Repeated Aerosolized-Boosting with Gamma-Irradiated Mycobacterium bovis BCG Confers Improved Pulmonary Protection against the Hypervirulent Mycobacterium tuberculosis Strain HN878 in Mice.
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.
Department of Microbiology, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea.
Seung Bin
SB
Cha
Department of Microbiology, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea.
Woo Sik
WS
Kim
Department of Microbiology, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea.
Jong-Seok
JS
Kim
Department of Microbiology, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea; Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea.
Hongmin
H
Kim
Department of Microbiology, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea; Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea.
Kee Woong
KW
Kwon
Department of Microbiology, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea.
Seung Jung
SJ
Han
Division of Immunopathology and Cellular Immunology, International Tuberculosis Research Center, Changwon, South Korea.
Seok-Yong
SY
Eum
Department of Microbiology, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea; Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea.
Sang-Nae
SN
Cho
Department of Microbiology, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea; Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea.
Sung Jae
SJ
Shin
D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood / Q000276:immunology; D001500:BCG Vaccine / Q000008:administration & dosage / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D007117:Immunization, Secondary; D007156:Immunologic Memory; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000472:pathogenicity; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control; D014611:Vaccination; D015164:Vaccines, Inactivated; D014774:Virulence
D000907:Antibodies, Bacterial; D001500:BCG Vaccine; D016207:Cytokines; D015164:Vaccines, Inactivated