Supramolecular nanofiber vaccines

 说明(申请人提供)：虽然疫苗是医学上的成就之一，但尚未开发出针对许多毁灭性疾病的高效疫苗，包括疟疾、癌症、艾滋病毒/艾滋病或结核病，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T细胞记忆和抗体反应的特异性和表型，这一多样性是困难的 以目前可用的有限的给药系统和佐剂武器库实现。该项目涉及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，将专注于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。由于它们的模块化非共价结构，以及能够整合各种不同剂量的不同抗原和免疫刺激化合物，我们假设这些材料可以快速和系统地进行调整，以独立地优化B细胞和T细胞反应的强度和表型。对于FDA批准的佐剂选择有限的当前亚单位疫苗、全生物疫苗，甚至其他自组装系统，T和B细胞反应的独立调节受到更多限制。此外，我们最近发现，与其他临床和研究佐剂相比，多肽纳米纤维可以激发强烈的T细胞和B细胞反应，但它们在免疫部位不会引起明显的炎症反应。这些纳米纤维的活性需要通过MyD88发出信号，尽管它们通过这一途径具有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。第一个是阐明自组装肽纳米纤维如何刺激T细胞(Aim 1)和B细胞(Aim 2)的强烈免疫反应的机制。T细胞激活的工作模式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提呈细胞(APC)，并且它们只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/抗体反应的工作模式是，Q11纳米纤维激活补体，并通过补体受体2(CR2)最初与边缘带B细胞接合，后者将Q11抗原运送到B细胞滤泡，在那里它们与抗原特异性B细胞接合。第二个目标是为纳米纤维系统设计新的功能，包括包括折叠蛋白抗原的新方法，包括特定数量的选定TLR激动剂的方法，以及刺激CD8T细胞反应的策略。结合新材料和获得的机理洞察力，我们将反复提炼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.