centre efficacy trials in newborns. A Phase 2a dose-defining study of MTBVAC to evaluate the safety, reactogenicity, immunogenicity, and potential for IGRA conversion and reversion, of MTBVAC in South African newborns. Ninety-nine HIV unexposed, BCG naïve newborns will be randomized to receive either BCG 2.5 x 105 CFU (n=24) or MTBVAC at one of three dose levels (n=75). Allocation will be double blind. Enrolment will be sequential into 3 cohorts of increasing MTBVAC dose (Cohort 1: n=25 MTBVAC 2.5 x 10E+04 and n=8 BCG; Cohort 2: n=25 MTBVAC 2.5 x 10E+05 and n=8 BCG; Cohort 3: n=25 MTBVAC 2.5 x 10E+06 and n=8 BCG). Dose escalation will be staggered to allow gradual evaluation of safety; final selection of the dose for Cohort 3 will be based on all available safety and immunogenicity data.

Official Title
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Phase 2a Dose-Defining Safety and Immunogenicity Study of MTBVAC in South African Neonates Living in a High-Burden Tuberculosis-Endemic Region

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 of Newborns: Newborns of mothers who provided informed consent will be enrolled within 96 hours of birth if they are in general good health during pregnancy and delivery Weight ≥2450 grams at birth Apgar score at 5 minutes ≥7 Estimated gestational age ≥37 weeks. Exclusion Criteria of Newborns: If received routine BCG vaccination prior to enrolment Have any significant antenatal or intrapartum or postpartum complications Have unknown or positive maternal HIV test; or Have prior history of close contact with a TB patient, antenatal or postnatal, whether maternal, other family member or other household member.

Ages Eligible for Study
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Maximum Age: 96 Hours

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: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MTBVAC Group 1<br>MTBVAC intermediate dose 2.5 x 10E+04 CFU/0.05 mL | Biological: MTBVAC<br>* Live-attenuated Mycobacterium tuberculosis based on the deletion of phoP and fadD26 virulence genes<br>|
| Experimental: MTBVAC Group 2<br>MTBVAC high dose 2.5 x 10E+05 CFU/0.05 mL | Biological: MTBVAC<br>* Live-attenuated Mycobacterium tuberculosis based on the deletion of phoP and fadD26 virulence genes<br>|
| Experimental: MTBVAC Group 3<br>MTBVAC highest dose 2.5 x 10E+06 CFU/0.05 mL | Biological: MTBVAC<br>* Live-attenuated Mycobacterium tuberculosis based on the deletion of phoP and fadD26 virulence genes<br>|
| Active Comparator: BCG Group 4<br>BCG control 2.5 x 10E+05 CFU/0.05 mL | Biological: BCG<br>* Live-attenuated Mycobacterium bovis obtained by subculture passaging in ox-bile and glycerated potatoes between 1908-1921 by Albert Calmette and Camille Guerin. BCG is the only licensed vaccine today against tuberculosis (TB) mainly used in TB-endemic countries.<br>* Other names: Licensed BCG;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-related adverse events as defined in protocol. | Solicited systemic adverse events: fever, irritability, vomiting, diarrhea, drowsiness, poor feeding, skin rash. Solicited injection site reaction adverse events: pain, redness, swelling, ulceration, drainage, and regional lymphadenopathy Unsolicited adverse events and serious adverse events | 365 days post-vaccination | 
| Immunogenicity analysis in infants | Measure of CD4 and CD8 T cells expressing specific cytokines in whole blood. | 365 days post-vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTBVAC-induced QFT conversion and reversion kinetics | Quantitative and qualitative results of the QFT Gold Plus assay up to day 365 post-vaccination. | 365 days post-vaccination |