Design and characterization of biomimetic nanobiomaterials to elicit CD1-restricted T cell responses during sub-unit vaccination

仿生纳米生物材料的设计和表征，以在亚单位疫苗接种过程中引发 CD1 限制性 T 细胞反应

• 批准号: 10444924
• 负责人: Evan A. Scott
• 金额: $ 76.14万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10444924
• 关键词: Adjuvant; Antibody Response; Antigen Presentation; Antigens; Attenuated; Attenuated Vaccines; BCG Live; Bacterial Vaccines; Benchmarking; Biological Assay; Biomedical Engineering; Biomimetics; CD1 Antigens; Chronic; Collaborations; Combined Vaccines; Custom; Data; Engineering; Equilibrium; Family; Formulation; Genetic Polymorphism; Glycolates; Human; Hydrogels; Hydrophobicity; Immune response; Immune system; Immunity; Immunization; Immunologic Memory; Immunologics; Immunologist; Immunotherapeutic agent; Immunotherapy; In Vitro; Intranasal Administration; Lipids; Lung; Methodology; Methods; Micelles; Modeling; Mus; Mycobacterium tuberculosis; Mycolic Acid; Nanosphere; Nanostructures; Peptides; Phase; Polymers; Precipitation; Protein Isoforms; Proteins; Reproducibility; Research; Route; Safety; Subunit Vaccines; Sulfides; System; T cell response; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Toxic effect; Transgenic Mice; Transgenic Organisms; Tuberculosis; Tuberculosis Vaccines; Vaccinated; Vaccination; Vaccines; Virulent; aqueous; autoreactivity; base; cost; design; effector T cell; ethylene glycol; humanized mouse; immunoregulation; in vivo; in vivo evaluation; lipid transport; mouse model; nano; nanobiomaterial; nanoparticle; neglect; next generation; novel; pathogen; pathogenic bacteria; propylene; protective efficacy; recruit; targeted delivery; vaccination strategy; vaccine delivery; vaccine formulation; vaccine strategy

PROJECT SUMMARY Subunit vaccines combine immunodominant protein or peptide antigens from pathogens with select adjuvants, aiming to provide a more scalable, reproducible, low cost and rapid alternative to attenuated vaccines that contain live pathogens. Unfortunately, current subunit vaccines lack lipid antigens and rarely achieve the broad T cell responses required for lasting immunological memory and protection. In contrast, attenuated vaccines lack customization and scalability, but incorporate the entire pathogen to provide both protein and lipid antigens during immunization. This combination of lipid and protein antigens activates a broad spectrum of effector T cells, including conventional MHC-restricted T cells that respond to peptides and display considerable polymorphism, as well as nonpolymorphic CD1-restricted T cells that are directed against specific lipids. A more biomimetic strategy that simultaneously activates both lipid- and peptide-specific T cells may therefore show enhanced efficacy and control compared to subunit vaccines limited to protein antigens. The neglect of lipid antigens from current subunit vaccines and immunotherapies is primarily due to 1) difficulties in targeted delivery of lipids, and 2) a lack of suitable mouse models. In humans, the CD1 family consists of group 1 CD1 molecules (CD1a, CD1b, and CD1c) and the group 2 CD1 molecule CD1d. Mice, however, only express CD1d. This project, which involves a close collaboration between research groups led by a bioengineer and a basic immunologist, aims to overcome these obstacles by designing nanobiomaterials for enhanced dual delivery of both lipid and protein antigens in combination with adjuvants to induce CD1- and MHC- restricted T cell response in humanized CD1 transgenic (hCD1Tg) mice. To characterize, optimize and benchmark these novel nanobiomaterials against the most frequently used attenuated vaccine in the world, the bacillus Calmette-Guérin (BCG) tuberculosis (TB) vaccine, the following aims are proposed: In Aim 1, in vitro and in vivo approaches will identify the optimal nanobiomaterials and adjuvant combination for eliciting a combined CD1- and MHC-restricted T cell response. In Aim 2, a lipid/protein multi-antigen approach will be validated in hCD1Tg mice challenged with virulent Mycobacterium tuberculosis (Mtb). In Aim 3, a novel hydrogel delivery system will be employed for controlled and sustained release of lipid-antigen-loaded nanobiomaterials to assess efficacy and safety of chronic CD1-restricted T cell activation. The proposed study will provide a “proof of concept” that combining Mtb lipids and proteins into a single subunit vaccine formulation that targets both conventional and unconventional T cell subsets can enhance overall immunity to Mtb infection. The methodology and antigen/adjuvant delivery systems developed in this study will guide the next generation of multi-subunit vaccines for TB and other bacterial pathogens to provide scalable routes of rapid vaccine fabrication.

项目概要 亚单位疫苗将来自病原体的免疫显性蛋白或肽抗原与精选的 佐剂，旨在提供一种更具规模化、可重复性、低成本和快速的减毒疫苗替代品 含有活病原体。不幸的是，目前的亚单位疫苗缺乏脂质抗原，并且很少能达到 持久的免疫记忆和保护所需的广泛 T 细胞反应。相比之下，减弱 疫苗缺乏定制化和可扩展性，但包含整个病原体以提供蛋白质和脂质 免疫过程中的抗原。这种脂质和蛋白质抗原的组合可激活广泛的 效应 T 细胞，包括传统的 MHC 限制性 T 细胞，它们对肽有反应并表现出相当大的 多态性，以及针对特定脂质的非多态性 CD1 限制性 T 细胞。一个更多 因此，同时激活脂质和肽特异性 T 细胞的仿生策略可能表明 与仅限于蛋白质抗原的亚单位疫苗相比，其功效和控制能力增强。 当前亚单位疫苗和免疫疗法忽视脂质抗原的主要原因是：1) 脂质靶向递送的困难，以及2）缺乏合适的小鼠模型。在人类中，CD1 家族 由第 1 组 CD1 分子（CD1a、CD1b 和 CD1c）和第 2 组 CD1 分子 CD1d 组成。老鼠， 然而，仅表达CD1d。该项目涉及以下研究小组之间的密切合作 一名生物工程师和一名基础免疫学家，旨在通过设计纳米生物材料来克服这些障碍 与佐剂结合增强脂质和蛋白质抗原的双重递送以诱导 CD1- 和 人源化 CD1 转基因 (hCD1Tg) 小鼠中 MHC 限制性 T 细胞反应。表征、优化和 将这些新型纳米生物材料与世界上最常用的减毒疫苗（即 卡介苗 (BCG) 结核病 (TB) 疫苗，提出以下目标： 在目标 1 中，体外 体内方法将确定最佳的纳米生物材料和佐剂组合，以引发 结合 CD1 和 MHC 限制性 T 细胞反应。在目标 2 中，脂质/蛋白质多抗原方法将是 在用剧毒结核分枝杆菌 (Mtb) 攻击的 hCD1Tg 小鼠中得到验证。在目标 3 中，一种新型水凝胶 递送系统将用于负载脂质抗原的纳米生物材料的受控和持续释放 评估慢性 CD1 限制性 T 细胞激活的功效和安全性。拟议的研究将提供“证据 概念”，将结核分枝杆菌脂质和蛋白质结合成单一亚单位疫苗制剂，同时针对两者 常规和非常规 T 细胞亚群可以增强对 Mtb 感染的整体免疫力。方法论 本研究开发的抗原/佐剂递送系统将指导下一代多亚基 结核病和其他细菌病原体疫苗，以提供可扩展的快速疫苗制造途径。