A Phase I/IIa AERAS-456 in HIV-Negative Adults With & Without Latent Tuberculosis Infection (C-035-456)

This is a Phase I/IIa, double-blind, randomized, placebo-controlled, dose- and regimen-finding study in healthy adults with and without LTBI, who are BCG-vaccinated, HIV negative, and have no history or evidence of TB disease. The investigational product is AERAS-456 at 3 dose levels: 5, 15, and 50ug of H56 antigen with 500 nmol IC31. The vaccine is administered by IM injection.

This is a Phase I/IIa, double-blind, randomized, placebo-controlled, dose- and regimen-finding study in healthy adults with and without latent Tuberculosis (TB) Infection, who are Bacille Calmette Guerin (BCG)-vaccinated, HIV negative, and have no history or evidence of TB disease. The investigational product is AERAS-456 at 3 dose levels: 5, 15, and 50ug of H56 antigen with 500 nmol IC31. The vaccine is administered by intramuscular (IM) injection. The study will be conducted at two sites in South Africa.

A total of 98 subjects will be enrolled in 2 phases into 4 groups based on Latent TB Infection (LTBI) status. The initial phase will be a dose ranging study of a 2-dose regimen at 3 dosage levels in LTBI(-) subjects, to select a dosage for the second phase. In the second phase, the study will be expanded to evaluate both 2-dose and 3-dose regimens and to include LTBI(+) subjects. In the first phase, 50 LTBI(-) subjects will be enrolled in Group 1 and randomized at a ratio of 3:3:3:1 to receive 2 doses of 5/500, 15/500, or 50/500 of AERAS-456, or placebo given at Study Days 0 and 56 (Table 0 1).

One dose level of AERAS-456 will be selected by the sponsor and SSI for the second phase of the study, based on analysis of unblinded safety and immunogenicity data through 28 days after the second dose in the first phase, in conjunction with safety and immunogenicity data from study C-032-456. The criteria for dose-selection will be specified in a statistical analysis plan to be finalized prior to the unblinded review. The selected dose, in conjunction with the unblinded safety and immunogenicity data, will be submitted to the SMC for review. In the second phase, 48 subjects will be enrolled concurrently into Group 2 (LTBI\[-\]) and into Groups 3 and 4 (LTBI\[+\], Table 0 2). In each of Groups 2 and 4, 16 subjects will be randomized at a ratio of 3:1 to receive 3 doses of AERAS-456 or placebo given at Study Days 0, 56, and 112. In Group 3, 16 subjects will be randomized at a ratio of 3:1 to receive 2 doses of AERAS-456 or placebo given at Study Days 0 and 56.

All subjects will stay on the study for 292 days after receiving the first vaccination. The subjects in Groups 1 and 3 will be followed up for 236 days after the second vaccination and subjects in Groups 2 and 4 will be followed up for 180 days after the third vaccination. The sample size for each study cohort was selected because it was judged to be adequate for preliminary safety and immunogenicity evaluations for a Phase I/IIa study rather than for statistical reasons. Given 12 and 15 subjects in individual AERAS-456 dosing groups, the study will have an 80% probability of detecting at least 1 specified event which occurs at a rate of 12.5% and 10.0%, respectively. If no such events are observed among 12 and 15 subjects receiving active study vaccine, an approximation to the upper one-sided 95% confidence bound on the rate of occurrence for that event would be 22% and 18%, respectively.

Eligibility Criteria:
Inclusion Criteria:

Subjects must meet all of the following criteria prior to Study Day 0 vaccination:

1. Has completed the written informed consent process prior to the start of screening evaluations.
2. Is male or female.
3. Is age 18 through 50 years at the time of randomization.
4. Received BCG vaccination at least 5 years prior to randomization.
5. Females: Ability to avoid pregnancy during the trial: Women physically capable of pregnancy (not sterilized and still menstruating or within 1 year of the last menses if menopausal) in sexual relationships with men must avoid pregnancy with an acceptable method of avoiding pregnancy from 28 days prior to administration of the study vaccine through the end of the study.
6. Has general good health, confirmed by medical history and physical examination at screening.
7. Is able and willing to complete the full follow-up period of 292 days as required by the protocol.
8. Agrees to avoid elective surgery for the full duration of the study.
9. \[Groups 1 and 2\] Does not have LTBI, determined by a negative QFT at screening or\[Groups 3 and 4\] Has LTBI, determined by a positive QFT at screening.

Exclusion Criteria:

Subjects must meet none of the following criteria prior to Study Day 0 vaccination:

1. Acute illness at the time of randomization.
2. Oral temperature 37.5 degrees C at the time of randomization.
3. Abnormal laboratory values from blood collected within 21 days prior to Study Day 0 vaccination.
4. Abnormal urinalysis that, in the opinion of the investigator, indicates systemic or local disease.
5. History or evidence of tuberculosis disease, including but not limited to pulmonary tuberculosis, pleural tuberculosis, lymph node tuberculosis or tuberculosis meningitis.
6. Received a TST within 21 days prior to a scheduled study vaccination.
7. Received investigational Mtb vaccine at any time prior to Study Day 0.
8. History or evidence of autoimmune disease.
9. History or laboratory evidence of HIV-1 infection at screening.
10. Positive test for hepatitis B surface antigen or hepatitis C antibody at screening.
11. Used immunosuppressive medication (other than inhaled or topical immunosuppressants) within 21 days prior to Study Day 0.
12. Received immunoglobulin or blood products within 21 days prior to Study Day 0.
13. Received any investigational product within 21 days prior to Study Day 0, or plans to participate in any other study involving administration of investigational product during the study period.
14. Inability to discontinue current chronic prescription medications, except contraceptives, inhaled or topical immunosuppressants, or nutritional supplements, during the study period.
15. Documented history of allergic reaction or hypersensitivity to any component of the study vaccine.
16. All female subjects: currently pregnant or lactating/nursing; or positive serum pregnancy test during screening; or positive urine pregnancy test on the day of any study vaccination.
17. History or evidence of any systemic disease or any acute or chronic illness that, in the opinion of the investigator, may compromise the safety of the subject in the study or interfere with the evaluation of the safety or immunogenicity of the vaccine.
18. History of dermatologic disease or skin features that, in the opinion of the investigator, may interfere with the assessment of injection site reactions.
19. History or evidence of any medical, psychiatric, occupational, or substance abuse problems that, in the opinion of the investigator, will make it unlikely that the subject will comply with the protocol.