A Phase I Study to Evaluate Safety and Immunogenicity of AERAS 404 (C-011-404)

A Phase I Randomized Placebo-Controlled, Double-Blind Study to Evaluate Safety and Immunogenicity of AERAS 404 When Administered as a Single Adjuvant Amount With Different Antigen Amounts in HIV-Negative BCG-Vaccinated Adults Without Evidence of Tuberculosis Infection

This Phase I study will be conducted as a randomized, placebo-controlled, double-blind, dose-escalation study in four groups of healthy adult male and female subjects who are BCG-vaccinated, HIV-negative, and have no evidence of tuberculosis infection. The study will be conducted at one or two sites located in South Africa. The purpose is to evaluate the safety and immunogenicity of two injections of AERAS 404 prepared with four escalating amounts of antigen in healthy adult male and female subjects who are BCG-vaccinated, HIV-negative, and have no evidence of tuberculosis infection.

This Phase I study will be conducted as a randomized, placebo-controlled, double-blind, dose-escalation study in four groups of healthy adult male and female subjects who are BCG-vaccinated, HIV-negative, and have no evidence of tuberculosis infection. The study will be conducted at one or two sites located in South Africa.

Forty subjects will be sequentially enrolled into one of four study groups (i.e., Group 1, Group 2, Group 3, or Group 4) based on time of completion of screening, with 10 subjects enrolled into each group. Within each study group, subjects will be randomized to a treatment regimen of either AERAS-404 or placebo control administered by intramuscular injection on Study Day 0 and Study Day 56. All subjects will receive the same treatment on Study Day 0 as they receive on Study Day 56. The dose of antigen will increase between study groups. All subjects will be followed for safety and immunogenicity evaluations for 182 days. A total of eleven clinic visits are planned (excluding screening) for all subjects.

Inclusion Criteria

Subjects must have met all of the following criteria:

1. Had completed written informed consent
2. Was male or female
3. Was age 18 through 50 years on Study Day 0
4. Had BCG vaccination at least 5 years ago, documented through medical history or presence of scar
5. Had general good health, confirmed by medical history and physical examination
6. Had a Body Mass Index (BMI) between 19 and 33 (weight in kg/[height in m]2)
7. Agreed to complete a follow-up period of 182 days as required by the protocol
8. Females: Agreed to avoid pregnancy from 28 days prior to Study Day 0 through the follow-up period of 182 days.
9. Agreed to avoid elective surgery for the duration of the study
10. Agreed to stay in contact with the investigative site for the duration of the study
11. Had completed simultaneous enrollment in Aeras Vaccine Development Registry protocol

Exclusion Criteria

Subjects must not have:

1. Acute illness on Study Day 0
2. Oral temperature equal to or greater than 37.5 degrees C on Study Day 0
3. Evidence of significant active infection
4. Used immunosuppressive medication within 42 days before Study Day 0 (inhaled and topical corticosteroids are permitted)
5. Received immunoglobulin or blood products within 42 days before Study Day 0
6. Received any investigational drug therapy or investigational vaccine within 182 days before Study Day 0
7. Received inactivated influenza vaccine or inactivated tick-borne encephalitis vaccine within 14 days before entry into the study, or any other standard vaccine within 42 days before Study Day 0 (the use of licensed drugs or vaccines medically indicated during the study interval was permitted)
8. Current chronic drug therapy including hormone replacement such as thyroxin, insulin, etc. Estrogen and progesterone replacement and contraceptives were acceptable.
9. History or laboratory evidence of any past, present or future possible immunodeficiency state which included (but was not limited to) any laboratory indication of HIV infection
10. History of allergic disease or reactions, including eczema, likely to be exacerbated by any component of the study vaccine
11. Previous medical history that may have compromised the safety of the subject in the study
12. Evidence of a new acute illness that may have compromised the safety of the subject in the study
13. Evidence of chronic hepatitis (e.g., hepatitis B core antibody or hepatitis C antibody)
14. Inability to discontinue daily medications except contraceptives during the study period
15. History of alcohol or drug abuse within the past 2 years
16. Tobacco or cannabis smoking 3 or more days per week
17. Positive urine test for illicit drugs (opiates, cocaine, amphetamines)
18. History or evidence of any systemic disease on physical examination or any acute or chronic illness that, in the opinion of the investigator, may have interfered with the evaluation of the safety or immunogenicity of the vaccine, including axillary lymphadenopathy
19. History or evidence (including chest X-ray) of active tuberculosis
20. Shared a residence within the last year with an individual on anti-tuberculosis treatment or with culture or smear positive tuberculosis
21. All females: Positive urine pregnancy test during screening; positive serum pregnancy test on the day of study vaccination; were nursing
22. Abnormal (per local laboratory parameters) chemistry, hematology or urinalysis obtained within 36 hours prior to randomization.
23. Laboratory evidence of Mtb infection, defined as a positive QuantiFERON-TB Gold (QFT-G) test.
24. History of a positive tuberculin skin test within the past ten years (defined according to local guidelines).
25. Received a tuberculin skin test within 3 months (90 days) prior to Study Day 0.