Mucosal Vaccination with a Self-Adjuvanted Lipopeptide Is Immunogenic and Protective against Mycobacterium tuberculosis

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,
ESAT61–20 and TB10.43–11 from Mycobacterium tuberculosis (Mtb), were covalently
conjugated to the TLR2-ligand Pam2Cys 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.