BCG Vaccination Delivered Intradermally, Orally and by Combined Routes

This study will assess the safety of a Bacillus Calmette-Guérin (BCG) vaccine against tuberculosis (TB) and will evaluate if giving the vaccine by mouth, injection, or by both methods produces greater results. BCG vaccine and/or placebo (substance containing no medication) will be given by mouth and/or by injection into the skin. This study, conducted at Saint Louis University, will enroll 60 (up to 80) healthy volunteers, 18-40 years old, who are negative for a TB test (QuantiFERON®-Gold) and human immunodeficiency virus (HIV). Study procedures will include a physical exam; review of TB exposure history and medical history; collection of multiple samples of blood, urine, stool, tears, and nose fluid; and skin and blood tests for TB. Volunteers may participate for about 24 months.

Vaccination with Bacillus Calmette-Guérin (BCG) is used as part of tuberculosis (TB) control strategies in most of the world outside of the United States and constitutes the most widely implemented vaccination strategy worldwide. However, despite widespread use of BCG, TB remains a leading infectious cause of death worldwide and it is estimated that one-third of the world's population is chronically and asymptomatically (latently) infected with Mycobacterium tuberculosis (Mtb), the causative agent of TB. This is a phase I, single-center, randomized, vaccine trial including six double-blind, placebo-controlled groups and one open-label group. Approximately 68 (up to 80) healthy male and female subjects 18-40 years old, inclusive, who are negative for QuantiFERON®-TB Gold and human immunodeficiency virus will be enrolled. The expected total duration of the volunteer enrollment, vaccination, and follow-up (volunteer participation) for this study is 30 months. All volunteers are expected to be enrolled over a period of 9 months and on study for 24 months. Detailed immune studies with frozen samples will be expected to continue after collection of all samples and after the protocol has been completed. Eligibility will be determined by volunteer's health at prescreening and eligible subjects will give study specific main study informed consent for enrollment in the study. Subjects randomized to Groups A-F will receive, at Day 0 and 1 year later, BCG intradermally, orally, or by both routes. PBS (PO) and Sauton medium (injectable) placebo will be used to blind the study. Subjects randomized to Group G will receive BCG intradermally at Day 0 only. The primary study objectives are the assessment of the safety of combined and individual intradermal (ID) and oral (PO) vaccination with Statens Serum Institut (SSI) BCG in healthy, immunologically naïve volunteers; comparisons of mycobacteria-specific interferon-gamma responses and mucosal immunoglobulin-A induced by SSI BCG vaccination given intradermally, orally and by both routes combined; and comparison of safety and immunogenicity of Danish and Connaught BCG given intradermally. The secondary study objectives are the assessment of purified protein derivative skin test responses as an indication of cutaneous T cell trafficking after vaccination with SSI BCG; and quantitation of BCG replication in Sanofi Pasteur ID BCG ulcerative lesions after ID BCG vaccination. The exploratory study objectives are comparisons of intracellular killing activity induced by SSI BCG vaccination given intradermally, orally, and by both routes combined; and characterization of mycobacteria-specific T cells induced intradermally, orally, or both routes by vaccination with SSI BCG using dendritic cells as antigen-presenting cells and stored peripheral blood mononuclear cells as a source for matched T cells collected before and after vaccination. Parent protocol to sub-study 12-0110 and 10-0026.