Research Article: Cell wall skeleton of Mycobacterium bovis BCG enhances the vaccine potential of antigen 85B against tuberculosis by inducing Th1 and Th17 responses

Date Published: March 8, 2019

Publisher: Public Library of Science

Author(s): Yong Woo Back, Seunga Choi, Han-Gyu Choi, Ki-Won Shin, Yeo-Jin Son, Tae-Hyun Paik, Hwa-Jung Kim, Yung-Fu Chang.


A safe and effective adjuvant is necessary to induce reliable protective efficacy of the protein-based vaccines against tuberculosis (TB). Mycobacterial components, such as synthetic cord factor and arabinogalactan, have been used as one of the adjuvant components. Mycobacterium bovis bacillus Calmette- Guérin cell-wall skeleton (BCG-CWS) has been used as an effective immune-stimulator. However, it is not proven whether BCG-CWS can be an effective adjuvant for the subunit protein vaccine of TB. In this study, we demonstrated that the BCG-CWS effectively coupled with Ag85B and enhanced the conjugated Ag85B activity on the maturation of dendritic cells (DCs). Ag85B-BCG-CWS-matured DCs induced significant Th1 and Th17 responses when compared to BCG-CWS or Ag85B alone. In addition, significant Ag85B-specific Th1 and Th17 responses were induced in Ag85B-BCG-CWS-immunized mice before infection with M. tuberculosis and maintained after infection. Moreover, Ag85B-BCG-CWS showed significant protective effect comparable to live BCG at 6 weeks after infection and maintained its protective efficacy at 32 weeks post-challenge, whereas live BCG did not. These results suggest that the BCG-CWS may be an effective adjuvant candidate for a protein-based vaccine against TB.

Partial Text

Tuberculosis (TB) is a major infectious disease that causes 1.3 million deaths per year worldwide [1]. The reactivation risk of the latent TB in an immunosuppressed individual and the advent of multidrug-resistant TB have made the control of TB difficult [2–4]. Vaccination is one of the best methods to control infectious diseases. The only TB vaccine, Mycobacterium bovis bacillus Calmette-Guérin (BCG), is unable to significantly prevent adult pulmonary TB and the reactivation of dormant TB [5]. Research on the protein-based vaccines have been focusing on a reliable candidate for BCG-prime boosting. Because a protein alone induces a weak immune response, the adjuvants or viral vectors have been used as an antigen delivery system. Therefore, an adjuvant with a strong immunostimulatory effect is essential to develop these subunit vaccines. In recent years, the multistage TB subunit vaccines using new adjuvant systems, such as IC31, AS01, and GLA-SE, are currently under clinical development [6]. However, better adjuvants that are safe and effective in humans must be developed.

It is a critical goal to develop an effective antigen delivery system in TB vaccine research field [7]. In general, adjuvants are mixed with the antigen as a form of emulsions or liposomes. However, these mixtures enable activation of surrounding APCs that do not present the delivered antigen and are probable cause of induction of autoimmune responses [23, 24]. In addition, a high adjuvant dosage is required to induce a satisfactory immune response to the antigen and leads to unnecessary side effects [25]. In contrast, an antigen-adjuvant conjugate can ensure that both the antigen and adjuvant reach the APC simultaneously, and strongly induce immune response, compared to an antigen-adjuvant mixture [26]. Recently, the antigen-adjuvant conjugation has attracted attention, because it can induce a stronger immune response at a lower concentration than the antigen-adjuvant mixture [26]. In this study, we demonstrated that the immunization of the BCG-CWS conjugated with Ag85B elicits Th1 and Th17 responses and a long-term protective response against TB in mice.




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