Supramolecular nanofiber vaccines

 描述（由申请人提供）：虽然疫苗代表了医学的胜利之一，但尚未开发出用于许多毁灭性疾病的高效疫苗，包括疟疾，癌症，HIV/AIDS或结核病，也没有通用的流感疫苗。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。 以目前可用的有限的输送系统和佐剂来实现。该项目涉及由一名生物工程师和一名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，旨在自组装成生物材料。由于它们的模块化非共价结构和掺入各种各样和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和系统地调节以独立地优化B细胞和T细胞应答的强度和表型。T和B细胞应答的独立调节对于具有有限选择的FDA批准的佐剂的当前亚单位疫苗、对于全生物体疫苗或甚至对于其它自组装系统来说更加有限。此外，我们最近发现肽纳米纤维引起强烈的T细胞和B细胞应答，但它们在免疫部位不引起可辨别的炎症，这与其他临床和研究佐剂形成对比。这些纳米纤维需要通过MyD 88进行信号传导以实现其活性，尽管尚未阐明其通过该途径的免疫原性的完整机制。因此，该项目包括两个综合目标。第一个是阐明自组装肽纳米纤维如何刺激强烈免疫反应的机制，针对T细胞（Aim 1）和B细胞（Aim 2）。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MyD 88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，颗粒佐剂如明矾在注射部位激活更广泛的APC群体。刺激B细胞/抗体应答的工作模型是Q11纳米纤维激活补体，并最初通过补体受体2（CR2）接合边缘区B细胞，边缘区B细胞将抗原Q11穿梭至B细胞滤泡，在那里它们接合抗原特异性B细胞。第二个目标是设计新的功能到CD 8 + T细胞系统中，包括用于包括折叠蛋白抗原的新方法，包括特定量的选定TLR激动剂的方法，以及刺激CD 8 + T细胞应答的策略。结合所获得的新材料和机械见解，我们将反复完善和测试多抗原自组装作为小鼠流感疫苗。

 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.