Glucan Particles as a Vaccine Platform for Protective Immunity

葡聚糖颗粒作为保护性免疫的疫苗平台

基本信息

批准号：
8715685
负责人：
Stuart Michael Levitz
金额：
$ 54.22万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-06 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8715685
关键词：
Address Adjuvant Adjuvanticity Afferent Pathways Agonist Antibodies Antibody Formation Antigens B-Lymphocytes CD4 Positive T Lymphocytes Cell Shape Cell Wall Cells Clinical Complement Complement Activation Complement Receptor Complex DNA Dendritic Cells Development Disease Drug Formulations Elderly Encapsulated Event FDA approved Funding Fungal Antigens Glucans Histoplasma capsulatum Histoplasmosis Human Immune Immune response Immune system Immunity Immunization Immunocompetent Immunocompromised Host Individual Infection Inflammation Inflammatory Injection of therapeutic agent Lead Licensing Ligands Limb structure Mediator of activation protein Memory Microcapsules drug delivery system Mus Mycoses Nature Pathway interactions Phagocytes Pharmacologic Substance Phase Population Populations at Risk Recombinants Saccharomyces cerevisiae Shapes Small Interfering RNA System T cell response T-Lymphocyte T-Lymphocyte Subsets Testing Translations United States National Institutes of Health Vaccinated Vaccination Vaccine Research Vaccines Work Yeasts arm base dectin 1 design fungus immunogenicity improved lymph nodes migration neoplastic novel strategies novel vaccines particle public health relevance receptor research study response uptake vaccine development vaccine-induced immunity vaccinology

项目摘要

DESCRIPTION (provided by applicant): This proposal is focused on developing glucan particles (GPs) as a novel vaccine platform and adjuvant that promotes protective T cell and antibody responses. GPs are hollow, highly purified yeast cell walls composed predominantly of ?-1,3-glucan. Preliminary studies demonstrate robust and long-lasting adaptive T cell and antibody responses following immunization of mice with GPs "loaded" with antigen. Moreover, mice vaccinated with GPs containing antigen from Histoplasma capsulatum (Hc) survive otherwise lethal experimental histoplasmosis. The experiments will address the central hypothesis that antigen-loaded GPs make effective vaccine platforms by alerting the immune system to the presence of "danger", directing antigens into DCs and stimulating protective adaptive T and B cell responses. It is further hypothesized that the immune response can be beneficially manipulated by the addition to the GP platform of other adjuvants, such as TLR agonists and siRNA targeting negative regulators of inflammation. Aim 1 is to decipher the afferent pathways stimulated by GPs that shape T cell and antibody responses. The hypothesis to be tested is "administration of GPs containing encased Ag results in complement activation, uptake by DCs via complement receptors and Dectin-1, migration of DCs containing GPs to draining lymph nodes and stimulation of a robust adaptive immune response including antibody and Th1/Th17-biased CD4+ T cell responses". Aim 2 is to investigate the efferent mechanisms by which fungal antigens complexed in GPs protect against Hc infection in mice. The hypothesis to be tested is "uptake of antigen-bearing GPs by DCs shapes the immune response to generate a protective Th1 and/or Th17 response". Aim 3 is to explore novel approaches to boosting the immunogenicity of the GP platform. The hypothesis to be tested is "the capacity of GP-formulated vaccines to protect against challenge with Hc can be augmented by specific stimulators of the innate immune response". We anticipate that at the end of the funding period, we will have created GP-based vaccines using FDA- approved materials capable of eliciting robust and durable antibody and Th1-/Th17-biased responses that protect immunocompetent and immunocompromised mice against challenge with Hc. Moreover, we anticipate that by altering the composition of the vaccines (such as by the addition of TLR ligands or siRNA), we will positively impact the nature of the responses. The studies address an NIH-identified need for development of a vaccine to protect immunocompromised and immunocompetent individuals in endemic regions from histoplasmosis. In addition, the studies should establish a proof of principle regarding the efficacy of GP-based vaccine platforms that should be applicable to other vaccine-preventable diseases and form the basis for eventual testing in humans.

描述（由申请人提供）：该提案的重点是开发葡聚糖颗粒（GP）作为新型疫苗平台和佐剂，促进保护性 T 细胞和抗体反应。 GP 是中空的、高度纯化的酵母细胞壁，主要由 β-1,3-葡聚糖组成。初步研究表明，用“装载”抗原的 GP 对小鼠进行免疫后，会产生强大且持久的适应性 T 细胞和抗体反应。此外，接种含有荚膜组织胞浆菌 (Hc) 抗原的 GP 疫苗的小鼠可以在致命的实验性组织胞浆菌病中存活下来。这些实验将解决一个中心假设，即负载抗原的 GP 通过警告免疫系统“危险”的存在、将抗原引导至 DC 并刺激保护性适应性 T 和 B 细胞反应，从而成为有效的疫苗平台。进一步假设，通过在 GP 平台中添加其他佐剂（例如 TLR 激动剂和针对炎症负调节因子的 siRNA），可以有益地控制免疫反应。目标 1 是破译 GP 刺激的传入通路，从而形成 T 细胞和抗体反应。要测试的假设是“施用含有包裹 Ag 的 GP 会导致补体激活，DC 通过补体受体和 Dectin-1 摄取，含有 GP 的 DC 迁移至引流淋巴结，并刺激包括抗体和 Th1 在内的强大适应性免疫反应/Th17 偏向 CD4+ T 细胞反应”。目标 2 是研究 GP 中复合的真菌抗原保护小鼠免受 Hc 感染的传出机制。待检验的假设是“DC 摄取携带抗原的 GP 塑造免疫反应，从而产生保护性 Th1 和/或 Th17 反应”。目标 3 是探索增强 GP 平台免疫原性的新方法。待测试的假设是“GP 配制的疫苗抵御 Hc 攻击的能力可以通过先天免疫反应的特定刺激剂来增强”。我们预计，在资助期结束时，我们将使用 FDA 批准的材料创建基于 GP 的疫苗，这些材料能够引发强大而持久的抗体和 Th1-/Th17 偏向反应，保护免疫功能正常和免疫功能低下的小鼠免受 Hc 的攻击。此外，我们预计通过改变疫苗的成分（例如添加 TLR 配体或 siRNA），我们将对反应的性质产生积极影响。这些研究解决了 NIH 确定的开发疫苗的需求，以保护流行地区免疫功能低下和免疫功能正常的个体免受组织胞浆菌病的侵害。此外，这些研究应建立关于基于 GP 的疫苗平台功效的原则证明，该平台应适用于其他疫苗可预防的疾病，并构成最终人体测试的基础。