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Abstract
Background: BCG protection is suboptimal and there is significant interest to develop new tuberculosis (TB) vaccines. However, there are significant limitations of the current vaccine evaluation systems in the mouse model. Here, we developed a BCG-challenge rabbit skin model as a new way to evaluate the protective efficacy of selected TB subunit vaccine candidates.Methods: Rabbits were immunized with subunit vaccines, including EAMM (ESAT6-Ag85B-MPT64<190−198>-Mtb8.4), MH (Mtb10.4-HspX), and LT70 (ESAT6-Ag85B-MPT64<190−198>-Mtb8.4-Rv2626c) three times subcutaneously every 3-weeks and challenged with the attenuated Mycobacterium bovis BCG intradermally 6-weeks after last immunization. The immune response induced by the vaccine candidates was measured, the histopathology induced by the BCG challenge was studied, and the number of bacilli in the liquefied caseum was determined.Results: The subunit vaccines generated high antigen-specific IgG antibodies and fastened the liquefaction and healing process, and significantly reduced the viable BCG load. The subunit vaccine LT70 and EAMM-MH reduced BCG bacterial load in comparison to proteins EAMM, MH, Rv2626c, and also BCG itself. The Koch phenomena induced by the LT70 and combination of EAMM-MH were the same as that produced by BCG itself and were more rapid than those induced by the other proteins and the saline controls.Conclusions: The subunit vaccines LT70 and the combination of EAMM-MH showed promising protective efficacy as expected in the rabbit skin model, which can serve as a visual and convenient new model for evaluating TB vaccines.
Highlights
Tuberculosis (TB) remains a major threat to global public health
We found that the subunit vaccines LT70 and EAMM-MH showed promising protective efficacy in the rabbit skin model, which indicates the rabbit skin model is a convenient and more visual model to evaluate TB vaccine candidates
Langhans giant cells were present along with unabsorbed liquefied material and necrosis (Figure 1). These findings showed that BCG could cause significant lesions typical of tuberculosis and were not induced by contaminating bacteria, and that BCG could serve as a challenge organism for vaccine evaluation
Summary
Tuberculosis (TB) remains a major threat to global public health. About one-third of the world’s population is infected with Mycobacterium tuberculosis (M. tuberculosis) (Lonnroth et al, 2010). The current TB vaccine BCG has a high efficacy in preventing infants and children from miliary and meningeal tuberculosis (Colditz et al, 1994; Trunz et al, 2006), but shows variable efficacy against pulmonary tuberculosis (ranging from 0 to 80%) in adults (Fine, 1995). Subunit vaccines have shown comparable or even better protective efficacy than BCG (Lindenstrom et al, 2009). BCG protection is suboptimal and there is significant interest to develop new tuberculosis (TB) vaccines. There are significant limitations of the current vaccine evaluation systems in the mouse model. We developed a BCG-challenge rabbit skin model as a new way to evaluate the protective efficacy of selected TB subunit vaccine candidates
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