BCG + hsp, a New Tuberculosis Vaccine

DESCRIPTION (provided by applicant): This proposal describes research that will examine the safety and efficacy of a novel strain of BCG in which the heat shock repressor gene has been deleted, resulting in the overexpression of a heat shock protein (hsp70). Heat shock proteins show a good deal of promise in the protection against and treatment of tuberculosis, and this novel BCG strain produces a T-cell response indicative of a more protective immune response. The Specific Aims of this Phase I proposal are: 1. In a guinea pig model of tuberculosis (TB), we will compare the efficacies of (1) intradermally administered (i.d.) BCGdeltahspR; (2) i.d. parent BCG; (3) subcutaneously administered (s.c.) BCGdeltahspR; (4) s.c. parent BCG; and (5) no vaccination (control). 2. In a mouse model of tuberculosis, we will compare the efficacies of (1) BCGdeltahspR administered subcutaneously; (2) parent BCG, administered subcutaneously; and (3) no vaccination (control). We believe it is important to test this vaccine in several different strains of mice that represent a spectrum of susceptibility to TB, as it is not known which strain might be the best model of TB in humans. Therefore, we will test the efficacy of rBCGdeltahspR in C57BI6, DBA/2, and CBA. 3. We will examine the safety of this modified BCG as compared to the parent BCG. We will infect mice and guinea pigs with each BCG strain and examine lungs for pathology, and count the CFU of BCG still pre-sent. We will also examine the antibiotic sensitivity of this rBCGdeltahspR to 10 commonly used TB drugs to ensure that the genetic manipulations performed have not made it less sensitive to drug treatment.