Development of New Preventive and Therapeutic Vaccines for Tuberculosis

Abstract

Tuberculosis (TB) is a contagious disease that has been responsible for the death of one billion people in the last 200 years. Until now, the only vaccine approved for the prevention of TB is Bacillus Calmette-Guérin (BCG), which is prepared by attenuating Mycobacterium bovis. However, one of the limitations of BCG is that its preventive effect against pulmonary TB varies from person to person. Therefore, there arises a need for a new TB vaccine to replace or supplement BCG. In this review, we have summarized the findings of current clinical trials on preventive and therapeutic TB vaccine candidates. In addition, we have discussed a novel vaccination approach using the cell-based vaccine presenting early secretory antigenic target-6 (ESAT-6), which is a potent immunogenic antigen. The role of ESAT-6 in hosts has also been described.

Keywords: Adjuvant; Cell-based therapy; Cell-based vaccine; Early secretory antigenic target-6; Tuberculosis; Viral vector.

Figure 1

Total TB cases and new TB cases from 2001 to 2016 in the Republic of Korea. The total cases and new cases of TB patients from 2001 to 2016 in the Republic of Korea are shown as the number per 100,000 individuals. The data are obtained from National Tuberculosis Management Guidelines (The Korea Centers for Disease Control and Prevention, 2017).

Figure 2

Countries with high burden of TB, MDR-TB, and TB/HIV. Countries with TB, MDR-TB, and HIV-related TB are shown as modified from the WHO Global Tuberculosis Report 2016. DPR Korea is included in both TB and MDR-TB sectors in the WHO TB high-burden country lists. DR Congo, Democratic Republic of the Congo; UR Tanzania, United Republic of Tanzania.

Figure 3

Classification of TB vaccines. TB vaccines were divided into preventive and therapeutic vaccines. Priming vaccines induce immune responses prior to Mycobacterium tuberculosis infection. Boosting vaccines are applied to reinforce immune responses elicited after priming. Therapeutic vaccines are used to cure TB or its symptoms with anti-mycobacterial medications.

Figure 4

Mechanism of APC-based cell vaccines through NKT cell activation. The APC-based cell vaccine expressing antigen-triggered antigen-specific immune response. Antigens presented on APCs stimulate CD8⁺ T cells to express IFN-γ and sufficiently induce a CTL response against infected cells. Since antigen presentation induced by viral vectors is MHC class I-dominant, an appropriate adjuvant is required to enhance the CD4⁺ T cell response. α-GalCer, which is loaded on the CD1d molecule of APCs, can act as an adjuvant for immunization. NKT cells activated by α-GalCer up-regulate MHC class II molecules on APCs. Moreover, α-GalCer-loaded APCs activate NKT cells, thus allowing them to produce IL-21 to enhance the natural killer (NK) cell and CD4⁺ T cell response. Activated CD4⁺ T cells consequently accelerate antibody production in plasma cells for preventing or protecting against Mycobacterium tuberculosis. In addition to the APC-based cell vaccine, NKT cell activation using α-GalCer induces stronger immune responses by activating NKT and NK cells. As a result, the APC-based cell vaccine could be a potent candidate that functions by activating NKT cells against M. tuberculosis.

Figure 5

Mechanism of inflammatory responses in Mycobacterium tuberculosis-infected cells. In M. tuberculosis-infected host cells, the bacterium is internalized through phagocytosis. M. tuberculosis replicates and secretes its own peptides that induce pathogenic effects in the phagosome/endosome. During the life cycle of M. tuberculosis, the bacteria escape the phagosome and reach the cytosol; this process is dependent on ESAT-6, which is secreted by the ESX-1 excretion system. Cytosolic mycobacterial DNA produced by the defense mechanisms of the host cell is sensed by cGAS and AIM2. Activated cGAS uses adenosine triphosphate (ATP) and GTP to synthesize cGAMP, which acts as a secondary messenger in the host cell. cGAMP activates STING, which phosphorylates TBK-1. TBK-1 phosphorylates IRF3 and induces ubiquitination to bacteria, thus triggering autophagy. Consequently, the dimerization of phosphorylated IRF3 activates IFN-β, which suppresses the M. tuberculosis burden. On the other hand, cytosolic mycobacterial DNA is also sensed by an AIM2 DNA sensor, one of the components of the inflammasome. Activated AIM2 protein induces the protease effect of the AIM2 inflammasome, which cleaves procaspase-1 to caspase-1. Cleaved caspase-1, in turn, cleaves pro-IL-1β to IL-1β to be secreted into the extracellular space.