A nanoparticle-based vaccine against leishmaniasis

基于纳米颗粒的利什曼病疫苗

• 批准号: 8318569
• 负责人: Diane McMahon Pratt
• 金额: $ 29.4万
• 依托单位: L2 DIAGNOSTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8318569
• 关键词: Acute; Adjuvant; Adverse effects; Affect; Afghanistan; American Leishmaniasis; Amphotericin; Antigen Presentation; Antigens; Antimony; Area; Brazil; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Child; Chronic; Contracts; Costa Rica; Country; Cutaneous; Cutaneous Leishmaniasis; Cyclic GMP; Developing Countries; Development; Diffuse; Disease; Dose; Drosophila genus; Drug Formulations; Drug resistance; Encapsulated; Escherichia coli; Glycolates; Greece; Guatemala; Human; Human Resources; Immune response; Immunity; Immunization; Individual; Infection; Inferior; Interferon Type II; Interleukin-10; Interleukin-13; Interleukin-2; Iraq; Israel; Leishmania; Leishmaniasis; Life; Mediating; Memory; Methods; Mexico; Military Personnel; Miltefosine; Modeling; Mus; Oligonucleotides; Parasites; Parasitic Diseases; Patients; Pharmaceutical Preparations; Phase; Policies; Procedures; Production; Proteins; Recombinants; Red Cross; Regimen; Relapse; Risk; Study models; Subunit Vaccines; T cell response; T-Lymphocyte; TNF gene; Testing; Travel; Treatment Failure; United States; Vaccines; Viannia; Viral; Viral Antigens; Visceral; West Nile virus; Zoonoses; base; disease transmission; efficacy testing; immunogenicity; milligram; monophosphoryl lipid A; mouse model; nanoparticle; nonhuman primate; particle; prevent; prophylactic; response; therapeutic vaccine; trend; vaccine development; vaccine efficacy

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.

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。该疫苗将包含两种蛋白质抗原，TSA/TryP和P-4。这两种抗原在利什曼原虫属物种中高度保守，被人类患者的T细胞识别，并在鼠模型研究中赋予针对活攻击的保护。我们期望使用PLGA纳米颗粒与这两种蛋白质一起进行免疫将赋予针对由许多利什曼原虫属物种引起的疾病的保护。将表达的TSA/TryP和P-4蛋白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）。将评价不同制剂在小鼠中的免疫原性和免疫应答（记忆）持续时间。我们预期包封在PLGA颗粒中的蛋白质将引发持久的免疫应答。已显示针对利什曼原虫的保护主要由T细胞介导，特别是对IL-2、TNF α和IFN-γ呈双阳性或三阳性的CD 4 +/CD 8 + T细胞。我们将选择引发最高比例的应答性CD 4/CD 8 T细胞的两种制剂。然后将在两种利什曼病鼠模型中测试这两种制剂的功效。第一个模型是一个挑战与L。主要的，主要的物种负责利什曼病在旧世界。第二种模式是感染L.（Viannia）panamensis，新世界利什曼病的模型，可能是一种更严格的疫苗效力测试。在该项目的第二阶段，我们预计在非人灵长类动物利什曼病模型中测试最有前途的制剂的疗效。