BCG Vaccination Delivered Intradermally, Orally and by Combined Routes

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.