Abstract
Mycobacterium bovis bacillus Calmette-Guérin (BCG) is currently the only vaccine available for preventing tuberculosis (TB), however, BCG has varying success in preventing pulmonary TB. In this study, a recombinant BCG (rBCG::Ag85A) strain overexpressing the immunodominant Ag85A antigen was constructed, and its immunogenicity and protective efficacy were evaluated. Our results indicated that the Ag85A protein was successfully overexpressed in rBCG::Ag85A, and the Ag85A peptide–MHC complexes on draining lymph node dendritic cells of C57BL/6 mice infected with rBCG::Ag85A were detectable 4 h post-infection. The C57BL/6 mice infected with this strain had stronger antigen-specific interferon-gamma (IFN-γ) responses and higher antibody titers than those immunized with BCG, and the protective experiments showed that rBCG::Ag85A can enhance protection against Mycobacterium tuberculosis (M. tuberculosis) H37Rv infection compared to the BCG vaccine alone. Our results demonstrate the potential of rBCG::Ag85A as a candidate vaccine against TB.
Highlights
Tuberculosis (TB) is caused by the intracellular pathogen Mycobacterium tuberculosis is (M. tuberculosis), and is responsible for about 2 million deaths each year and an estimated 9 million new cases annually (Rappuoli, 2014)
The results demonstrate that the 31 kDa antigen 85A (Ag85A) protein levels are increased two-fold in recombinant BCG (rBCG)::Ag85A compared with those of bacillus Calmette-Guérin (BCG) (Figure 1), while the 30 and 31.5 kDa proteins represent Ag85B and Ag85C, respectively
The Ag85 complex proteins have been extensively explored, it has been shown that rBCG overexpressing Ag85B enhanced the immunogenicity of BCG and induced a robust and long-lasting immune response (Xu et al, 2007; Wang et al, 2009; Shen et al, 2010)
Summary
Tuberculosis (TB) is caused by the intracellular pathogen Mycobacterium tuberculosis is (M. tuberculosis), and is responsible for about 2 million deaths each year and an estimated 9 million new cases annually (Rappuoli, 2014). 12 new TB vaccines have entered clinical trials, which are focused on two goals: (1) improve the existing vaccine by replacing BCG with attenuated bacterial strains derived from BCG or M. tuberculosis, for Recombinant BCG Overexpressing Ag85A example, VPM1002 (rBCG ureC::hly) was an attenuated strain, which was safe and immunogenic for B-cell and T-cell responses, and it is the most advanced recombinant vaccine in clinical trial (Grode et al, 2013), while rBCG30 strain was obtained by engineering BCG to overexpress Ag85B to induce better immune response (Gillis et al, 2014), (2) improve the TB vaccine by boosting BCG induced immunity using protein-based vaccines delivered in the presence of adjuvants or with viral vectors. The H1 vaccine comprises a fusion protein of Ag85BESAT6 in the adjuvant IC31, while others were delivered via DNA or viral vectors, such as MVA85A and Ad5HUAG85A (Rappuoli and Aderem, 2011; Knudsen et al, 2014)
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