Coler Rhea N, Goto Yasuyuki, Bogatzki Lisa, Raman Vanitha, Reed Steven G
Infectious Disease Research Institute, 1124 Columbia St., Suite 400, Seattle, WA 98104, USA.
Infect Immun. 2007 Sep;75(9):4648-54. doi: 10.1128/IAI.00394-07. Epub 2007 Jul 2.
The Leishmania-derived recombinant polyprotein Leish-111f or its three component proteins, thiol-specific antioxidant (TSA), Leishmania major stress-inducible protein 1 (LmSTI1), and Leishmania elongation initiation factor (LeIF), have previously been demonstrated to be efficacious against cutaneous or mucosal leishmaniasis in mice, nonhuman primates, and humans. In this study we demonstrate that Leish-111f is also a vaccine antigen candidate against visceral leishmaniasis (VL) caused by Leishmania infantum. We evaluated the immune response and protection induced by Leish-111f formulated with monophosphoryl lipid A in a stable emulsion (Leish-111f+MPL-SE) and demonstrated that mice developed strong humoral and T-cell responses to the vaccine antigen. Analysis of the cellular immune responses of immunized, uninfected mice demonstrated that the vaccine induced a significant increase in CD4(+) T cells producing gamma interferon, interleukin 2, and tumor necrosis factor cytokines, indicating a Th1-type immune response. Experimental infection of immunized mice and hamsters demonstrated that Leish-111f+MPL-SE induced significant protection against L. infantum infection, with reductions in parasite loads of 99.6%, a level of protection greater than that reported for other vaccine candidates in animal models of VL. Taken together, our results suggest that this vaccine represents a good candidate for use against several Leishmania species. The Leish-111f+MPL-SE product we report here is the first defined vaccine for leishmaniasis in human clinical trials and has completed phase 1 and 2 safety and immunogenicity testing in normal, healthy human subjects.
利什曼原虫衍生的重组多蛋白Leish-111f或其三种组成蛋白，即硫醇特异性抗氧化剂（TSA）、硕大利什曼原虫应激诱导蛋白1（LmSTI1）和利什曼原虫延伸起始因子（LeIF），先前已被证明对小鼠、非人灵长类动物和人类的皮肤或黏膜利什曼病有效。在本研究中，我们证明Leish-111f也是一种针对婴儿利什曼原虫引起的内脏利什曼病（VL）的疫苗抗原候选物。我们评估了用单磷酰脂质A在稳定乳剂中配制的Leish-111f（Leish-111f+MPL-SE）诱导的免疫反应和保护作用，并证明小鼠对该疫苗抗原产生了强烈的体液和T细胞反应。对免疫的未感染小鼠的细胞免疫反应分析表明，该疫苗诱导产生γ干扰素、白细胞介素2和肿瘤坏死因子细胞因子的CD4(+) T细胞显著增加，表明是一种Th1型免疫反应。对免疫小鼠和仓鼠的实验性感染表明，Leish-111f+MPL-SE诱导了对婴儿利什曼原虫感染的显著保护作用，寄生虫载量降低了99.6%，这种保护水平高于在VL动物模型中报道的其他疫苗候选物。综上所述，我们的结果表明这种疫苗是针对几种利什曼原虫物种的良好候选物。我们在此报告的Leish-111f+MPL-SE产品是人类临床试验中首个明确的利什曼病疫苗，已在正常、健康的人类受试者中完成了1期和2期安全性及免疫原性测试。
