Mucosal Vaccination with a Self-Adjuvanted Lipopeptide Is Immunogenic and Protective against <i>Mycobacterium tuberculosis</i>.
Ashhurst AS, McDonald DM, Hanna CC, Stanojevic VA, Britton WJ, Payne RJ.
Tuberculosis (TB) remains a staggering burden on global public health. Novel preventative tools are desperately needed to reach the targets of the WHO post-2015 End-TB Strategy. Peptide or protein-based subunit vaccines offer potential as safe and effective generators of protection, and enhancement of local pulmonary immunity may be achieved by mucosal delivery. We describe the synthesis of a novel subunit vaccine via native chemical ligation. Two immunogenic epitopes, ESAT6<sub>1-20</sub> and TB10.4<sub>3-11</sub> from <i>Mycobacterium tuberculosis</i> (Mtb), were covalently conjugated to the TLR2-ligand Pam<sub>2</sub>Cys to generate a self-adjuvanting lipopeptide vaccine. When administered mucosally to mice, the vaccine enhanced pulmonary immunogenicity, inducing strong Th17 responses in the lungs and multifunctional peripheral T-lymphocytes. Mucosal, but not peripheral vaccination, provided substantial protection against Mtb infection, emphasizing the importance of delivery route for optimal efficacy.