title: Preclinical study and clinical trial of a novel therapeutic vaccine against multi-drug resistant tuberculosis.
abstract: [Purpose] Multi-drug resistant (MDR), Mycobacterium tuberculosis (TB) is a big problem in the world. We have developed novel TB therapeutic vaccine (HVJ-E/HSP65 DNA +IL-12 DNA). [Methods and Results] DNA vaccine expressing TB heat shock protein 65 and IL-12 was delivered by the hemagglutinating virus of Japan (HVJ)-envelope. This vaccine provided remarkable protective efficacy and strong therapeutic efficacy against MDR-TB and XDR-TB in murine models. Furthermore, this vaccine provided therapeutic efficacy of prolongation of survival time of TB infected monkeys and augmented the immune responses. Therefore, the preclinical tests were studied for clinical trial. The injection of 100 μg of the vaccine /mouse i.m. three times in two weeks induced significantly strong production of IFN-γ and IL-2. 100 μg and 200 μg DNA vaccine/mouse i.m. augmented the production of these cytokines compared with 25 μg DNA vaccine/mouse i.m.. The ratio of 100 μg pDNA to 1AU HVJ-E enhanced the production of IFN-γ and IL-2. The decrease in the number of M. tuberculosis in liver of mice was observed by the vaccination of 100μg pDNA. By using these conditions, safety pharmacology study and toxicology test is being studied in monkeys administered by GMP level DNA vaccines. By the toxicology test using monkeys, high dose GMP level vaccine/ monkey is administrated. Safety pharmacological study of repeated administration is also being investigated in GLP level. Furthermore, we have planned to do clinical phase I trial. Targets are human patients with MDR-TB. The safety and tolerability of the vaccine will be evaluated. [Conclusion and recommendations] These data indicate that our novel vaccine might be useful against tuberculosis including XDR-TB and MDR-TB for human therapeutic clinical applications.
authors.affiliation: a Clinical Research Center, National Hospital Organization Kinki-chuo Chest Medical Center , Kita-ku, Sakai City , Osaka , Japan.
authors.forename: Masaji
authors.initials: M
authors.lastname: Okada
authors.affiliation: a Clinical Research Center, National Hospital Organization Kinki-chuo Chest Medical Center , Kita-ku, Sakai City , Osaka , Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Kita
authors.affiliation: a Clinical Research Center, National Hospital Organization Kinki-chuo Chest Medical Center , Kita-ku, Sakai City , Osaka , Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Hashimoto
authors.affiliation: a Clinical Research Center, National Hospital Organization Kinki-chuo Chest Medical Center , Kita-ku, Sakai City , Osaka , Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakatani
authors.affiliation: a Clinical Research Center, National Hospital Organization Kinki-chuo Chest Medical Center , Kita-ku, Sakai City , Osaka , Japan.
authors.forename: Shiho
authors.initials: S
authors.lastname: Nishimastu
authors.affiliation: a Clinical Research Center, National Hospital Organization Kinki-chuo Chest Medical Center , Kita-ku, Sakai City , Osaka , Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Kioka
authors.affiliation: a Clinical Research Center, National Hospital Organization Kinki-chuo Chest Medical Center , Kita-ku, Sakai City , Osaka , Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Takami
mesh_terms: D000818:Animals; D058491:Bacterial Load; D017321:Clinical Trials, Phase I as Topic; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D000882:Haplorhini; D007167:Immunotherapy / Q000379:methods*; D007564:Japan; D008099:Liver / Q000382:microbiology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000276:immunology / Q000302:isolation & purification; D016896:Treatment Outcome; D032581:Tuberculosis Vaccines / Q000627:therapeutic use*; D018088:Tuberculosis, Multidrug-Resistant / Q000628:therapy*; D019444:Vaccines, DNA / Q000627:therapeutic use
chemical_list: D032581:Tuberculosis Vaccines; D019444:Vaccines, DNA
keywords: IL-2; IL-6); XDR-TB; clinical trial; cytokines (IFN-γ; immune responses against TB; mouse and monkey; multi-drug resistant tuberculosis; mycobacterium tuberculosis (M. TB); pharmacological efficacy; preclinical study; therapeutic vaccine