Journal
HUMAN VACCINES & IMMUNOTHERAPEUTICS
Volume 9, Issue 3, Pages 526-533Publisher
LANDES BIOSCIENCE
DOI: 10.4161/hv.23230
Keywords
therapeutic vaccine against; tuberculosis; HSP65 DNA + IL-12 DNA vaccine; granulysin vaccine; Ksp37 vaccine; chemotherapy; Ksp37 transgenic mouse; synergistic therapeutic efficacy; MDR-TB; XDR-TB
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Funding
- MHLW
- Research on Publicly Essential Drugs and Medical Devices, Japan Health Science Foundation
- Association for Preventive Medicine of Japan
- Ministry of Education, Culture, Sports, Science and Technology Japan
- Osaka Tuberculosis Foundation
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Purpose: Multi-drug resistant tuberculosis (MDR-TB) and extremely drug resistant (XDR) TB are big problems in the world. We have developed novel TB therapeutic vaccines, HVJ-Envelope/HSP65 + IL-12 DNA vaccine (HSP65-vaccine), granulysin vaccine and killer specific secretory protein of 37kDa (Ksp37) vaccine. Results and Methods: HSP65 vaccine showed strong therapeutic effect against both MDR-TB and XDR-TB in mice. Intradermal immunization of HSP65-vaccine showed stronger therapeutic effect against TB than intramuscular or subcutaneous immunization. Furthermore, the synergistic therapeutic effect was observed when the vaccine was administrated in combination with Isoniazid (INH), which is a first line drug for chemotherapy. The combination of types of vaccines (HSP65- and granulysin-vaccines) also showed synergistic therapeutic effect. In the monkey model, granulysin-vaccine prolonged the survival period after the infection of TB and long-term survival was observed in vaccine-treated group. We examined the potential of two kinds of novel DNA vaccines (Ksp37-vaccine and granulysin-vaccine). Both vaccines augmented in vivo differentiation of CTL against TB. We measured the amount of Ksp37 protein in human serum and revealed that the level of Ksp37 protein of patients with tuberculosis was lower than that of healthy volunteers. Therefore, we established Ksp37 transgenic mice as well as granulysin transgenic mice to elucidate the function of those proteins. Both transgenic mice were resistant to TB infection. Conclusion: These data indicate the potential of combinational therapy; the combination of two DNA vaccines or combination of DNA vaccine with antibiotic drug. Thus, it will provide a novel strategy for the treatment of MDR-TB.
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