Abstract
Mycobacterium bovis bacillus Calmette-Guerin (BCG), the only licensed vaccine, shows limited protection efficacy against pulmonary tuberculosis (TB), particularly hypervirulent Mycobacterium tuberculosis (Mtb) strains, suggesting that a logistical and practical vaccination strategy is urgently required. Boosting the BCG-induced immunity may offer a potentially advantageous strategy for advancing TB vaccine development, instead of replacing BCG completely. Despite the improved protection of the airway immunization by using live BCG, the use of live BCG as an airway boosting agent may evoke safety concerns. Here, we analyzed the protective efficacy of γ-irradiated BCG as a BCG-prime boosting agent for airway immunization against a hypervirulent clinical strain challenge with Mycobacterium tuberculosis HN878 in a mouse TB model. After the aerosol challenge with the HN878 strain, the mice vaccinated with BCG via the parenteral route exhibited only mild and transient protection, whereas BCG vaccination followed by multiple aerosolized boosting with γ-irradiated BCG efficiently maintained long-lasting control of Mtb in terms of bacterial reduction and pathological findings. Further immunological investigation revealed that this approach resulted in a significant increase in the cellular responses in terms of a robust expansion of antigen (PPD and Ag85A)-specific CD4+ T cells concomitantly producing IFN-γ, TNF-α, and IL-2, as well as a high level of IFN-γ-producing recall response via both the local and systemic immune systems upon further boosting. Collectively, aerosolized boosting of γ-irradiated BCG is able to elicit strong Th1-biased immune responses and confer enhanced protection against a hypervirulent Mycobacterium tuberculosis HN878 infection in a boosting number-dependent manner.
Highlights
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a significant global health threat and led to 1.5 million deaths worldwide in 2013 [1]
Recent clinical studies using meta-analyses have shown that the absence of mycobacterial exposure prior to bacillus Calmette–Guerin (BCG) vaccination is associated with higher efficacy [4], and BCG is still advantageous against Mtb infection [5]
As previously reported [31], the protective efficacy of BCG against the hypervirulent HN878 strain is abrogated over time (0.61 log10 reduction at 5 weeks vs. 0.27 log10 reduction at 10 weeks post-infection)
Summary
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a significant global health threat and led to 1.5 million deaths worldwide in 2013 [1]. The only vaccine currently available for TB, Mycobacterium bovis bacillus Calmette–Guerin (BCG), is included in neonate or childhood vaccination programs in many countries despite the variable efficacy of protection against pulmonary TB shown in many clinical studies [2, 3]. Recent clinical studies using meta-analyses have shown that the absence of mycobacterial exposure prior to BCG vaccination is associated with higher efficacy [4], and BCG is still advantageous against Mtb infection [5]. As BCG-induced immunity would be expected to wane over time [8] and more than 80% of people received this vaccine when they are neonates, boosting the BCG-induced immunity is a more practical strategy than new TB vaccine development
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