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.
Highlights
The global spread of tuberculosis (TB)continues to be a major threat to public health
Our observations suggest that a protective immune response in recombinant Bacille Calmette-Guérin (rBCG)/rAd35vaccinated nonhuman primates was associated with enhanced major histocompatibility complex (MHC) class I antigen presentation and activation of CD8+ effector T-cell responses at the local site of infection in Mycobacterium tuberculosis (Mtb)-challenged animals
We studied in vivo expression and distribution of immune cells and antimicrobial effector molecules in Mtb-infected lung and spleen tissue obtained from rBCG/rAd35- or Bacille Calmette-Guérin (BCG)/rAd35-vaccinated and unvaccinated control nonhuman primate (NHP)
Summary
The global spread of tuberculosis (TB)continues to be a major threat to public health. The efficacy of BCG vaccination is highly variable (0–80%) [1], and the cause of these large differences in vaccine-induced protection is poorly understood. Some of its limitations may involve short-lived BCG-induced immune reactivity and a failure to generate strong major histocompatibility complex (MHC) class I–restricted CD8+ T-cell responses. This underlines the necessity to replace the current BCG vaccine by a more effective vaccine against TB or improve the potency of the already existing BCG. The immune response to Mycobacterium tuberculosis (Mtb) is a dynamic process, and TB control depends on cellmediated immunity involving polyfunctional CD4+ and CD8+ T-cell responses [2]. Our recent studies on immunopathogenesis in human TB [6,7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
