In a study published in the Journal of Infectious Disease, Dr. Yushi Yao, a postdoctoral fellow in Dr. Zhou Xing’s lab, shows a new TB vaccine testing system utilizing humanized mice (Hu-mice). By using Hu-mice developed by Dr. Ali Ashkar’s lab, Yao et al. showed that a novel virus-vectored (VV) respiratory mucosal tuberculosis (TB) vaccine developed in their lab which has undergone phase I human studies, was able to activate T cells in Hu-mice as it does in humans. Post-immunization, respiratory mucosal (RM) immunization resulted in greater antigen-specific, poly-functional CD4 T cell responses in the lung, compared to parenteral immunization. Post-M. tb infection, RM-immunized mice had significantly more CD4 T cells in the airways and lung. The vaccine was able to reduce human-like lung TB outcomes (illness scores, lung M. tb bacillary burden, lung pathologies) when administered through the respiratory route, but not the parenteral route, further emphasizing the importance of mucosal vaccination. This study demonstrates that the Hu-mice model is a suitable model to test the potency of TB vaccines and strategies, and that the novel respiratory mucosal VV immunization strategy can significantly improve lung TB protection in a T cell-dependent manner.