Safety and Immunogenicity of VPM1002 Vaccination or BCG Revaccination Against TB in Pre-Adolescents Living With and Without HIV in South Africa

Study Overview
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Brief Summary
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The purpose of this study is to assess whether Mycobacterium bovis rBCGΔureC::hly (VPM1002) vaccination and Mycobacterium bovis bacille Calmette-Guérin (BCG) revaccination are safe and immunogenic in pre-adolescents with and without HIV and with and without Mycobacterium tuberculosis (M.tb) sensitization.

Detailed Description
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Phase I/II, double-blinded, placebo-controlled, randomized (1:1:1) multi-center study. Randomization will be stratified by HIV status and M.tb sensitization status. The study will enroll approximately 480 pre-adolescents (8-14 years of age inclusive) with or without HIV and with or without M.tb sensitization who received BCG vaccination at birth. Participants with HIV will be immunocompetent and virologically suppressed on antiretroviral therapy. Participants will be randomized to one of three study product arms: VPM1002 Vaccine, BCG Vaccine, or Placebo. Each participant will receive a single intradermal injection of the assigned study product.

Official Title
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Phase I/II Randomized, Placebo-Controlled Study of the Safety and Immunogenicity of VPM1002 Vaccination or BCG Revaccination Against Tuberculosis in Pre-Adolescents Living With and Without HIV in South Africa

Conditions
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Tuberculosis, HIV Infections

Intervention / Treatment
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* Biological: VPM1002 Vaccine
* Biological: BCG Vaccine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Parent or legal guardian is willing and able to provide written informed consent; when applicable potential participant is willing and able to provide written assent Age 8-14 years (inclusive) at entry Received birth dose of BCG vaccine Has a negative nucleic acid test result for M.tb at screening and no other evidence of current active TB disease at screening M.tb sensitization status (positive or negative) determined based on IGRA testing at screening HIV status determined For participants living with HIV: has been receiving antiretroviral therapy for at least six months prior to study entry, has a CD4+ cell count of at least 200 cells/mm^3 at screening, has had a suppressed HIV viral load for at least three months prior to entry Has normal or grade 1 results for all of the following at screening: Hemoglobin, White blood cell count, Platelet count, Creatinine, ALT, AST, Total bilirubin Has a normal temperature and no signs or symptoms of acute illness For participants assigned female sex at birth or who could otherwise become pregnant: not pregnant For participants assigned female sex at birth or who could otherwise breastfeed: not breastfeeding Expected to be available for 48 weeks of study participation Not expected to participate in any other study of an investigational agent during the 48 weeks of study participation Exclusion Criteria: Known significant exposure to TB or receipt of tuberculin skin test in the six months prior to study entry Receipt of treatment for active TB disease in the 24 months prior to study entry Receipt of TB preventive therapy within 30 days prior to study entry or expected to initiate TB preventive therapy within the 48 weeks following study entry For participants living with HIV, current active AIDS-defining condition Receipt of any of the following: Any investigational TB vaccine, More than 14 consecutive days of systemic immunosuppressants or other immune-modifying therapy within the six months prior to study entry, Any immunoglobulin or other blood product within the three months prior to study entry, Receipt of any vaccine within the 30 days prior to study entry or is expected to receive any vaccine between study entry and the Week 4 Visit Receipt of allergy treatment with an antigen injection within the 30 days prior to study entry or is expected to receive one or more antigen injections between study entry and the Week 48 Visit History of any of the following: serious adverse reaction to any vaccine, allergy or hypersensitivity to BCG vaccine, allergy or hypersensitivity to the components of VPM1002 vaccine, anaphylaxis, generalized urticaria, autoimmune disease, diabetes mellitus type 1 or type 2, mild persistent, moderate, or severe asthma, bleeding disorder, malignancy, any condition resulting in the absence of a functional spleen (asplenia), including but not limited to sickle cell disease History of seizure or use of any medication to prevent or treat seizure within the three years prior to entry History of suspected or confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection diagnosed within the 30 days prior to entry Any other documented or suspected clinically significant medical, psychiatric, or behavioral condition or any other condition that, in the opinion of the site investigator, would make participation in the study unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 14 Years

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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VPM1002 Vaccine Arm<br>Participants stratified by HIV and M.tb sensitization status. | Biological: VPM1002 Vaccine<br>* 0.1 mL (2-8x10^5 CFU)<br>|
| Experimental: BCG Vaccine Arm<br>Participants stratified by HIV and M.tb sensitization status. | Biological: BCG Vaccine<br>* 0.1mL (0.075 Mycobacterium bovis)<br>|
| Placebo Comparator: Placebo Arm<br>Participants stratified by HIV and M.tb sensitization status. | Drug: Placebo<br>* 0.1 mL (sodium chloride for injection 0.9%)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All adverse events | Proportion of participants, based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017 | Through Week 48 | 
| Solicited adverse events | Proportion of participants, based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017 | Through Week 16 | 
| Grade 3 or higher adverse events | Proportion of participants, based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017 | Through Week 48 | 
| Serious adverse events | Proportion of participants, based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017 | Through Week 48 | 
| Adverse pregnancy outcomes | Proportion of participants, based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017 | Through Week 48 or delivery or other pregnancy outcome, whichever occurs later | 
| Frequency and response of VPM1002-specific and BCG-specific CD4+ and CD8+ T cells expressing Th1 and/or Th17 cytokines | Measured by ICS and flow cytometry on cryopreserved PBMCs | Through Week 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency and response of VPM1002-specific and BCG-specific CD4+ and CD8+ T cells expressing Th1 and/or Th17 cytokines | Measured by ICS and flow cytometry on cryopreserved PBMC | Weeks 24 and 48 | 
| Mycobacteria-specific IgA, IgG, and IgM binding antibodies | Measured using BAMA | Entry and Weeks 4, 10, 24, and 48 | 
| Association of HIV and IGRA with primary safety outcomes (All AEs, solicitated AEs, grade 3 or higher AEs, serious adverse events, adverse pregnancy outcomes). | Based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017 | Through Week 48 or delivery or other pregnancy outcome, whichever occurs later | 
| Cellular immunogenicity outcome measures associated with HIV and IGRA status | VPM1002-specific and BCG-specific CD4+ and CD8+ T cells expressing Th1 and/or Th17 cytokines, measured by ICS and flow cytometry on cryopreserved PBMCs | Through Week 48 | 
| Humoral immunogenicity outcome measures associated with HIV and IGRA status | Mycobacteria-specific IgA, IgG, and IgM binding antibodies, measured using BAMA | Through Week 48 | 
| Gene expression profiles | Measured by RNA-seq in whole blood | Entry and Weeks 1, 4, and 10 | 
| Differential leukocyte count and immunophenotype | Measured in cryopreserved ex vivo whole blood (DLC-ICE) by flow cytometry | Entry and Weeks 1, 4, and 10 | 
| Measurement of soluble proinflammatory mediators | Based on serum measurement | Entry and Weeks 1, 4, and 10 | 
| Acceptability of the study products | Based on scores derived from questionnaire responses | Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bacterial and fungal diseases, Tuberculosis, Vaccine, Live vaccine, rBCG