IV BCG Vaccination and Aerosol BCG Revaccination Induce Mycobacteria-Responsive æ T Cells Associated with Protective Efficacy against M. tb Challenge

Intravenously (IV) delivered BCG provides superior tuberculosis (TB) protection compared with the intradermal (ID) route in non-human primates (NHPs). We examined how gamma delta T cell responses changed in vivo after IV BCG vaccination of NHPs, and whether these correlated with protection against aerosol M. tuberculosis challenge. In the circulation, V delta 2 T cell populations expanded after IV BCG vaccination, from a median of 1.5% (range: 0.8-2.3) of the CD3+ population at baseline, to 5.3% (range: 1.4-29.5) 4 weeks after M. tb, and were associated with TB protection. This protection was related to effector and central memory profiles; homing markers; and production of IFN-gamma, TNF-alpha and granulysin. In comparison, V delta 2 cells did not expand after ID BCG, but underwent phenotypic and functional changes. When V delta 2 responses in bronchoalveolar lavage (BAL) samples were compared between routes, IV BCG vaccination resulted in highly functional mucosal V delta 2 cells, whereas ID BCG did not. We sought to explore whether an aerosol BCG boost following ID BCG vaccination could induce a gamma delta profile comparable to that induced with IV BCG. We found evidence that the aerosol BCG boost induced significant changes in the V delta 2 phenotype and function in cells isolated from the BAL. These results indicate that V delta 2 population frequency, activation and function are characteristic features of responses induced with IV BCG, and the translation of responses from the circulation to the site of infection could be a limiting factor in the response induced following ID BCG. An aerosol boost was able to localise activated V delta 2 populations at the mucosal surfaces of the lung. This vaccine strategy warrants further investigation to boost the waning human ID BCG response.