A double-blind, placebo-controlled study of Mycobacterium-specific human immune responses induced by intradermal bacille Calmette-Guerin vaccination

Recent studies have indicated that type 1 T cell responses (potent interfer on-gamma and cytolytic responses, with absence of interleukin-4 production) are important for protective immunity against mycobacteria. These observat ions suggest that assays of type 1 T cell responses may be useful as surrog ate markers of protective immunity in the evaluation of new tuberculosis va ccines. To be useful as surrogate markers, immunologic assays must distingu ish between vaccine recipients and control subjects in clinical trials. Pre vious studies have shown that bacille Calmette-Guerin (BCG) vaccination can induce human type 1 T cell responses, but randomized trials have not been done to determine whether measurement of these responses can distinguish be tween BCG recipients and control subjects. We have conducted a double-blind , placebo-controlled trial of intradermal vaccination with two different BC G strains. We compared the mean lymphoproliferative, cytotoxic, Th1 and Th2 cytokine, and antibody responses detected in BCG and placebo recipients. T hese studies demonstrated that significant increases in Mycobacterium-speci fic T cell proliferative responses and type 1 cytokine responses were induc ed by BCG when compared with results with a placebo. In addition, BCG induc ed significant increases in Mycobacterium-specific antibody responses with an isotype profile characteristic of a type 1 cytokine bias. T cell and ant ibody assays involving the use of mycobacterial whole cell lysates or live BCG were able to discriminate between BCG and placebo recipients better tha n were assays using mycobacterial culture filtrates. These studies provide important information for the development of immunologic assays that might be useful as surrogate markers of protective immunity in future trials of n ew tuberculosis vaccines.