Combinational PRR Agonists in Liposomal Adjuvant Enhances Immunogenicity and Protective Efficacy in a Tuberculosis Subunit Vaccine

Front Immunol. 2020 Sep 30:11:575504. doi: 10.3389/fimmu.2020.575504. eCollection 2020.

Abstract

Bacillus Calmette-Guerin (BCG) is the only licensed vaccine to prevent children from tuberculosis (TB), whereas it cannot provide effective protection for adults. Our previous work showed a novel vaccine candidate, liposomal adjuvant DMT emulsified with a multistage antigen CMFO, could protect mice against primary progressive TB, latency, and reactivation. To develop a more effective vaccine against adult TB, we aimed to further understand the role of pattern recognition receptor (PRR) agonists monophosphoryl lipid A (MPLA) and trehalose-6,6'-dibehenate (TDB) of the liposomal adjuvant DMT in the CMFO subunit vaccine-induced protection. Using C57BL/6 mouse models, the current study prepared different dimethyldioctadecylammonium (DDA)-based liposomal adjuvants with MPLA, TDB, or both (DMT), and then compared the immunogenicity and the protective efficacy among different liposomal adjuvanted CMFO subunit vaccines. Our study demonstrated that CMFO/DMT provided stronger and longer-lasting protective efficacy than the CMFO emulsified with adjuvants DDA or DDA/TDB. In addition, DDA/MPLA adjuvanted CMFO conferred a comparable protection in the lung as CMFO/DMT did. Higher levels of IFN-γ, IL-2, TNF-α, and IL-17A secreted by splenocytes were related with a more powerful and durable protection induced by CMFO/DMT through a putative synergistic effect of both MPLA and TDB via binding to TLR4 and Mincle. IL-2+ CD4+ T cells, especially IL-2+ CD4+ TCM cells, in the lung after infection were significantly associated with the vaccine-induced protection, whereas stronger IL-10 response and lower IL-2+ CD4+ T cells also contributed to the inferior protection of the DDA/TDB adjuvanted CMFO subunit vaccine. Given their crucial roles in vaccine-induced protection, combinational different PRR agonists in adjuvant formulation represent a promising strategy for the development of next-generation TB vaccine.

Keywords: Bacillus Calmette-Guerin; adjuvant; monophosphoryl lipid A; pattern-recognition receptor agonist; primary infection; subunit vaccine; trehalose-6,6’-dibehenate; tuberculosis.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / chemistry
  • Adjuvants, Immunologic / pharmacology*
  • Animals
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / microbiology
  • Cytokines / metabolism
  • Disease Models, Animal
  • Drug Compounding
  • Female
  • Glycolipids / chemistry
  • Glycolipids / pharmacology*
  • Host-Pathogen Interactions
  • Immunogenicity, Vaccine*
  • Lipid A / analogs & derivatives*
  • Lipid A / chemistry
  • Lipid A / pharmacology
  • Liposomes
  • Lung / drug effects*
  • Lung / immunology
  • Lung / metabolism
  • Lung / microbiology
  • Mice, Inbred C57BL
  • Mycobacterium tuberculosis / immunology
  • Mycobacterium tuberculosis / pathogenicity*
  • Quaternary Ammonium Compounds / chemistry
  • Quaternary Ammonium Compounds / pharmacology*
  • Receptors, Pattern Recognition / agonists*
  • Receptors, Pattern Recognition / metabolism
  • Time Factors
  • Tuberculosis Vaccines / chemistry
  • Tuberculosis Vaccines / pharmacology*
  • Tuberculosis, Pulmonary / immunology
  • Tuberculosis, Pulmonary / metabolism
  • Tuberculosis, Pulmonary / microbiology
  • Tuberculosis, Pulmonary / prevention & control*
  • Vaccination
  • Vaccines, Subunit / chemistry
  • Vaccines, Subunit / pharmacology
  • Virulence

Substances

  • Adjuvants, Immunologic
  • Cytokines
  • Glycolipids
  • Lipid A
  • Liposomes
  • Quaternary Ammonium Compounds
  • Receptors, Pattern Recognition
  • Tuberculosis Vaccines
  • Vaccines, Subunit
  • trehalose 6,6'-dibehenate
  • dimethyldioctadecylammonium
  • monophosphoryl lipid A