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.

项目总结