A transfollicular nanovaccine against leishmaniasis

抗利什曼病的经滤泡纳米疫苗

• 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
• 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

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，全球有超过 3.5 亿人面临罹患利什曼病的风险，感染率达 1,400 万人。每年有 200 万人感染利什曼原虫，其中 27 万人死亡。利什曼病是当今影响美国军队最重要的寄生虫病之一，超过 2500 名美国军人被诊断患有皮肤利什曼病 (CL)。目前的非免疫治疗方法效果参差不齐，毒性高，价格昂贵，而且没有疫苗投入临床使用。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）能够接触皮肤驻留树突状细胞（DC）的疫苗，2）鉴定与人类生物学相关的利什曼原虫抗原。基于针头的疫苗绕过了这些具有免疫能力的皮肤细胞。 该提案的长期目标是开发一种基于纳米级聚合物囊泡的疫苗，通过滤泡免疫（TFI）将抗原和佐剂递送至皮肤树突状细胞。我们将描述将 Toll 样受体 7/8 激动剂瑞西莫德 (RSQ) 整合到聚合物囊膜中并将模型利什曼原虫抗原（激活 C 激酶 (LACK) 受体的利什曼原虫同源物）封装到水核中的可行性。然后我们将评估其在体内产生 TH1 型细胞因子谱和功能性细胞毒性 CD8+ T 细胞的功能特性。我们假设LACK和RSQ共封装到纳米疫苗中可以以逐步的方式实现，并且所得的纳米疫苗将渗透毛囊并激活皮肤DC。我们还假设局部施用这种纳米疫苗将诱导 LACK 特异性 T 细胞反应。最后，我们假设这种纳米疫苗将在仓鼠模型中防止内脏利什曼原虫菌株的攻击。目的 1 构建封装抗原 LACK 和 TLR7/8 激动剂 RSQ (LACK/RSQ-NPS) 的纳米疫苗。目标 2 确定 LACK/RSQ 纳米疫苗穿透毛囊管、激活皮肤 DC 并诱导 LACK 特异性适应性免疫反应的最佳理化特性。目标 3 确定 LACK/RSQ-纳米疫苗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产生一种商业上可行的局部纳米疫苗，可以通过滤泡途径进入皮肤树突状细胞。 NIAID 支持利什曼病等免疫介导疾病的基础、临床前和临床研究以及有效疫苗的开发。 SBIR 第一阶段计划提出的目标与 NIAID 的使命宣言一致。 公共卫生相关性：世界卫生组织估计，全球有超过 3.5 亿人面临罹患利什曼病的风险，感染率达 1,400 万人。每年有 200 万人感染利什曼原虫，其中 27 万人死亡。利什曼病是当今影响美国军队的最重要的寄生虫病之一。我们计划开发一种针对利什曼原虫的纳米疫苗，通过毛囊管输送疫苗有效负载，刺激皮肤免疫细胞，而无需使用针头。利什曼原虫疫苗设计的这一重大进步可能会提供第一种针对利什曼原虫的有效疫苗，并将通过美国军事合同和利什曼病国家的国际政府合同在美国创造生物技术就业岗位。