Mechanistic evaluation of mast cell agonists combined with TLR, NOD and STING agonists.

肥大细胞激动剂联合 TLR、NOD 和 STING 激动剂的机制评估。

• 批准号: 10657847
• 负责人: Kristy M Ainslie
• 金额: $ 64.52万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-03 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657847
• 关键词: Acids; Adjuvant; Agonist; Anaphylaxis; Animal Model; Antigen-Presenting Cells; Antigens; Area; Attenuated; Autoimmunity; Autopsy; Binding; Biocompatible Materials; Blood Chemical Analysis; CD8-Positive T-Lymphocytes; Categories; Cell Degranulation; Cells; Cold Chains; Contracts; Data; Delayed Hypersensitivity; Dextrans; Dose; Elderly; Emulsions; Encapsulated; Ensure; Environment; Evaluation; Formulation; Genes; Genetic; Genetic Variation; Goals; Histamine; Histology; Human; Hydrophobicity; IgE; Immune; Immune response; Immune system; Immunity; Immunization; Immunohistochemistry; Immunologic Stimulation; In Vitro; Inbred Strains Mice; Infection; Knockout Mice; Langerhans cell; Leukocytes; Leukotrienes; Lipid A; Liposomes; Lymphocyte; Maps; Measures; Memory; Memory B-Lymphocyte; Methods; Modeling; Mouse Strains; Mus; Nucleotides; Ovalbumin; Pathology; Pattern recognition receptor; Peptides; Population; Population Heterogeneity; Predisposition; Production; Prostaglandins; Proteins; Receptor Cell; Recombinants; Reporting; Resources; Safety; Schedule; Serum; Severity of illness; Site; Smallpox; Stimulator of Interferon Genes; Subunit Vaccines; T cell response; TLR2 gene; Toll-like receptors; Toxic effect; Tryptase; United States National Institutes of Health; Vaccination; Vaccine Research; Vaccines; Vaccinia; Vaccinia Vaccine; Viral; Work; adaptive immune response; aged; aging population; aluminum sulfate; antigen test; antigen-specific T cells; controlled release; cytokine; cytotoxicity; draining lymph node; human model; in vivo; insight; mast cell; monocyte; mouse model; particle; pathogen; protective effect; recruit; response; small molecule; synergism; tool; vaccine efficacy; vaccine evaluation; vaccine formulation

ABSTRACT Subunit vaccines are safer and can more broadly be applied across the population then other vaccine formulations such as live-attenuated. However, subunit antigens are often poorly antigenic and require formulation with an immune stimulating adjuvant to garner protection. Additionally, some vaccines require more than one adjuvant, necessitating combined adjuvants to stimulate a protective response. Also, a combined adjuvant could decrease vaccination boosts and provide longer protection. One avenue to evaluate combined adjuvants is with mast cell (MC) agonists. MCs are throughout the body and reside at many interfaces of the host and the environment. When activated MCs recruit monocytes and leukocytes to the local area and help to promote an adaptive response. MC agonists combined with toll-like receptor (TLR), nucleotide-binding oligomerization domain-containing protein 2 (NOD-2), or stimulators of interferon genes (STING) agonists should elicit not only a humoral response, but also a cellular response to create an efficacious and effective vaccine. Herein we will evaluate combined MC agonists with TLR, NOD-2 or STING agonist to identify synergistic pairs. Pairs will be evaluated in mice and human cells as well as with cells from collaborative cross (CC) strains. The CC strains are a large panel of recombinant inbred mouse strains with genetic variation that can mimic the human population as well as give insight into genetic variables that contribute to adjuvant mechanism. To ensure that the adjuvants are co-delivered as well as offer dose sparring, storage outside the cold chain and controlled release of adjuvant, we will formulate them into acetalated dextran (Ac-DEX) microparticles. Ac-DEX formulations have illustrated enhanced delivery of STING, NOD-2, TLR and MC agonists in vitro and in vivo, above that of other carriers like liposomes or PLGA particles. The best identified adjuvant combination will be evaluated in a mouse model of a vaccinia vaccine with subunit antigen BR8. We will use pattern recognition receptor (PRR) knock-out mice as well as cell deficient mice to elucidate aspects of the combination adjuvant's mechanism. Additionally, we will employ genetic sequencing tools to mechanistically identify the combination adjuvants mechanism.

摘要