A transfollicular nanovaccine against leishmaniasis

抗利什曼病的经滤泡纳米疫苗

基本信息

批准号：
8199961
负责人：
Paiman Peter Ghoroghchian
金额：
$ 30万
依托单位：
VINDICO NANOBIOTECHNOLOGY, INC.
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-20 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8199961
关键词：
Activities of Daily Living Address Adjuvant Affect Agonist Antibodies Antigens Area Basic Science Biotechnology Bypass CD8B1 gene Cells Child Clinical Clinical Research Communicable Diseases Conflict (Psychology)Contracts Country Cream Cutaneous Leishmaniasis Data Dendritic Cells Dendritic cell activation Department of Defense Development Diagnosis Disease Dose Drug Formulations Duct (organ) structure Encapsulated Generations Goals Government Hair follicle structure Hamsters Heating Homologous Gene Human Immune Immune response Immune system Immunity Immunization Infection Infectious Skin Diseases International Kinetics Knowledge Lead Leishmania Leishmaniasis Life Mediating Membrane Methods Military Personnel Mission Modeling Monitor Mus National Institute of Allergy and Infectious Disease Needles Occupations Parasites Parasitic Diseases Pathway interactions Penetration Phase Prevalence Prevention strategy Property Regimen Resolution Risk Rodent Model Role Route Skin Small Business Innovation Research Grant Solubility System T cell response T-Lymphocyte TLR7 gene Technology Testing Topical application Translating Vaccination Vaccine Adjuvant Vaccine Design Vaccines Visceral Visceral Leishmaniasis World Health Organization aqueous base cancer prevention cytokine cytotoxic design disorder prevention human TLR7 protein immunogenic in vivo killings nanomaterials nanoparticle nanoscale novel pre-clinical research programs prophylactic receptors for activated C kinase resiquimod subcutaneous vaccine delivery

项目摘要

DESCRIPTION (provided by applicant): The World Health Organization estimates that over 350 million people are at risk of developing leishmaniasis and infection prevalence is 14 million people in the world. Annually, 2 million people are infected with Leishmania species and 270,000 will die. Leishmaniasis is one of the most important parasitic diseases affecting the U.S. military today, with over 2500 U.S. military personnel diagnosed with cutaneous leishmaniasis (CL). Current non-immunization based treatments are variably effective, highly toxic, expensive, and there are no vaccines in clinical use. Significant evidence has supported the role of the immune system in controlling Leishmania infection. Thus, a vaccination remains an attractive disease prevention strategy. Two significant scientific knowledge gaps must be addressed: 1) a vaccine that can access the skin resident dendritic cells (DCs), and 2) the identification of Leishmania antigens that are biologically relevant in humans. Needle based vaccines bypass these immunopotent skin cells. The long-term objective of this proposal is to develop a nanoscale polymersome-based vaccine that delivers an antigen and adjuvant to skin dendritic cells through transfollicular immunization (TFI). We will characterize the feasibility of integrating the Toll-like receptor 7/8 agonist resiquimod (RSQ) into the polymersome membrane and encapsulating a model Leishmania antigen, Leishmania homolog of receptors for activated C kinase (LACK), into the aqueous core. We will then evaluate its functional properties in generating a TH1-type cytokine profile and functional cytotoxic CD8+ T cells in vivo. We hypothesize that co-encapsulation of LACK and RSQ into the nanovaccine can be achieved in a stepwise manner and that the resulting nanovaccine will penetrate the follicle and activate skin DCs. We also hypothesize that the topical administration of this nanovaccine will induce a LACK-specific T cell response. Finally, we hypothesize that this nanovaccine will protect against challenge with a visceral Leishmania strain in a hamster model. AIM 1 Construct a nanovaccine encapsulating the antigen LACK and TLR7/8 agonist RSQ (LACK/RSQ-NPS). AIM 2 Determine the optimal physicochemical properties of LACK/RSQ-nanovaccine to penetrate the follicular duct, activate skin DCs, and induce a LACK-specific adaptive immune response. AIM 3 Determine if the LACK/RSQ-nanovaccine induces protective immune responses in vivo. We anticipate the data generated from this proposal will result in a commercially viable topical nanovaccine that can access skin DCs via the transfollicular route. The NIAID supports basic, preclinical, and clinical research on immune-mediated diseases such as leishmaniasis and the development of effective vaccines. The aims proposed in this SBIR Phase I program are consistent with the mission statement of the NIAID. PUBLIC HEALTH RELEVANCE: The World Health Organization estimates that over 350 million people are at risk of developing leishmaniasis and infection prevalence is 14 million people in the world. Annually, 2 million people are infected with Leishmania species and 270,000 will die. Leishmaniasis is one of the most important parasitic diseases affecting the U.S. military today. We plan to develop a nanovaccine against Leishmania that delivers the vaccine payload through the hair follicle duct to stimulate skin immune cells, all without a needle. This major advance in Leishmania vaccine design may provide the first effective vaccine against Leishmania and would create biotechnology jobs in the US via US military contracts and international government contracts in countries suffering from leishmaniasis.

