STRATEGIES FOR TUBERCULOSIS VACCINE DEVELOPMENT AND SCRE

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The purpose of this application in response to PA-97-101, "Basic mechanisms of vaccine efficacy", is to conduct basis research into mechanisms of vaccine-induced immunity in the lungs, using a highly pertinent and relevant tuberculosis infection model. An underlying motive is the plethora of new TB vaccine candidates currently being screened in mouse and guinea pig models, in which the Mycobacteria Research Laboratories [MRL] at Colorado State University are playing a central role. As the number of vaccine candidates tested has gradually increased, it has become increasingly apparent that fundamental information regarding vaccine strategies against this serious bacterial respiratory pathogen, particularly as it pertains to expression of immunity in the lungs, is almost completely lacking. Accordingly, this application proposes to address four major areas of concern, which in each case has the potential to derive important new information which may improve and broaden our overall approach to tuberculosis vaccination. These areas are [1] development of a widely applicable approach to identification of potential protein antigens, and specific application of this approach to the identification of key target antigens of Mycobacterium tuberculosis, an approach that will draw on our considerable experience in bacterial cultivation, antigen extraction, and proteomic analysis; [2] a further exploration of the potential for cytokine enhancement of vaccination, based on our recent success in this area; [3] work to determine the basis of down-regulation in vaccination, specifically in terms of interference with the BCG vaccine; and [4] the nature and antigenic targets of the CD8 T cell response in the lungs and the potential for CD8-directed vaccination strategies. These studies will exploit our extensive state of the art Level III biohazard facilities, our expertise in bulk cultivation and antigen purification, our new access to sophisticated cell sorting technology, and our demonstrated experience in using and developing the mouse low dose aerosol tuberculosis infection model.