Dissecting the role of vaccine-promoted Th17 cells in protective immunity against tuberculosis - ABSTRACT An effective vaccination strategy is urgently needed to combat tuberculosis (TB), but lack of knowledge on protective immunity remains a major bottleneck for rational design, testing, and down selection of new candidates. Although essential for host defense, Th1-produced IFNγ is not sufficient for vaccine protection and there is growing consensus that novel immune responses, not induced by TB itself, may be needed for optimal disease control. In recent years, Th17 cells have gained increasing attention as a target for vaccine optimization due to their association with protection signals in both mice and non-human primates. However, their significance in protective immunity against TB is still unresolved. As none of the existing vaccine candidates induce robust Th17 responses, we developed the novel vaccine candidate H107e/CAF® to maximize Th1/Th17 induction across species. In 2024, this entered phase Ia/Ib trials as the first subunit vaccine with these properties. However, other than safety and magnitude of the immune responses, which historically does not correlate with protection, there are no validated biomarkers for vaccine pipeline decision-making on topics including dose optimization and progression to efficacy trials. With preliminary data suggesting that Th17 cells account for ≥50% of the H107e/CAF®-induced protection in mice, the goal of this proposal is to determine the role of vaccine-induced Th17 cells in local immunity and pathology as well as to identify and validate related signatures in human samples. Displaying a range of unique characteristics, Th17 cells could play several non-redundant roles and we will focus on three separate leads, guided by preliminary data. In Aim 1, we will determine the contribution of vaccine-Th17 cells in early neutrophil recruitment and test the hypothesis that the earliest wave of neutrophils mediate trafficking of bacteria to the draining lymph node to accelerate T cell priming. We will also examine how Th17 cells are regulated in vivo at later time points and test whether vaccine-induced IFNγ responses down regulate late neutrophils to prevent tissue destruction. In Aim 2, we will investigate whether accelerated formation of inducible bronchus associated lymphoid tissue (iBALT) is unique to H107e/CAF® compared to other clinically relevant vaccines and determine the role of vaccine-induced Th17 cells iBALT formation. We will also assess the significance of iBALT in H107e/CAF®-mediated protection with the hypothesis that iBALT mediates efficient trafficking and localization of protective immune cells in TB lesions. In Aim 3, we test the hypothesize that vaccine-promoted Th17 cells display IFNγ-independent protective effector functions and define a set of biomarkers that tracks with Th17-protection and regulation across Aims 1-3. These are validated in banked NHP and human H107e/CAF® clinical trial samples. Together, this project will benefit from utilizing a vaccine in clinical trials to elucidate the fundamental role of Th17 cells in vaccine-induced immunity to TB. With complementary expertise in basic science and translational vaccinology in our labs, we have designed these studies to identify biomarkers that will inform development of new TB vaccines and support the clinical testing of H107e/CAF®.