描述（由申请人提供）：世界卫生组织估计，有超过3.5亿人有发展利什曼病和感染的风险，世界上有1400万人。每年，200万人感染了利什曼原虫，270,000人将死亡。利什曼病是今天影响美国军队的最重要的寄生虫病之一，有2500多名美国军事人员被诊断出患有皮肤利什曼病（CL）。当前的基于非免疫的治疗方法可变，有效，有毒，昂贵，并且在临床用途中没有疫苗。大量证据支持免疫系统在控制利什曼原虫感染中的作用。因此，疫苗接种仍然是一种有吸引力的疾病预防策略。必须解决两个重要的科学知识差距：1）一种可以进入皮肤常驻树突状细胞（DC）的疫苗，以及2）鉴定在人类生物学上相关的利什曼原虫抗原。基于针的疫苗绕过这些免疫细胞细胞。该提案的长期目标是开发一种基于纳米级的多晶疫苗，该疫苗通过转基因免疫（TFI）提供抗原和辅助对皮肤树突状细胞的辅助。我们将表征将类似Toll样受体的7/8激动剂重置（RSQ）整合到多聚膜膜中的可行性，并封装模型Leishmania抗原，Leishmania抗原，利什曼原虫同源物，用于激活的C激酶（Lav）的受体（Leishmania antimia antimia antimia抗原）。然后，我们将在体内评估其在生成Th1型细胞因子谱和功能性细胞毒性CD8+ T细胞中的功能特性。我们假设可以逐步实现缺乏和RSQ进入纳米酮，并且所得的纳米酮将穿透卵泡并激活皮肤DC。我们还假设该纳米酮的局部给药会引起缺乏特异性的T细胞反应。最后，我们假设这种纳米酮将通过仓鼠模型中的内脏利什曼原虫菌株来防止挑战。 AIM 1构建一种纳米霉素，封装了抗原缺乏和TLR7/8激动剂RSQ（LAV/RSQ-NPS）。 AIM 2确定缺乏/RSQ-纳诺维霉素的最佳物理化学特性，可以穿透卵泡管，激活皮肤DC并诱导缺乏特异性的适应性免疫反应。 AIM 3确定缺乏/rsq-nanovacine是否在体内诱导保护性免疫反应。我们预计该提案产生的数据将导致商业上可行的局部纳米酮，该纳米酮可以通过转基因途径访问皮肤DC。 NIAID支持有关免疫介导的疾病（如利什曼病）和有效疫苗的发展的基本，临床前和临床研究。 SBIR I期计划中提出的目标与NIAID的任务陈述一致。公共卫生相关性：世界卫生组织估计，有超过3.5亿人有发展利什曼病和感染的风险，世界上有1400万人。每年，200万人感染了利什曼原虫，270,000人将死亡。利什曼病是影响当今美国军队的最重要的寄生疾病之一。我们计划开发针对利什曼尼亚的纳米甲霉素，该纳米霉素通过毛囊管道提供疫苗有效载荷，以刺激皮肤免疫细胞，而无需针。利什曼尼亚疫苗设计中的这一重大进步可能会为利什曼尼亚提供首款有效的疫苗，并将通过美国军事合同和遭受利什曼病的国家的国际政府合同在美国创造生物技术工作。