Randomized, Placebo Controlled, Partially Blinded Phase II Study to Evaluate Safety, Immunogenicity, and Prevention of Infection with Mycobacterium tuberculosis of AERAS-404 and BCG Revaccination in Healthy Adolescents

This Phase II, randomized, 3-arm, placebo controlled, partially blinded, clinical trial will be conducted in 990 healthy, HIV-uninfected, QFT-GIT negative, previously BCG vaccinated adolescents. The trial will be conducted at the South African Tuberculosis Vaccine Initiative (SATVI) site in the Western Cape region of South Africa, where epidemiological studies involving thousands of adolescents have been conducted over the last decade to characterize rates of Mtb infection and active TB disease in this age group. Subjects will be enrolled in two sequential cohorts and within each cohort subjects will be randomized in a 1:1:1 ratio to receive either AERAS-404 or saline placebo on Days 0 and 56, or BCG Vaccine SSI on Day 0. The first 90 subjects (30 from each arm) will form the Safety & Immunogenicity Cohort and will be subject to more intensive collection of safety data, with data reviewed by the Data Monitoring Committee (DMC), principal investigator and local medical monitor. Selected immunogenicity assays, including whole blood intracellular cytokine staining (ICS), will also be performed in this cohort. The remaining 900 subjects will be enrolled into the Correlates Cohort. All 990 subjects in the study will be evaluated for safety and biomarker outcomes, and for prevention of Mtb infection.

The primary Mtb infection endpoint will be QFT-GIT conversion from a negative to positive test, using the manufacturer's recommended threshold of 0.35 IU/mL, at any time-point after Day 84 and through end of follow-up for the primary endpoint. The 84-day 'wash-out' period is stipulated in order to exclude subjects who may have already been Mtb infected, but not yet converted their QFT-GIT test at screening, thus subjects who convert their QFT-GIT at Day 84 will not be included in the analyses of prevention of Mtb infection.

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
4. For female subjects: agrees to avoid pregnancy from 28 days prior to Study Day 0 and for the full duration of the study.
5. Has general good health, confirmed by medical history and physical examination
6. Had BCG vaccination at least 5 years ago documented through medical history or by presence of healed BCG scar
7. Tests QFT-GIT negative at screening, using the manufacturer's recommended threshold of 0.35 IU/mL

Exclusion Criteria:

1. Acute illness on Study Day 0
2. Oral temperature ≥37.5°C on Study Day 0
3. Clinically significant (and no more than Grade 1 on the Toxicity Scale) abnormal laboratory values from blood collected within 21 days
4. Evidence of clinically significant (and no more than Grade 1 on the Toxicity Scale) systemic or local disease on urinalysis
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 study vaccine 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 residence with an individual receiving anti-TB treatment, or known incompletely treated culture or smear positive TB
9. History of autoimmune disease or immunosuppression
10. Used immunosuppressive medication within 42 days before Study Day 0
11. Received immunoglobulin or blood products within 42 days before Study Day 0
12. Received any investigational drug therapy or investigational vaccine within 182 days before Study Day 0
13. Received investigational TB vaccine, other than BCG
14. Planned administration/administration of a licensed vaccine in the period starting 28 days before and ending 28 days after each dose of study vaccine
15. History or laboratory evidence of any past or present possible immunodeficiency state not limited to any lab indication of HIV-1 infection
16. History of allergic disease likely to be exacerbated by any component of the study vaccine
17. History of alcohol or drug abuse
18. All female subjects: currently pregnant or lactating/nursing; or positive urine pregnancy test during screening
19. Received a (TST) within 3 months (90 days) prior to Study Day 0.
20. Any current medical, psychiatric, occupational, substance abuse problems problems that in opinion of investigator will make unlikely for the subject to comply with the protocol

Unsolicited AEs: 28 days post each vaccination Solicited AEs: 7 days post each vaccination (with diary cards used for 7 days after each vaccination for Safety and Immunogenicity Cohort only) Solicited and unsolicited injection site reaction AEs: BCG Group - 84 days post vaccination; H4:IC31/Placebo Groups - 28 days post vaccination Serious adverse events, adverse events of special interest, and SUSARs: Entire study period (minimum of 6 months following last dose of study vaccine)