Safety and Immunogenicity Study of AERAS-456 Vaccine for Tuberculosis

This is a Phase I, open-label, dose-escalation study with three study groups. This study will be conducted in 25 HIV negative subjects, 17 of whom will have Latent Tuberculosis Infection (LTBI) and 8 of whom will not have LTBI at study enrollment. The investigational product is AERAS-456 at a dose of 15 ug of H56 antigen with IC31 500 nmol KLK (15/500), and a dose of 50 ug of H56 antigen with IC31 500 nmol KLK (50/500). The vaccine is administered by intramuscular injection.

This is a Phase I, open-label, dose-escalation study with three study groups. This study will be conducted in 25 HIV negative subjects, 17 of whom will have Latent Tuberculosis Infection (LTBI) and 8 of whom will not have LTBI at study enrollment. The investigational product is H56:IC31 (AERAS-456) at a dose of 15 ug of H56 antigen with IC31 500 nmol KLK (15/500), and a dose of 50 ug of H56 antigen with IC31 500 nmol KLK (50/500). The vaccine is administered by intramuscular (IM) injection.

Subjects will be assigned to a study group based on LTBI status at enrollment and time of completion of screening. Subjects without LTBI will be assigned to Group 1. Subjects with LTBI will be sequentially assigned to Groups 2 and 3 based on the order in which they complete screening. All subjects will receive a first dose of study vaccine on Study Day 0, a second dose of study vaccine on Study Day 56, and a third dose of study vaccine on Study Day 112. Enrollment of subjects into Group 2 will begin only after a review of safety data from the 14-day period after initial vaccination of all subjects in Group 1. Likewise, enrollment of subjects into Group 3 will begin only after the corresponding review of safety data from Group 2.

The total duration of study follow-up for all subjects is 210 days. Study groups 1-2 will enroll 8 subjects each and study group 3 will enroll 9 subjects. This study is planned at a single clinical site in South Africa. The sizes specified for each study group were selected because they are judged to be adequate for preliminary safety and immunogenicity evaluations for a Phase I study rather than for statistical reasons.

Eligibility Criteria:
Inclusion Criteria:

1. Has completed the written informed consent process
2. Is male or female
3. Is aged 18 through 50 years on Study Day 0
4. 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.
5. Has general good health, confirmed by medical history and physical examination
6. Is able and willing to complete the full follow-up period of 210 days as required by the protocol
7. Is able and willing to commit to avoiding elective surgery for the duration of the study
8. Is able and willing to stay in contact with the study site for the duration of the study
9. \[Groups 2 \& 3\] Has latent tuberculosis infection (LTBI), diagnosed by a positive Quantiferon (QFT)
10. Has completed simultaneous enrollment in the Registry Protocol

Exclusion Criteria:

1. Axillary temperature 37.5 C
2. Abnormal laboratory values from blood collected within 7 days prior to Study Day 0 vaccination as follows:

   * hemoglobin, hematocrit, platelet count, absolute neutrophil count, or absolute lymphocyte count below lower limit of normal (LLN).
   * white blood cell count above upper limit of normal (ULN) or below LLN
   * alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, alkaline phosphatase (ALP), or creatinine above ULN.
3. Abnormal urinalysis that, in the opinion of the investigator, indicates systemic or local disease.
4. History or evidence of tuberculosis disease, including but not limited to pulmonary tuberculosis, pleural tuberculosis, lymph node tuberculosis or tuberculosis meningitis.
5. \[Group 1\] Evidence of latent tuberculosis infection (LTBI), defined as a positive screening QFT or a history of a positive TST or QFT.
6. Received a tuberculin skin test (TST) or bacillus Calmette-Guerin (BCG) within 45 days prior to Study Day 0.
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 infection.
10. History or laboratory evidence of Hepatitis B or C.
11. Used immunosuppressive medication (other than inhaled or topical immunosuppressants) within 45 days prior to Study Day 0.
12. Received immunoglobulin or blood products within 45 days prior to Study Day 0
13. Received any investigational product within 45 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 daily 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. Female subjects: currently pregnant or lactating/nursing; or positive serum pregnancy test during screening; or positive urine pregnancy test on the day of Study Day 0, Study Day 56, or Study Day 112 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.