We have developed a novel
tuberculosis (TB)
vaccine; a combination of the
DNA vaccines expressing mycobacterial
heat shock protein 65 (HSP65) and
interleukin 12 (IL-12) delivered by the hemagglutinating virus of Japan (HVJ)-envelope and -
liposome (HSP65 +
IL-12/HVJ). An
IL-12 expression vector (IL-12DNA) encoding single-chain
IL-12 proteins comprised of p40 and p35 subunits were constructed. This
vaccine provided remarkable protective efficacy in mouse and guinea pig models compared to the
BCG vaccine on the basis of C.F.U of number of TB, survival, an induction of the CD8 positive CTL activity and improvement of the histopathological
tuberculosis lesions. This
vaccine also provided therapeutic efficacy against multi-
drug resistant TB (MDR-TB) and extremely
drug resistant TB (
XDR-TB) (prolongation of survival time and the decrease in the number of TB in the lung) in murine models. Furthermore, we extended our studies to a cynomolgus monkey model, which is currently the best animal model of human
tuberculosis. This novel
vaccine provided a higher level of the protective efficacy than BCG based upon the assessment of mortality, the ESR,
body weight, chest X-ray findings and immune responses. All monkeys in the control group (saline) died within 8 months, while 50% of monkeys in the HSP65+hIL-12/HVJ group survived more than 14 months post-
infection (the termination period of the experiment). Furthermore, the BCG priming and HSP65 +
IL-12/HVJ
vaccine (booster) by the priming-booster method showed a synergistic effect in the TB-infected cynomolgus monkey (100% survival). In contrast, 33% of monkeys from BCG Tokyo alone group were alive (33% survival). Furthermore, this
vaccine exerted therapeutic efficacy (100% survival) and augmentation of immune responses in the TB-infected monkeys. These data indicate that our novel
DNA vaccine might be useful against Mycobacterium tuberculosis including
XDR-TB and MDR-TB for human therapeutic clinical trials.