Parenteral-Mucosal prime-boost with a TB subunit vaccine enhances early lung T cells against aerosol M. tuberculosis infection with transient improved protection.

Abstract

Abstract Background T cell mediated immunity is critical to control M.tuberculosis (Mtb) infection and tuberculosis (TB) disease. However, Mtb actively delays the adaptive T cell response after initial infection. Thus, a cornerstone of TB vaccine development is to overcome this delay and recruit T cells for direct contact with infected lung phagocytes to control early bacterial growth. Given parenterally, the H56:CAF01 subunit vaccine results in an early CD4 T cell response in Mtb-infected lungs and significant reduction in CFU. Here, we investigate mucosal prime-boost delivery of H56:CAF01 to elicit a lung-localized/homing memory T cell population for further accelerated lung T cell recruitment and Mtb control. Methods CB6F1 mice vaccinated with H56 (Ag85B-ESAT6-Rv2660) adjuvanted with CAF01 (Th1/Th17-skewing liposomes) either 3× s.c., or 2× s.c. + i.n. boost(s) were rested to memory phase and then challenged with aerosol Mtb. Tissue-localized Mtb-specific T cells were enumerated by flow cytometry, and bacterial CFU determined. In vivo intravascular staining identified lung-localized from vasculature-localized T cells. Results Prime-boost with H56 resulted in a 10-fold increase in recruited/expanded Mtb-specific T cells in the lung parenchyma early after Mtb challenge over s.c.-only vaccination and a reduction in lung CFU at peak infection. However, no CFU difference was observed the chronic stage. Inhibition of S1P1 did not enhance the early protective effect, suggesting against local Trm as driving protection. Overall, the limited increased protection despite significant lung T cell enhancement suggests a constrained ability of vaccine T cells to control early Mtb replication.