Challenge Model for Assessment of Human TB Immunity

This is a Phase I open-label, dose escalation trial to evaluate the use of Tice® BCG as a challenge for future assessment of in vivo TB immunity. Subjects will be recruited from the target population reflecting the community at 2 VTEU sites. Enrollment will occur over 14 months. Subjects who provide informed consent will be screened, and up to 120 eligible, HIV and TB uninfected subjects, 18-45 years, inclusive, will be enrolled for study interventions and sequentially assigned to 1 of 4 dose groups. Doses of Tice BCG from 2 to 16x10\^6 cfu will be delivered ID in a dose escalation format to 4 groups of 30 subjects per dose group. Primary Objectives: 1) Evaluate the safety of different doses of ID Tice BCG for use as a human challenge model for TB infection. 2) Examine shedding from ID challenge sites after administration of different doses of Tice BCG in TB naive healthy subjects. 3) Evaluate the reproducibility of BCG shedding over time with both quantitative PCR and culture.

This is a Phase I open-label, dose escalation trial to evaluate the use of Tice® BCG as a challenge for future assessment of in vivo TB immunity. Subjects will be recruited from the target population reflecting the community at large at 2 VTEU sites. It is anticipated that enrollment will occur over a 14-month period. Subjects who provide informed consent will be considered for eligibility (screened), and up to 120 eligible, willing, healthy, HIV and TB uninfected subjects aged 18 to 45 years, inclusive, will be enrolled for study interventions and sequentially assigned to 1 of 4 dose groups. Dose titrations of Tice® BCG from 2x10\^6 cfu to 16x10\^6 cfu will be delivered intradermally in a dose escalation format to 4 groups of 30 subjects per dose group. In the first dose group, subjects will be immunized intradermally with a single dose of 2x10\^6 cfu Tice® BCG. The Tice® BCG doses will be increased sequentially from 2x10\^6 cfu to 4x10\^6 cfu to 8x10\^6 cfu to a maximum dose of 16x10\^6 cfu following assessment of safety and reactogenicity data from previous dose groups and sentinel subjects. Following administration of Tice® BCG, intradermal (ID) site reactions will be assessed for at least 30 minutes as well as by memory aid on a daily basis throughout the first 15 days. Subjects will also return to the clinic on Days 22, 25, 29, 32, 36, 39, 43, 46, 50, 53, and 57 to evaluate the ID challenge site, assess for lymphadenopathy if indicated based on review of interim medical history and clinical assessment, and review AEs/SAEs, concomitant medications and health status, and collect and dispose of returned biohazard materials. A final clinic visit will be performed at approximately 3 months (Day 99) following administration of Tice® BCG to evaluate the ID challenge site, assess for lymphadenopathy if indicated based on review of interim medical history and clinical assessment, and review SAEs and health status. At approximately 6 months (Day 181) following administration of Tice® BCG a telephone call will be performed to query for any SAEs that may have occurred since the last visit. Based on this information, subjects may be asked to return to the clinic to be evaluated. The duration of the study for each subject will be up to approximately 7 to 8 months. Primary Objectives: 1) Evaluate the safety of different doses of intradermal Tice® BCG for use as a human challenge model for Mycobacterium tuberculosis infection. 2) Examine BCG shedding from intradermal challenge sites after administration of different doses of Tice® BCG in TB naive healthy subjects. 3) Evaluate the reproducibility of BCG shedding over time with both quantitative PCR and culture techniques. Secondary objectives: 1) Determine a tolerable dose of intradermal Tice® BCG that will induce optimal reproducibility of BCG shedding. 2) Determine the method of mycobacterial quantitation that will result in the least variable results. 3) Characterize the magnitude and kinetics of BCG shedding after intradermal Tice® BCG administration at 4 different doses. Parent protocol to sub-study 12-0096.