Okada Masaji, Kita Yoko
Clinical Research Center, National Hospital Organization Kinki-chuo Chest Medical Center, 1180 Nagasone-cho, Kita-ku, Sakai-shi, Osaka 591-8555, Japan.
Kekkaku. 2010 Jun;85(6):531-8.
CDC and ACET in U.S.A. reported that novel vaccines instead of BCG are required for the protection against infection of Mycobacterium tuberculosis worldwide. However, no novel vaccine for clinical use has not yet been developed in the world including U.S.A. and Europe. 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). This vaccine provided remarkable protective efficacy in mouse 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 multidrug resistant TB (MDR-TB) and extremely drug resistant TB (XDR-TB) 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. 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). 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. The review also provides recent advances of the precise studies of induction of immunity including CD8 positive cytotoxic T cells and effector molecules such as granulysin by these vaccines, against multi-drug resistant tuberculosis and extremely drug resistant tuberculosis.
美国疾病控制与预防中心（CDC）和美国动物实验咨询委员会（ACET）报告称，全球范围内预防结核分枝杆菌感染需要新型疫苗而非卡介苗（BCG）。然而，包括美国和欧洲在内的全球范围内尚未开发出可用于临床的新型疫苗。我们研发了一种新型结核病（TB）疫苗；由日本血凝病毒（HVJ）包膜和脂质体递送的表达分枝杆菌热休克蛋白65（HSP65）和白细胞介素12（IL-12）的DNA疫苗组合（HSP65 + IL-12/HVJ）。基于结核杆菌数量的菌落形成单位（C.F.U）、生存率、CD8阳性细胞毒性T淋巴细胞（CTL）活性的诱导以及组织病理学结核病变的改善，与卡介苗相比，这种疫苗在小鼠中提供了显著的保护效果。这种疫苗在鼠模型中对耐多药结核病（MDR-TB）和广泛耐药结核病（XDR-TB）也具有治疗效果。此外，我们将研究扩展到食蟹猴模型，这是目前人类结核病的最佳动物模型。基于死亡率、红细胞沉降率（ESR）、体重、胸部X光检查结果和免疫反应的评估，这种新型疫苗比卡介苗提供了更高水平的保护效果。此外，通过初免 - 加强方法使用卡介苗初免和HSP65 + IL-12/HVJ疫苗（加强）在感染结核的食蟹猴中显示出协同效应（100%存活）。此外，这种疫苗在感染结核的猴子中发挥了治疗效果（100%存活）并增强了免疫反应。这些数据表明，我们的新型DNA疫苗可能对包括XDR-TB和MDR-TB在内的结核分枝杆菌用于人类治疗性临床试验有用。该综述还提供了这些疫苗针对耐多药结核病和广泛耐药结核病诱导免疫的精确研究的最新进展，包括CD8阳性细胞毒性T细胞和效应分子如颗粒溶素。
