Mucosal delivery of nanofiber booster vaccine enhances generation of antigen-specific memory T cells in the lung parenchyma

Abstract Tuberculosis (TB) infection caused by Mycobacterium tuberculosis (Mtb) is a serious threat to global health with 10 million new infections each year and 1–2 million deaths. The only licensed vaccine approved for human use, Mycobacterium bovis Bacille Calmette-Guerin (BCG), has been administered to 4 billion people despite variable efficacy. Heterologous vaccine regimens that boost T cell memory generated through BCG priming, however, may be an effective immunization strategy. Our lab previously demonstrated efficacy of a nanofiber (NF) vaccine platform containing co-assembled CD8+ and CD4+ epitopes as evidenced by the generation of polyfunctional CD8+ T cells and protection from aerosol challenge with Mtb. In recent investigations, we observed that boosting BCG-primed mice through a pulmonary route with the NF-based vaccine bearing Ag85B CD4+T cells epitopes generated increased frequency of Mtb antigen-specific T cells in the lung parenchyma as indicated by number of tetramer (I-Ab:Ag85B) positive CD4+T cells. The frequency of Mtb-specific CD4+T cells was further increased by adoptive transfer of dendritic cells pulsed with Ag85B-bearing NF. The Ag85B-specific T cells were further characterized as tissue resident memory (Trm) and effector memory (Tem) T cells based on the surface marker phenotypes (I-Ab:Ag85B+ CD69+/− CCR7− CD44+ CD62Llo). In memory recall experiments, splenocytes from vaccinated mice also expressed polyfunctional cytokines that have been associated with protective immunity. These results suggest that protective immunity following vaccination with a NF subunit vaccine in a prime/boost strategy with BCG is associated with expansion of Trm CD4+T cells in lung parenchyma that recognize the Ag85B epitope.