Mycolic acid nanoparticle vaccination leads to antigen persistence and unique differentiation of mycobacterial lipid antigen-specific T cells

Abstract Tuberculosis remains a serious global epidemic and with the rise of multi-drug resistant strains, an efficacious vaccine solution is imperative. Vaccines currently being developed for Mtb utilize protein antigens, which target MHC-restricted conventional T cells, overlooking the potential of Mycobacterium tuberculosis (Mtb) lipid antigens such as mycolic acid (MA), a key lipid found in Mtb cell wall. Mycobacterial lipids are presented by group 1 CD1 molecules (CD1a, b, c) to cognate T cells. Group 1 CD1-restricted T cells can be identified in patients with TB and have been shown to provide protection in Mtb infection. Using biocontinuous nanospheres (BCNs), a type of self-assembled nanostructure able to load both hydrophobic and hydrophilic molecules, we have created a vaccine containing MA. We found that MA BCN is able to effectively activate CD1b-restricted MA-specific T cells in vitro and in vivo. Interestingly, we discovered that MA persists within lung alveolar macrophages for at least 6 weeks after intratracheal vaccination with MA BCN. Antigen archiving was in part due to the encapsulation of MA within BCN. Nanoparticle vaccinations carrying lipid antigens may thus lead to persistent depots of antigen that could offer long-lasting immune response and protection. Supported by grants from NIH (5R01AI145345-03, 1F30AI157314-01, 5T32GM008152-35)