Novel therapeutic vaccines [(HSP65 + IL-12)DNA-, granulysin- and Ksp37-vaccine] against tuberculosis and synergistic effects in the combination with chemotherapy

Abstract

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.

Methods and Results: 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.

Keywords: :

• HSP65 DNA + IL-12 DNA vaccine
• Ksp37 transgenic mouse
• Ksp37 vaccine
• MDR-TB
• XDR-TB
• chemotherapy
• granulysin vaccine
• synergistic therapeutic efficacy
• therapeutic vaccine against
• tuberculosis

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

This study was supported by Health and Labour Science Research Grants from MHLW, Research on Publicly Essential Drugs and Medical Devices, Japan Health Science Foundation, The Association for Preventive Medicine of Japan and Grant-in-Aid for Scientific Research (B,C) from the Ministry of Education, Culture, Sports, Science and Technology Japan, and Grant of Osaka Tuberculosis Foundation.