Mucosal Delivery of Fusion Proteins With Bacillus subtilis Spores Enhances Protection Against Tuberculosis by Bacillus Calmette-Guérin

Front Immunol. 2018 Mar 12;9:346. doi: 10.3389/fimmu.2018.00346. eCollection 2018.

Abstract

Tuberculosis (TB) is the most deadly infectious disease in existence, and the only available vaccine, Bacillus Calmette-Guérin (BCG), is almost a century old and poorly protective. The immunological complexity of TB, coupled with rising resistance to antimicrobial therapies, necessitates a pipeline of diverse novel vaccines. Here, we show that Bacillus subtilis spores can be coated with a fusion protein 1 ("FP1") consisting of Mycobacterium tuberculosis (Mtb) antigens Ag85B, ACR, and HBHA. The resultant vaccine, Spore-FP1, was tested in a murine low-dose Mtb aerosol challenge model. Mice were primed with subcutaneous BCG, followed by mucosal booster immunizations with Spore-FP1. We show that Spore-FP1 enhanced pulmonary control of Mtb, as evidenced by reduced bacterial burdens in the lungs. This was associated with elevated antigen-specific IgG and IgA titers in the serum and lung mucosal surface, respectively. Spore-FP1 immunization generated superior antigen-specific memory T-cell proliferation in both CD4+ and CD8+ compartments, alongside bolstered Th1-, Th17-, and Treg-type cytokine production, compared to BCG immunization alone. CD69+CD103+ tissue resident memory T-cells (Trm) were found within the lung parenchyma after mucosal immunization with Spore-FP1, confirming the advantages of mucosal delivery. Our data show that Spore-FP1 is a promising new TB vaccine that can successfully augment protection and immunogenicity in BCG-primed animals.

Keywords: adjuvants; immunity; spores; tuberculosis; vaccine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Animals
  • Antibodies, Bacterial / immunology
  • Antigens, Bacterial* / genetics
  • Antigens, Bacterial* / immunology
  • Antigens, Bacterial* / pharmacology
  • Bacillus subtilis* / genetics
  • Bacillus subtilis* / immunology
  • Drug Delivery Systems*
  • Female
  • Immunity, Mucosal / drug effects*
  • Immunization, Secondary
  • Immunoglobulin A / immunology
  • Immunoglobulin G / immunology
  • Mice
  • Mycobacterium bovis / immunology*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / immunology
  • Recombinant Fusion Proteins / pharmacology
  • Spores, Bacterial* / genetics
  • Spores, Bacterial* / immunology
  • T-Lymphocytes, Helper-Inducer / immunology
  • Tuberculosis / immunology
  • Tuberculosis / prevention & control*
  • Tuberculosis Vaccines* / genetics
  • Tuberculosis Vaccines* / immunology
  • Tuberculosis Vaccines* / pharmacokinetics

Substances

  • Antibodies, Bacterial
  • Antigens, Bacterial
  • Immunoglobulin A
  • Immunoglobulin G
  • Recombinant Fusion Proteins
  • Tuberculosis Vaccines