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（由适用提供）：尽管疫苗代表了医学的胜利之一，但尚未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）开发出高效的疫苗，也没有一种普遍的影响疫苗。这些疾病中的每一个都需要不同调整的免疫响应，具有独特的规格和T细胞记忆和抗体反应的表型，这是困难的多样性 为了实现有限的武器库，目前可用的交付系统和调节器。该项目涉及由生物工程师和基本免疫学家领导的研究小组之间的密切合作，它将着重于开发潜在的新疫苗平台，该疫苗平台基于抗原辣椒和蛋白质，旨在自组装成纳米纤维材料。借助其模块化的非共价结构，并能够结合各种不同的抗原和免疫刺激化合物的能力，我们指出这些材料可以快速，系统地调节以独立优化B细胞和T细胞反应的强度和表型。对于当前的亚基疫苗，对FDA批准的调节器，全生物疫苗，甚至对于其他自组装系统的当前亚基疫苗，对T和B细胞反应的独立调整更为有限。此外，我们最近发现，胡椒纳米纤维会引起强烈的T细胞和B细胞反应，但它们在免疫抑制部位没有可见的炎症，这与其他临床和研究辅助剂相反。这些纳米纤维需要通过MyD88发出信号才能进行活性，尽管尚未阐明其通过该途径的免疫原性的全部机制。据此，该项目由两个综合目标组成。首先是阐明T细胞（AIM 1）和B细胞（AIM 2）的自组装肽纳米纤维如何刺激强烈的免疫反应的机制。 T细胞激活的工作模型是，自组装纳米纤维通过需要衔接蛋白MyD88的信号传导途径刺激抗原呈递细胞（APC），并且仅激活在排水淋巴结中获得的树突状细胞（DCS）。相反，诸如明矾之类的特殊佐剂在注射部位激活了更广泛的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，并最初通过补体受体2（CR2），边缘区B细胞，将抗原-Q11驶向B细胞福利的边缘区B细胞，并在其中吸收抗原特异性B细胞。第二个目标是在纳米纤维系统中设计新功能，包括一种新的手段，用于包括折叠蛋白抗原，包括特定量的选定TLR激动剂的方法以及刺激CD8+ T细胞反应的策略。结合了获得的新材料和机械洞察力，我们将迭代地完善并测试多抗原自组件，作为对小鼠影响影响流感的疫苗。