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A novel therapeutic vaccine against multi-drug resistant tuberculosis by T cell mediated immunity in phase 1 clinical trial

Masaji Okada1, Kazunori Tomono2, Kazunari Tsuyuguchi1, Takefumi Saito3, Yoshikazu Inoue1, Akira Yamane4 ,Soichiro Watanabe5

1National Hospital Organization Kinki-chuo Chest Medical Center, 2Osaka University; 3NHO Ibaraki-higashi Hospital, 4NHO Tokyo Hospital, 5Muroran-city General Hospital  

Multi-drug resistant (MDR), especially extremely drug resistant (XDR), Mycobacterium tuberculosis (M. TB) is a serious problem in the world. We have developed novel TB therapeutic vaccine (HVJ-E/HSP65 DNA +IL-12 DNA vaccine) to eliminate MDR-TB by T cells. DNA vaccine expressing M.TB heat shock protein 65 and IL-12 was delivered by the hemagglutinating virus of Japan (HVJ)-envelope.  

Results: This vaccine provided remarkable therapeutic efficacy against MDR-TB and XDR-TB in murine models (decrease in the number of MDR-TB). Furthermore, this vaccine provided therapeutic efficacy of prolongation of survival time (100% survival) of TB infected monkeys and augmented the T cell immune responses.  Preclinical study by using monkeys in GLP level, safety of the vaccine was shown.

【Phase1 Investigator-initiated clinical trial】

Therefore, phase 1 clinical trial has been already started. Targets are human patients with MDR-TB. Primary evaluation is safety and tolerability. Secondary evaluation is anti-TB efficacy (sputum-culture conversion). A patient of First Patient In showed safety and tolerability of this therapeutic vaccine by pDNA concentration in the blood. Furthermore, anti-TB efficacy (MDR-TB negative conversion) was demonstrated by the Gaffky study and colony count of TB in the sputum. Anti-TB immunity (IFN-γ and IL-2 production) was augmented in the patient with this vaccination from 14~126 day.

Conclusion: These data indicate that HSP65 DNA+IL-12DNA vaccine is useful against XDR-TB and MDR-TB through T cells for human therapeutic clinical applications. （This research was supported by AMED,Japan.）