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，世界上有超过3.5亿人有患利什曼病的风险，感染率为1400万人。每年有200万人感染利什曼原虫，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，超过2500名美国军事人员被诊断患有皮肤利什曼病（CL）。目前基于非免疫的治疗是低效的、高毒性的、昂贵的，并且没有临床使用的疫苗。重要的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。必须解决两个重大的科学知识差距：1）可以进入皮肤驻留树突状细胞（DC）的疫苗，以及2）鉴定与人类生物学相关的利什曼原虫抗原。基于针的疫苗绕过这些免疫力强的皮肤细胞。 该提案的长期目标是开发基于纳米级聚合物体的疫苗，其通过经滤泡免疫（transfollicular immunization，TFI）将抗原和佐剂递送至皮肤树突细胞。我们将表征Toll样受体7/8激动剂瑞喹莫特（RSQ）整合到聚合物囊泡膜和封装模型利什曼原虫抗原，利什曼原虫同源物的受体活化C激酶（LACK），到水核心的可行性。然后，我们将评估其在体内产生TH 1型细胞因子谱和功能性细胞毒性CD 8 + T细胞方面的功能特性。我们假设可以以逐步的方式实现LACK和RSQ到纳米疫苗中的共包封，并且所得纳米疫苗将穿透毛囊并激活皮肤DC。我们还假设这种纳米疫苗的局部施用将诱导LACK特异性T细胞应答。最后，我们假设这种纳米疫苗将在仓鼠模型中保护免受内脏利什曼原虫菌株的攻击。目的1构建包裹LACK抗原和TLR 7/8激动剂RSQ的纳米疫苗。目的2确定LACK/RSQ纳米疫苗穿透毛囊导管、激活皮肤DC并诱导LACK特异性适应性免疫应答的最佳理化性质。目的3确定LACK/RSQ-纳米疫苗是否在体内诱导保护性免疫应答。 我们预计从该提案中产生的数据将导致商业上可行的局部纳米疫苗，其可以通过transfollicular途径进入皮肤DC。NIAID支持免疫介导的疾病（如利什曼病）的基础、临床前和临床研究以及有效疫苗的开发。SBIR第一阶段计划中提出的目标与NIAID的使命声明一致。 公共卫生相关性：世界卫生组织估计，全球有超过3.5亿人面临患上利什曼病的风险，感染率为1400万人。每年有200万人感染利什曼原虫，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，通过毛囊导管输送疫苗有效载荷，以刺激皮肤免疫细胞，所有这些都不需要针头。利什曼原虫疫苗设计的这一重大进展可能提供第一种有效的利什曼原虫疫苗，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工作岗位。