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

被引：21

作者：

Ashhurst, Anneliese S. ^{[1
,2
]}

McDonald, David M. ^{[1
]}

Hanna, Cameron C. ^{[1
]}

Stanojevic, Vicki A. ^{[1
]}

Britton, Warwick J. ^{[2
,3
]}

Payne, Richard J. ^{[1
]}

机构：

[1] Univ Sydney, Sch Chem, Camperdown, NSW 2050, Australia

[2] Univ Sydney, TB Res Program Centenary Inst, Camperdown, NSW 2050, Australia

[3] Univ Sydney, Fac Med & Hlth, Camperdown, NSW 2050, Australia

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2019年 / 62卷 / 17期

基金：

英国医学研究理事会;

关键词：

MULTIDRUG-RESISTANT TUBERCULOSIS; SOLID-PHASE SYNTHESIS; IMMUNOLOGICAL EVALUATION; EPIDEMIC SPREAD; TH17; CELLS; PEPTIDE; VACCINES; BCG; IMMUNIZATION; INFECTION;

D O I：

10.1021/acs.jmedchem.9b00832

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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(1_20) and TB10.4(3-11) from Mycobacterium tuberculosis (Mtb), were covalently conjugated to the TLR2-ligand Pam(2)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.

引用

页码：8080 / 8089

页数：10

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