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: 10207410
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10207410
• 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 development

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.

项目摘要 亚基疫苗结合了与选择的病原体的免疫主导蛋白或胡椒抗原 调节器，旨在提供更可扩展，可重复的，低成本和快速替代疫苗的替代品 其中包含活病原体。不幸的是，当前的亚基疫苗缺乏脂质抗原，很少达到 持久的免疫记忆和保护所需的广泛的T细胞反应。相比之下，衰减 疫苗缺乏自定义和可伸缩性，但结合了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激活了一定范围 效应T细胞，包括对Pepperides响应并显示出相当大的响应的常规MHC限制的T细胞 多态性以及针对特定脂质的非晶型CD1限制的T细胞。更多 因此，仅激活脂质和胡椒特异性T细胞的仿生策略可能显示 与仅限于蛋白质抗原的亚基疫苗相比，效率和控制增强。 从当前亚基疫苗和免疫疗法中忽略脂质抗原的主要原因是1） 靶向脂质的靶向输送困难，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， 但是，仅表示CD1D。该项目涉及由领导的研究小组之间的密切合作 生物工程师和基本免疫学家，旨在通过设计纳米生物材料来克服这些障碍 增强脂质和蛋白质抗原的双重递送与调节剂结合使用，以诱导CD1和 人源化CD1转基因（HCD1TG）小鼠的MHC限制T细胞反应。表征，优化和 基准这些新颖的纳米生物材料对世界上最常用的衰减疫苗， 芽孢杆菌Calmette-guérin（BCG）结核病（TB）疫苗，提出了以下目的：在AIM 1中，体外 并且体内方法将确定最佳纳米生物材料和可调节组合，以引起 CD1和MHC限制的T细胞反应组合。在AIM 2中，脂质/蛋白质多抗原方法将是 在受毒性分枝杆菌（MTB）挑战的HCD1TG小鼠中进行了验证。在AIM 3中，一种新颖的水凝胶 递送系统将用于控制和持续的脂质抗原负载的纳米材料材料 评估慢性CD1限制的T细胞激活的效率和安全性。拟议的研究将提供“证明 概念”将MTB脂质和蛋白质结合到单个亚基疫苗配方中 常规和非常规的T细胞子集可以增强对MTB感染的总体免疫学。方法 本研究中开发的抗原/辅助输送系统将指导下一代多生产 结核病和其他细菌病原体的疫苗可提供快速疫苗制造的可扩展途径。