Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata 700032, India.
Vaccine. 2013 Apr 8;31(15):1905-15. doi: 10.1016/j.vaccine.2013.02.025. Epub 2013 Feb 26.
Emergence of resistance against commonly available drugs poses a major threat in the treatment of visceral leishmaniasis (VL), particularly in the Indian subcontinent. Absence of any licensed vaccine against VL emphasizes the urgent need to develop an effective alternative vaccination strategy.
We developed a novel heterologous prime boost immunization strategy using kinetoplastid membrane protein-11 (KMP-11) DNA priming followed by boosting with recombinant vaccinia virus (rVV) expressing the same antigen. The efficacy of this vaccination regimen in a murine and hamster model of visceral leishmaniasis caused by both antimony resistant (Sb-R) and sensitive (Sb-S) Leishmania (L.) donovani is examined.
Heterologous prime-boost (KMP-11 DNA/rVV) vaccination was able to protect mice and hamsters from experimental VL induced by both Sb-S and Sb-R-L. (L.) donovani isolates. Parasite burden is kept significantly low in the vaccinated groups even after 60 days post-infection in hamsters, which are extremely susceptible to VL. Protection in mice is correlated with strong cellular and humoral immune responses. Generation of polyfunctional CD8(+) T cell was observed in vaccinated groups, which is one of the most important prerequisite for successful vaccination against VL. Protection was accompanied with generation of antigen specific CD4(+) and CD8(+) cells that produced effector cytokines such as IFN-γ, IL-2 and TNF-α. KMP-11-DNA/rVV vaccination also developed strong cytotoxic response and reversed T-cell impairment to induce antigen specific T cell proliferation.
KMP-11 is a unique antigen with high epitope density. Heterologous prime boost vaccination activates CD4(+) and CD8(+) T-cell mediated immunity to confer resistance to VL. This immunization method also produces high quality T-cells secreting multiple effector cytokines thus enhancing durability of the immune response. Thus the vaccination regime as described in the present study could provide a potent strategy for future anti-leishmanial vaccine development.
常见药物耐药性的出现对内脏利什曼病（VL）的治疗构成了重大威胁，尤其是在印度次大陆。由于缺乏针对 VL 的许可疫苗，因此迫切需要开发一种有效的替代疫苗接种策略。
我们使用金葡菌膜蛋白-11（KMP-11）DNA 进行初免，然后用表达相同抗原的重组牛痘病毒（rVV）进行加强，开发了一种新的异源初免-加强免疫接种策略。在耐锑（Sb-R）和敏感（Sb-S）利什曼原虫（L.）引起的小鼠和仓鼠内脏利什曼病模型中，检测了这种疫苗接种方案的疗效。
异源初免-加强（KMP-11 DNA/rVV）接种可保护小鼠和仓鼠免受 Sb-S 和 Sb-R-L 引起的实验性 VL。（L.）。在仓鼠中，即使在感染后 60 天，接种组的寄生虫负荷也保持明显较低，而仓鼠对 VL 非常敏感。在小鼠中的保护与强烈的细胞和体液免疫反应相关。在接种组中观察到产生多功能 CD8（+）T 细胞，这是成功接种 VL 的最重要前提之一。保护伴随着产生抗原特异性 CD4（+）和 CD8（+）细胞，这些细胞产生效应细胞因子，如 IFN-γ、IL-2 和 TNF-α。KMP-11-DNA/rVV 接种还产生了强烈的细胞毒性反应，并逆转了 T 细胞损伤，以诱导抗原特异性 T 细胞增殖。
KMP-11 是一种具有高表位密度的独特抗原。异源初免加强接种激活 CD4（+）和 CD8（+）T 细胞介导的免疫，从而对 VL 产生抵抗力。这种免疫接种方法还产生了高质量的 T 细胞，分泌多种效应细胞因子，从而增强免疫反应的持久性。因此，本研究中描述的免疫接种方案可为未来抗利什曼病疫苗的开发提供一种有力的策略。
