Prime-boost vaccination with rBCG/rAd35 enhances CD8⁺ cytolytic T-cell responses in lesions from Mycobacterium tuberculosis-infected primates

Mol Med. 2012 May 9;18(1):647-58. doi: 10.2119/molmed.2011.00222.

Abstract

To prevent the global spread of tuberculosis (TB) infection, a novel vaccine that triggers potent and long-lived immunity is urgently required. A plasmid-based vaccine has been developed to enhance activation of major histocompatibility complex (MHC) class I-restricted CD8⁺ cytolytic T cells using a recombinant Bacille Calmette-Guérin (rBCG) expressing a pore-forming toxin and the Mycobacterium tuberculosis (Mtb) antigens Ag85A, 85B and TB10.4 followed by a booster with a nonreplicating adenovirus 35 (rAd35) vaccine vector encoding the same Mtb antigens. Here, the capacity of the rBCG/rAd35 vaccine to induce protective and biologically relevant CD8⁺ T-cell responses in a nonhuman primate model of TB was investigated. After prime/boost immunizations and challenge with virulent Mtb in rhesus macaques, quantification of immune responses at the single-cell level in cryopreserved tissue specimen from infected organs was performed using in situ computerized image analysis as a technological platform. Significantly elevated levels of CD3⁺ and CD8⁺ T cells as well as cells expressing interleukin (IL)-7, perforin and granulysin were found in TB lung lesions and spleen from rBCG/rAd35-vaccinated animals compared with BCG/rAd35-vaccinated or unvaccinated animals. The local increase in CD8⁺ cytolytic T cells correlated with reduced expression of the Mtb antigen MPT64 and also with prolonged survival after the challenge. Our observations suggest that a protective immune response in rBCG/rAd35-vaccinated nonhuman primates was associated with enhanced MHC class I antigen presentation and activation of CD8⁺ effector T-cell responses at the local site of infection in Mtb-challenged animals.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Bacterial / immunology
  • Antigens, Bacterial / metabolism
  • BCG Vaccine / immunology*
  • Bacterial Proteins / immunology
  • Bacterial Proteins / metabolism
  • Collagen Type I / metabolism
  • Female
  • Immunization, Secondary
  • Interleukin-7 / metabolism
  • Macaca mulatta
  • Mycobacterium tuberculosis / immunology*
  • T-Lymphocytes, Cytotoxic / immunology*
  • Tuberculosis / immunology*
  • Tuberculosis / prevention & control*
  • Tuberculosis, Pulmonary / immunology
  • Tuberculosis, Pulmonary / metabolism
  • Tuberculosis, Splenic / immunology
  • Tuberculosis, Splenic / metabolism
  • Vaccination

Substances

  • Antigens, Bacterial
  • BCG Vaccine
  • Bacterial Proteins
  • Collagen Type I
  • Interleukin-7
  • MPB64 protein, Mycobacterium