From mouse to man: safety, immunogenicity and efficacy of a candidate leishmaniasis vaccine LEISH-F3+GLA-SE
From mouse to man: safety, immunogenicity and efficacy of a candidate leishmaniasis vaccine LEISH-F3+GLA-SE
复制标题
DOI：
10.1038/cti.2015.6
复制
发表时间：
2015-04-01
影响因子：
5.8
通讯作者：
Reed, Steven G.
中科院分区：
文献类型：
--
作者：
Coler, Rhea N.;Duthie, Malcolm S.;Reed, Steven G.
利什曼原虫属物种的关键抗原确定在宿主反应的背景下，在利什曼原虫暴露的个人从疾病流行区的优先发展的亚单位疫苗内脏利什曼病（VL），最致命的形式的利什曼病。两个利什曼原虫蛋白质核苷水解酶和甾醇24-C-甲基转移酶，其中每一个都是保护动物模型的VL时，适当的佐剂，作为一个单一的重组融合蛋白NS（LEISH-F3）的抗原生产和广泛的覆盖面的异质性主要组织相容性复合体人口容易产生。当与吡喃葡萄糖基脂质A稳定的水包油纳米乳剂（GLA-SE）（Toll样受体4 T（H）1（T辅助细胞1）促进纳米乳剂佐剂）一起配制时，LEISH-F3多蛋白诱导针对两种L. donovani和L.在小鼠的婴儿期，测量为肝脏寄生虫负荷的显著减少。在免疫小鼠中诱导了对疫苗各组分的强烈免疫应答，具有多功能CD 4 T（H）1细胞应答，其特征在于产生抗原特异性干扰素-γ、肿瘤坏死因子和白细胞介素-2（IL-2），以及低水平的IL-5和IL-10。我们还证明，CD 4 T细胞，而不是CD 8 T细胞，足以保护免受L。免疫小鼠的Donovani感染。基于临床前数据的总和，我们准备了GMP材料，并在美国健康未感染成人中进行了LEISH-F3+ GLA-SE的I期临床研究。候选疫苗被证明是安全的，并诱导强烈的抗原特异性免疫应答，如细胞因子和免疫球蛋白亚类数据所证明的。这些数据为在利什曼病流行国家对易感染VL的人群进行额外试验提供了强有力的依据。
Key antigens of Leishmania species identified in the context of host responses in Leishmania-exposed individuals from disease-endemic areas were prioritized for the development of a subunit vaccine against visceral leishmaniasis (VL), the most deadly form of leishmaniasis. Two Leishmania proteins-nucleoside hydrolase and a sterol 24-c-methyltransferase, each of which are protective in animal models of VL when properly adjuvanted-were produced as a single recombinant fusion protein NS (LEISH-F3) for ease of antigen production and broad coverage of a heterogeneous major histocompatibility complex population. When formulated with glucopyranosyl lipid A-stable oil-in-water nanoemulsion (GLA-SE), a Toll-like receptor 4 T(H)1 (T helper 1) promoting nanoemulsion adjuvant, the LEISH-F3 polyprotein induced potent protection against both L. donovani and L. infantum in mice, measured as significant reductions in liver parasite burdens. A robust immune response to each component of the vaccine with polyfunctional CD4 T(H)1 cell responses characterized by production of antigen-specific interferon-gamma, tumor necrosis factor and interleukin-2 (IL-2), and low levels of IL-5 and IL-10 was induced in immunized mice. We also demonstrate that CD4 T cells, but not CD8 T cells, are sufficient for protection against L. donovani infection in immunized mice. Based on the sum of preclinical data, we prepared GMP materials and performed a phase 1 clinical study with LEISH-F3+ GLA-SE in healthy, uninfected adults in the United States. The vaccine candidate was shown to be safe and induced a strong antigen-specific immune response, as evidenced by cytokine and immunoglobulin subclass data. These data provide a strong rationale for additional trials in Leishmania-endemic countries in populations vulnerable to VL.