Prospects in Mycobacterium bovis Bacille Calmette et Guérin (BCG) vaccine diversity and delivery: why does BCG fail to protect against tuberculosis?

Abstract

Mycobacterium tuberculosis (M.tb) infection leads to active tuberculosis (TB), a disease that kills one human every 18s. Current therapies available to combat TB include chemotherapy and the preventative vaccine Mycobacterium bovis Bacille Calmette et Guérin (BCG). Increased reporting of drug resistant M.tb strains worldwide indicates that drug development cannot be the primary mechanism for eradication. BCG vaccination has been used globally for protection against childhood and disseminated TB, however, its efficacy at protecting against pulmonary TB in adult and aging populations is highly variable. In this regard, the immune response generated by BCG vaccination is incapable of sterilizing the lung post M.tb infection as indicated by the large proportion of individuals with latent TB infection that have received BCG. Although many new TB vaccine candidates have entered the development pipeline, only a few have moved to human clinical trials; where they showed no efficacy and/or were withdrawn due to safety regulations. These trials highlight our limited understanding of protective immunity against the development of active TB. Here, we discuss current vaccination strategies and their impact on the generation and sustainability of protective immunity against TB.

Keywords: Mycobacterium bovis Bacille Calmette-Guérin (BCG); Mycobacterium tuberculosis; Tuberculosis; Vaccine.

Figure 1

A. Different routes of vaccination with BCG vary in their reduction of M.tb CFU in the lung of vaccinated animals. Shown is a graph compiling the relative protection conferred by distinct routes of vaccination against M.tb using BCG-Pasteur as a reference. The protection by BCG via subcutaneous/intradermal inoculation results in approximately one-log reduction in M.tb CFU in the lung. More immunogenic routes such as oral and intraperitoneal vaccination offer a greater degree of protection mainly due to their ability to stimulate systemic and mucosal immune responses. Immunization via BCG aerosol elicited the greatest degree of protection however this route is associated with lung tissue pathology. B. New vaccines/concepts that have shown greater reduction of M.tb CFU in the lung of vaccinated animals compared to BCG. There is a plethora of vaccines that have been investigated for enhanced protection against M.tb compared to BCG, however here only a few have been summarized. Based on published data, the graph shows the relative number of M.tb CFU in the lung of vaccinated animals challenged with M.tb. Novel strategies, such as the induction of autophagy or blocking of the IL-10R, have been shown to enhance the protective efficacy of the BCG vaccine. Interestingly, rBCG30 was shown to be more protective than BCG∷RD1-2F9, both of which encode highly immunogenic antigens. To date, the rBCG ΔUre:CHly+ vaccine has been shown to be the most protective vaccines in terms of reducing lung CFU.