A nanoparticle-based vaccine against leishmaniasis

描述（由申请人提供）：我们建议开发一种抗皮肤利什曼病的重组亚单位疫苗。这种疫苗将包含两种蛋白抗原，TSA/TryP和P-4。这两种抗原在利什曼原虫物种中高度保守，被人类患者的T细胞识别，并在小鼠模型研究中赋予抗活攻击的保护作用。我们预计，使用PLGA纳米颗粒和这两种蛋白质的免疫将赋予对许多利什曼原虫物种引起的疾病的保护。重组表达的TSA/TryP和P-4蛋白将被配制成含有两种佐剂之一的PLGA纳米颗粒，即CpG寡核苷酸和/或单磷酰脂质a （MPLA）。不同的配方将被评估免疫原性和免疫反应（记忆）的持续时间在小鼠。我们预计包裹在PLGA颗粒中的蛋白质将引发持久的免疫反应。对利什曼原虫的保护已被证明主要由t细胞介导，特别是CD4+/CD8+ t细胞对IL-2、TNFalpha和ifn - γ呈双阳性或三阳性。我们将选择引起CD4/CD8 T细胞应答比例最高的两种配方。然后将在两种利什曼病小鼠模型中测试这两种制剂的功效。第一种模式是对大利什曼杆菌的挑战，大利什曼杆菌是旧大陆造成利什曼病的主要物种。第二种模型是巴拿马L. （Viannia）感染，这是新世界利什曼病的一种模型，可能是对疫苗效力的更严格的测试。在该项目的第二阶段，我们预计将在非人类利什曼病灵长类动物模型中测试最有希望的配方的功效。

DESCRIPTION (provided by applicant): We propose to develop a recombinant subunit vaccine against cutaneous leishmaniasis. This vaccine will incorporate two protein antigens, TSA/TryP and P-4. Both antigens are highly conserved among Leishmania species, are recognized by T cells of human patients, and confer protection against a live challenge in murine model studies. We expect that immunization using PLGA nanoparticles together with these two proteins will confer protection against disease caused by many of the Leishmania species. Recombinantly expressed TSA/TryP and P-4 proteins will be formulated into PLGA nanoparticles containing one of two adjuvants, namely a CpG oligonucleotide and/or monophosphoryl lipid A (MPLA). Different formulations will be evaluated for immunogenicity and duration of the immune response (memory) in mice. We expect that proteins encapsulated in PLGA particles will elicit long-lasting immune responses. Protection against Leishmania has been shown to be mediated primarily by T-cells, and in particular CD4+/CD8+ T-cells double-positive or triple-positive for IL-2, TNFalpha, and IFN-gamma. We will select the two formulations eliciting the highest proportion responding CD4/CD8 T cells. These two formulations will then be tested for efficacy in two murine models of leishmaniasis. The first model is a challenge with L. major, the main species responsible for leishmaniasis in the Old World. The second model is an infection with L. (Viannia) panamensis, a model for New World leishmaniasis and possibly a more stringent test of vaccine efficacy. In Phase II of this project, we anticipate testing the efficacy of the most promising formulation in non-human primate models of leishmaniasis.