Design, sponsorship changed prior to initiation. No study procedures done.

This clinical trial will evaluate safety, immunogenicity, and efficacy (prevention of Mtb infection as measured by IGRA conversions) of H56:IC31 in remotely BCG vaccinated adolescents.

This clinical trial will evaluate safety, immunogenicity, and prevention of Mtb infection, (measured by IGRA conversion) of H56:IC31 in remotely BCG vaccinated adolescents. A TB vaccination strategy incorporating H56:IC31 in adolescents or young adults, if found to prevent Mtb infection, would likely have a major impact on TB disease, TB transmission, and control of the epidemic. If vaccination with H56:IC31 is shown to prevent infection with Mtb in this proof of concept study in adolescents, additional larger scale studies examining the impact on TB disease in more diverse populations would be warranted.

Primary objectives

• To evaluate the safety profile of H56:IC31 compared to placebo in HIV-uninfected, remotely BCG vaccinated adolescents.
• To evaluate prevention of Mtb infection by H56:IC31 compared to placebo, as measured by rates of conversion using an ESAT-6 free IGRA.

Secondary objectives

• To evaluate prevention of Mtb infection by H56:IC31 compared to placebo, as measured by rates of sustained conversion using an ESAT-6 free IGRA.
• To evaluate trends in ESAT-6 free IGRA prolonged/sustained conversions and late reversions (i.e., through more than 6 months post initial conversion) in ESAT-6 free IGRA converters.
• To investigate the immunogenicity of H56:IC31 in HIV-uninfected, remotely BCG vaccinated adolescents.

Inclusion Criteria:

1. Has completed the written informed consent and assent process
2. Is age ≥12 years and ≤17 years on Study Day 0
3. Agrees to stay in contact with the study site for the duration of the study, provide updated contact information as necessary, and has no current plans to move from the study area for the duration of the study
4. For female participants: agrees to avoid pregnancy from 21 days prior to Study Day 0 through 6 months after the last study vaccination. Women physically capable of pregnancy (not sterilized and still menstruating or within 1 year of the last menses) in sexual relationships with men must use an acceptable method of avoiding pregnancy during this period. Acceptable methods of avoiding pregnancy include a sterile sexual partner, sexual abstinence (not engaging in sexual intercourse), hormonal contraceptives (oral, injection, transdermal patch, or implant), vaginal ring, or intrauterine device (IUD)
5. Has general good health, confirmed by medical history and physical examination
6. Had BCG vaccination at least 5 years ago documented by confirmation of parent/guardian that the participant received all childhood vaccines or by presence of healed BCG scar
7. Tests ESAT-6 free IGRA and QFT-Plus negative at screening, using a pre-determined threshold for ESAT-6 free IGRA and the manufacturer's recommended threshold for QFT-Plus of 0.35 IU/mL in either of the TB antigen tubes after nil-subtraction

Exclusion Criteria:

1. Acute illness on Study Day 0

2. Axillary temperature ≥37.5 °C on Study Day 0

3. Abnormal laboratory values from the most recent blood collected prior to randomization as follows (abnormal results may be repeated once and if found to be resolved the participant will not be excluded):

   • Laboratory evidence of hematologic disease (white blood cell count <3000/mm^3 or >11,500/mm^3; hemoglobin <0.9 times the lower limit of normal of the testing laboratory, by age and gender; absolute neutrophil count <1300/mm^3; absolute lymphocyte count <1000/mm^3).
   • ALT, AST, alkaline phosphatase, total bilirubin, creatinine, blood urea nitrogen (BUN) >1.25 times the ULN

4. Urinalysis abnormality greater than Grade 1 on the Toxicity Scale (with the exception of hematuria in a menstruating female), or urinalysis abnormality judged clinically significant by the investigator

5. History or evidence of any clinically significant systemic disease, or any acute or chronic illness that might affect the safety, immunogenicity, or efficacy of investigational product in the opinion of the investigator

6. History of treatment for active TB disease or latent Mtb infection

7. History or evidence, including chest X-ray, of active TB disease

8. Shared household with an individual receiving anti-TB treatment, or known to have incompletely treated culture or smear positive TB, at screening

9. History of autoimmune disease or immunosuppression

10. Used immunosuppressive medication within 42 days before Study Day 0 (inhaled and topical corticosteroids are permitted)

11. Received immunoglobulin or blood products within 42 days before Study Day 0

12. Received any investigational drug or investigational vaccine within 180 days before Study Day 0, or planned participation in any other clinical trial during the study period

13. Received investigational TB vaccine at any time prior to Study Day 0

14. Planned administration/administration of a licensed vaccine in the period starting 28 days before and ending 28 days after each dose of investigational product

15. History or laboratory evidence of any past or present possible immunodeficiency state including, but not limited to, any laboratory indication of HIV 1 infection

16. History of allergic disease or reactions, including eczema, likely to be exacerbated by any component of the investigational product

17. History of alcohol or drug abuse

18. Any female currently pregnant or lactating/nursing, or positive urine pregnancy test during screening or Study Day 0

19. Received a tuberculin skin test (TST) within 3 months (90 days) prior to Study Day 0.

20. Any current medical, psychiatric, occupational, or substance abuse problems that, in the opinion of the investigator, will make it unlikely that the participant will comply with the protocol.

Random numbers generated by IWRS; Stratified by site. Syringes are masked with a translucent colored label, in order to maintain the study blind.