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.

结核病（Tuberculosis, TB）仍是全球公共卫生面临的沉重负担。当前迫切需要新型预防工具，以达成世界卫生组织（WHO）2015年后终结结核病战略的既定目标。基于肽或蛋白的亚单位疫苗具备成为安全有效防护手段的潜力，而黏膜递送策略可实现局部肺部免疫的增强。本研究通过天然化学连接（native chemical ligation）技术合成了一款新型亚单位疫苗：将结核分枝杆菌（Mycobacterium tuberculosis, Mtb）来源的两种免疫原性表位ESAT61–20与TB10.43–11，与Toll样受体2（TLR2）配体Pam2Cys进行共价偶联，制备得到一款自佐剂性脂肽疫苗。向小鼠实施黏膜给药后，该疫苗可增强肺部免疫原性，诱导肺部产生强烈的辅助性T细胞17（Th17）应答以及多功能性外周T淋巴细胞。相较于外周接种，黏膜接种可对结核分枝杆菌（Mtb）感染提供显著防护，这凸显了给药途径对实现最佳疗效的重要性。