Supramolecular nanofiber vaccines

超分子纳米纤维疫苗

• 批准号: 9217567
• 负责人: Anita S Chong
• 金额: $ 61.16万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9217567
• 关键词: Adaptor Signaling Protein; Adjuvant; Adverse effects; Agonist; Antibody Affinity; Antibody Response; Antigen-Presenting Cells; Antigens; Attention; Attenuated; Autoantigens; B-Lymphocytes; Biomedical Engineering; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Clinical; Collaborations; Complement; Complement 3d Receptors; Cross Presentation; Data; Dendritic Cells; Development; Disease; Dose; Engineering; FDA approved; Formulation; Generations; Goals; HIV; Health; Heterogeneity; Human; Immune response; Immunization; Immunoglobulin Class Switching; Immunologist; Immunology; Inflammation; Influenza; Injection of therapeutic agent; Investigation; Knock-in; Lead; Malaria; Malignant Neoplasms; Measurable; Medicine; Methicillin Resistance; Modeling; Mus; Operative Surgical Procedures; Particulate; Pathway interactions; Peptides; Phenotype; Poliomyelitis; Population; Production; Property; Protein Engineering; Proteins; Publishing; Receptors, Antigen, B-Cell; Research; Safety; Signal Pathway; Signal Transduction; Site; Smallpox; Specificity; Staphylococcus aureus; Subunit Vaccines; System; T cell response; T memory cell; T-Cell Activation; T-Lymphocyte; Tail; Technology; Testing; Time; Toxic effect; Tuberculosis; United States; Vaccinated; Vaccine Design; Vaccines; Whole Organism; Work; aluminum sulfate; base; clinical investigation; cost; cutinase; design; flexibility; immunogenicity; improved; in vivo; influenza virus vaccine; insight; killings; learning materials; lymph nodes; nanoassembly; nanofiber; novel; novel vaccines; pathogen; prevent; protein folding; public health relevance; response; seasonal influenza; self assembly; uptake; vaccine development

 DESCRIPTION (provided by applicant): Although vaccines represent one of the triumphs of medicine, highly effective vaccines have not yet been developed for many devastating diseases, including malaria, cancer, HIV/AIDs or tuberculosis, nor is there a universal vaccine for influenza. Each of these diseases requires a differently tuned immune response, with unique specificities and phenotypes of T cell memory and antibody responses, a diversity that is difficult to achieve with the limited arsenal of delivery systems and adjuvants that is currently available. This project, which involves a close collaboration between research groups led by a bioengineer and a basic immunologist, will focus on the development of a potentially new vaccine platform that is based on antigenic peptides and proteins that are designed to self-assemble into nanofiber materials. By virtue of their modular non-covalent construction and ability to incorporate a wide variety and dose of different antigens and immunostimulating compounds, we posit that these materials can be quickly and systematically tuned to independently optimize both the strength and phenotype of B cell and T cell responses. Independent tuning of T and B cell responses is more limited for current subunit vaccines with a limited choice of FDA-approved adjuvants, for whole-organism vaccines, or even for other self-assembling systems. Furthermore, we have recently found that peptide nanofibers elicit strong T cells and B cell response, yet they elicit no discernable inflammation at the site of immunization, which is in contrast with other clinical and investigational adjuvants. These nanofibers require signaling through MyD88 for their activity, although the full mechanism of their immunogenicity through this pathway has not yet been elucidated. Accordingly, this project consists of two integrated goals. The first is to elucidate the mechanism of how self- assembled peptide nanofibers stimulate strong immune responses, for T cells (Aim 1) and B cells (Aim 2). The working model of T cell activation is that self-assembling nanofibers stimulate antigen-presenting cells (APCs) via signaling pathways that require the adaptor protein, MyD88, and that they activate only the dendritic cells (DCs) in the draining lymph nodes that acquire the nanofibers. In contrast, particulate adjuvants such as alum activate broader populations of APCs at the injection site. The working model for the stimulation of B cell/antibody responses is that Q11 nanofibers activate complement and initially engage, via complement receptor 2 (CR2), marginal zone B cells that shuttle antigen-Q11 to the B cell follicles where they engage antigen-specific B cells. The second goal is to design new capabilities into the nanofiber system, including a novel means for including folded protein antigens, ways to include specific amounts of selected TLR agonists, and strategies to stimulate CD8+ T cell responses. Combining the new materials and mechanistic insight acquired, we will iteratively refine and test multi-antigen self-assemblies as vaccines against influenza in mice.

 描述（申请人提供）：虽然疫苗代表了医学的胜利之一，但针对许多毁灭性疾病，包括疟疾、癌症、艾滋病毒/艾滋病或结核病，尚未开发出高效的疫苗，也没有针对流感的通用疫苗。这些疾病中的每一种都需要不同的免疫反应，具有独特的特异性和 T 细胞记忆和抗体反应的表型，这种多样性是困难的 利用目前可用的有限的递送系统和佐剂来实现。该项目涉及由生物工程师和基础免疫学家领导的研究小组之间的密切合作，将重点开发一种潜在的新疫苗平台，该平台基于抗原肽和蛋白质，旨在自组装成纳米纤维材料。凭借其模块化非共价结构以及整合多种不同剂量的不同抗原和免疫刺激化合物的能力，我们认为这些材料可以快速、系统地调整，以独立优化 B 细胞和 T 细胞反应的强度和表型。对于目前 FDA 批准的佐剂选择有限的亚单位疫苗、整个生物体疫苗，甚至其他自组装系统，T 和 B 细胞反应的独立调节更加有限。此外，我们最近发现肽纳米纤维会引起强烈的 T 细胞和 B 细胞反应，但它们在免疫部位没有引起明显的炎症，这与其他临床和研究佐剂相反。这些纳米纤维的活性需要通过 MyD88 信号传导，尽管其通过该途径产生免疫原性的完整机制尚未阐明。因此，该项目由两个综合目标组成。首先是阐明自组装肽纳米纤维如何刺激 T 细胞（目标 1）和 B 细胞（目标 2）的强烈免疫反应的机制。 T 细胞激活的工作模型是自组装纳米纤维通过需要接头蛋白 MyD88 的信号通路刺激抗原呈递细胞 (APC)，并且它们仅激活获得纳米纤维的引流淋巴结中的树突状细胞 (DC)。相比之下，明矾等颗粒佐剂可在注射部位激活更广泛的 APC 群体。刺激 B 细胞/抗体反应的工作模型是 Q11 纳米纤维激活补体，并首先通过补体受体 2 (CR2) 与边缘区 B 细胞结合，将抗原 Q11 运送到 B 细胞滤泡，在那里它们与抗原特异性 B 细胞结合。第二个目标是为纳米纤维系统设计新功能，包括包含折叠蛋白抗原的新方法、包含特定量的选定 TLR 激动剂的方法以及刺激 CD8+ T 细胞反应的策略。结合新材料和获得的机制见解，我们将迭代完善和测试多抗原自组装体作为小鼠流感疫苗。