Different vaccine approaches needed for distinct populations |
Optimize animal models to test vaccines for naive, BCG-vaccinated, LTBI, and active TB. |
Optimal vaccine antigens not known |
Consider different antigens for distinct target populations.Examine antigen properties beyond frequency or magnitude of T cell responses.Prioritize antigens presented by HLA alleles prevalent in regions with high TB burdens. |
Vaccine-induced T cells require a combination of properties |
Assay vaccines for induction of T cells with appropriate state of differentiation, residence in lung tissue compartments, and expression of effector mechanisms beyond cytokine secretion. |
M. tuberculosis-infected cells evade T cell recognition |
Identify antigens less impacted by evasion mechanisms (nonsecreted antigens, antigens with evidence of selection pressure from T cell recognition); develop pharmacological interventions to overcome specific evasion mechanisms. Exploit trained innate immunity for T cell-independent protection. |
M. tuberculosis occupies diverse intracellular compartments |
Identify mechanisms for elimination of bacteria in immature phagosomes, cytoplasm, autophagosomes, and mature phagolysosomes. |
M. tuberculosis can be extracellular |
Determine the bacterial population fraction that is extracellular during distinct stages of infection; optimize antibodies and other humoral mediators. |
Range of inoculum size unknown in humans |
Examine vaccines efficacious against low-dose challenges for efficacy against higher inocula and more virulent bacterial strains. |
Correlates of immunity not identified |
Develop methods for analysis of cells in human tissues; apply analyses that account for nonlinear relationships between response and protection. |