Evaluating the safety, immunogenicity and efficacy of a robust attenuated Mtb vaccine in the setting of HIV co-infection - PROJECT SUMMARY/ABSTRACT. Novel vaccination strategies are necessary to contain the TB pandemic, as the currently licensed anti-tubercular vaccine, Bacille Calmette-Guerin (BCG), has limited and variable efficacy. Attenuated, live-replicating Mycobacterium tuberculosis (Mtb) express the full complement of protective antigens absent in BCG. As a result, these strains are most likely to induce long-lived immune responses towards a wider antigenic repertoire and could generate durable protection. Rhesus macaques vaccinated with an isogenic Mtb mutant in the allele encoding the stress-response master regular SigH (sigH) were protected from TB after infection with a lethal dose of Mtb and characterized by the presence of inducible bronchus associated lymphoid tissue (iBALT) in the lungs. Protection by sigH could be reversed by the depletion of iBALT. We have now validated the protection against TB by mucosal vaccination with sigH in cynomolgus macaques, a second NHP species. Our results show that sigH vaccination protects cynomolgus macaques from lethal TB by inducing T cell responses, T-B cell cooperation and iBALT in the lungs. This leads to the induction of strong IFNG responses, which inhibits Type I IFN signaling, conditions macrophages towards an IFNG-, rather than a Type I IFN-responsive phenotype, resulting in almost complete protection in the airways and lung granulomas. It is important however, to understand the safety, immunogenicity and efficacy of attenuated Mtb based vaccine candidates, as i) concerns remain about whether the candidate will be safer than BCG in the immunocompromised population and ii) whether Mtb/HIV co-infected individuals will be able to mount protective T cell-based responses to this vaccine, resulting in protection. Our current proposal addresses this by directly testing the hypothesis in the rhesus macaque model of Mtb/HIV co-infection. Additionally, we propose to develop the sigH vaccine platform by testing the immunogenicity and efficacy of two unmarked double/triple knock out mutants including sigH which we have generated. We contend that at the end of this proposal, we will be able to move sigH based DKO/TKO strains into human clinical development as anti-TB vaccines.
