Evaluating the Safety and Immunogenicity of MTBVAC

The purpose of this study is to evaluate the safety and immunogenicity of MTBVAC in adolescents and adults living with and without HIV in South Africa

Inclusion Criteria: * Age of 12 through 55 years, on the day of enrollment. * Access to a participating HVTN or ACTG CRS and willingness to be followed for the planned duration of the study. * For volunteers 18 years of age or older: ability and willingness to provide informed consent. * For volunteers less than 18 years of age: parent or legal guardian is willing and able to provide informed consent for potential participant's study participation; in addition, when applicable per ethics committee policies and procedures, potential participant is willing and able to provide written assent for study participation. * Assessment of Understanding (AoU): volunteer demonstrates understanding of this study and completes a questionnaire prior to vaccination with verbal demonstration of understanding of all questionnaire items answered incorrectly. * Prior receipt of BCG vaccine in infancy as determined by the site investigator. * Agrees not to enroll in another study of an investigational study product until after the last scheduled clinic visit. If a potential participant is already enrolled in another clinical trial, approvals from the other trial sponsor and the HVTN 605/A5421 PSRT are required prior to enrollment into HVTN 605/A5421. * Good general health as shown by medical history, physical exam, and screening laboratory tests and assessed by the site investigator. * Willingness to receive HIV-related test results. * For volunteers living without HIV: 1. Negative HIV-1 and -2 blood test: Non-US sites may use locally available assays that have been approved by HVTN Laboratory Operations 2. Assessed by the clinic staff as having a low likelihood of acquiring HIV and is committed to maintaining behavior that is consistent with a lower likelihood of acquiring HIV through the last required protocol clinic visit 3. Willingness to discuss their potential for HIV acquisition and is amenable to HIV risk reduction counseling * For volunteers living with HIV: 1. For both Cohorts 2 and 3: Completed one course of tuberculosis preventive treatment (TPT) as determined by the site investigator. Documented HIV viral suppression (Plasma HIV levels \< 50 copies/mL) collected at least three months and up to 15 months prior to enrollment (with no intervening HIV-1 RNA results ≥ 50 copies/mL) and from screening labs. Has been receiving at least 6 months of ART prior to enrollment, as determined by the site investigator 2. For Cohort 2: WHO HIV clinical stage 1 or 2 prior to initiation (or re-initiation in case of treatment interruption/default) of ART. CD4+ T-cell count of ≥ 200 cells/mm3 (during screening) 3. For Cohort 3: Advanced HIV disease (defined as CD4 count less than 200 cells/mm3 or WHO HIV clinical stage 3 or 4) prior to initiation (or re-initiation) of ART. Advanced HIV defined as CD4 count less than 200 cells/mm3 or WHO stage 3 or 4. Current CD4+ T-cell count of ≥ 100 cells/ mm3 (during screening) * Laboratory Inclusion Values - Has normal or Grade 1 results of all of the following at screening: Hemoglobin (≥ 9.5 g/dL or ≥ 5.88 mmol/L for males and females less than 13 years of age; ≥ 9.5 g/dL or ≥ 5.88 mmol/L for females 13 years of age and older; ≥ 10.0 g/dL or ≥ 6.19 mmol/L for males 13 years of age and older); White blood cell count (≥ 2000 cells/mm3 or ≥ 2.000 × 109 cells/L); Platelet count (≥ 100,000 cells/mm3 or ≥ 100.000 × 109 cells/L); Creatinine (≤ 1.3 × upper limit of normal \[ULN\]); Alanine aminotransferase (ALT) (\< 2.5 × ULN); Aspartate aminotransferase (AST) (\< 2.5 × ULN) * Negative Hepatitis B surface antigen (HBsAg). * Negative anti-Hepatitis C virus Abs (anti-HCV), or negative HCV nucleic acid test if the anti-HCV is positive * For volunteers assigned female sex at birth (AFAB) or intersex at birth and are of reproductive potential (hereafter referred to as "of pregnancy potential"): negative serum or urine beta human chorionic gonadotropin (β-HCG) pregnancy test at screening (ie, prior to randomization) and prior to study product administration on the day of study product administration. Persons who are NOT of pregnancy potential including having reached menopause (no menses for 1 year) or having undergone hysterectomy or bilateral oophorectomy, or tubal ligation (verified by medical records) are not required to undergo pregnancy testing. * Reproductive status: A volunteer of pregnancy potential: 1. Must agree to use effective contraception for sexual activity that could lead to pregnancy from at least 21 days prior to enrollment until 10 weeks after vaccination. 2. Volunteers of pregnancy potential must also agree not to seek pregnancy through alternative methods, such as artificial insemination, or in vitro fertilization until 10 weeks after vaccination. 3. Volunteers of pregnancy potential must also agree not to undergo oocyte retrieval. Exclusion Criteria: * Weight less than 40 kg * Known significant exposure to TB or receipt of tuberculin skin test in the six months prior enrollment, as determined by the site investigator based on potential participant/parent/guardian report and available medical records. \[Note: Significant exposure is defined as close contact with a person who has active TB and has not completed TB treatment. Close contact is defined as sleeping in the same contiguous house/dwelling, and/or working or socializing in close proximity in an enclosed space frequently (eg, several times a week).\] * History of prior active TB disease, as determined by the site investigator based on participant/parent/guardian report and available medical, laboratory or radiographic records. * Evidence of active TB disease as determined by the site investigator based on participant/parent/guardian report and available medical records, results from physical examination, two-view chest X-ray, and M.tb nucleic acid testing from an expectorated sputum, including a review of any available radiography; and, for volunteers living with HIV and a CD4 count \