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

J Med Chem. 2019 Sep 12;62(17):8080-8089. doi: 10.1021/acs.jmedchem.9b00832. Epub 2019 Aug 16.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / chemical synthesis
  • Adjuvants, Immunologic / chemistry
  • Adjuvants, Immunologic / pharmacology*
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / immunology
  • Anti-Bacterial Agents / pharmacology*
  • Dose-Response Relationship, Drug
  • Lipopeptides / chemistry
  • Lipopeptides / immunology
  • Lipopeptides / pharmacology*
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / immunology
  • Protective Agents / chemical synthesis
  • Protective Agents / chemistry
  • Protective Agents / pharmacology*
  • Structure-Activity Relationship
  • Vaccination

Substances

  • Adjuvants, Immunologic
  • Anti-Bacterial Agents
  • Lipopeptides
  • Protective Agents