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Repeated Aerosolized-Boosting with Gamma-Irradiated Mycobacterium bovis BCG Confers Improved Pulmonary Protection against the Hypervirulent Mycobacterium tuberculosis Strain HN878 in Mice

 Seung Bin Cha  ;  Woo Sik Kim  ;  Jong-Seok Kim  ;  Hongmin Kim  ;  Kee Woong Kwon  ;  Seung Jung Han  ;  Seok-Yong Eum  ;  Sang-Nae Cho  ;  Sung Jae Shin 
 PLOS ONE, Vol.10(10) : e0141577, 2015 
Journal Title
Issue Date
Animals ; Antibodies, Bacterial/blood ; Antibodies, Bacterial/immunology ; BCG Vaccine/administration & dosage ; BCG Vaccine/immunology* ; Cytokines/metabolism ; Disease Models, Animal ; Female ; Immunization, Secondary* ; Immunologic Memory ; Mice ; Mycobacterium tuberculosis/immunology* ; Mycobacterium tuberculosis/pathogenicity ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/metabolism ; Tuberculosis, Pulmonary/immunology* ; Tuberculosis, Pulmonary/microbiology ; Tuberculosis, Pulmonary/pathology ; Tuberculosis, Pulmonary/prevention & control ; Vaccination ; Vaccines, Inactivated* ; Virulence
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.
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5. Research Institutes (연구소) > Institute for Immunology and Immunological Disease (면역질환연구소) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
Yonsei Authors
Kim, Jong Seok(김종석)
Shin, Sung Jae(신성재) ORCID logo https://orcid.org/0000-0003-0854-4582
Cho, Sang Nae(조상래)
Cha, Seung Bin(차승빈)
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