ALTERNATIVE APPROACH TO DEVELOPMENT OF A TB VACCINE

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DESCRIPTION: Vaccines have to be developed that provide universal protection against mycobacterial diseases. This task seems to be approachable since targets of the cellular immune response to mycobacteria have recently be defined. Hsp 65-encoded epitopes represent the major antigenic sites. Since CTL specific for myobacterial hsp present two beneficial modes of activity, i.e. they eliminate the foci of infection and decrease the viability of released bacteria, it is proposed to develop a defined subunit vaccine that raises class I MHC restricted CTL to an hsp peptide. However, naturally occurring hsp-reactive CTL show cross-reactivity on host proteins endogenously produced in stressed cells. Thus, the direct use of mycobacterial hsp-65 as immunogen might elicit auto-reactive CTL potentially prone to initiate auto-immune diseases. This problem can be alleviated if one has access to a component vaccine that selectively induces CTL with specificities to epitopes unique to bacterial hsp, rather than bacterial and eukaryotic hsp. Since studies of the class I MHC molecules have suggested that un-related peptides bound to the same MHC molecule might present structures close enough to be recognized by the same TCR, we propose to develop a vaccine against bacterial hsp using an un-related, i.e., non-hsp, antigen. This strategy is employed to avoid cross-reactivity to self-proteins. In other situations, the same strategy might allow to raise responses to antigens that cannot be used by themselves due to their biological activity, e.g, toxicity. We have identified a candidate vaccine that is able to raise class I MHC- restricted responses selectively to bacterial hsp 65. In mice, this unrelated antigen, chicken ovalbumin, consistently elicits CTL specific for an mycobacterial hsp 65-peptide with no cross-reactivity to the murine homologue. These CTL effectively lyse bacterially infected cells. Since non-infectious preparations of ovalbumin and the specific ovalbumin-peptide are efficient immunogens for these class I MHC- restricted responses, we will examine whether injection of this antigen can protect animals against infection with two model pathogens, listeria monocytogenes and mycobacteria bovis (BCG), that have been used as models for mycobacterial diseases.