Mechanistic Studies of Combination Adjuvants to Target B Cells in Vaccines

疫苗中针对 B 细胞的组合佐剂的机理研究

• 批准号: 10218993
• 负责人: Luc Teyton
• 金额: $ 69.98万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-23 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10218993
• 关键词: Adjuvant; Adjuvanticity; Affinity; Agonist; Animal Model; Anti-Bacterial Agents; Antibodies; Antibody Response; Antigens; Attenuated; B-Lymphocytes; B-cell receptor repertoire sequencing; Biological; Biological Models; CD4 Positive T Lymphocytes; Categories; Cells; Cervarix; Child; Childhood; Complex; Conjugate Vaccines; Consensus; Coupled; Dendritic Cells; Dose; Europe; FDA approved; False Allegation; Formulation; Fright; Genetic Transcription; Goals; Guillain Barré Syndrome; Helper-Inducer T-Lymphocyte; Hepatitis B Vaccines; Hygiene; Immune response; Immunity; Immunology; Industry; Influenza A Virus, H1N1 Subtype; Injections; Knowledge; Lead; Ligands; MF59; Measures; Memory; Microbe; Molecular; Narcolepsy; Papillomavirus; Perception; Pertussis; Pertussis Vaccine; Phase; Polysaccharides; Preventive treatment; Reaction; Receptor Activation; Research; Safety; Saponins; Serotyping; Squalene; Streptococcus pneumoniae; Subunit Vaccines; Synthesis Chemistry; TLR7 gene; Toll-like receptors; Toxic effect; Toxin; Tween 80; Vaccination; Vaccine Design; Vaccines; alpha Tocopherol; aluminum sulfate; autism spectrum disorder; base; cell type; combinatorial; design; dosage; infectious disease treatment; influenza infection; influenza virus vaccine; nanomolar; neglect; pathogen; pathogenic microbe; prevent; protein expression; receptor; response; side effect; single cell technology; social stigma; synergism; uptake; vaccine development

In full response to RFA-AI-20-004, we propose to study the mechanisms of cooperativity between NKT cell and TLR adjuvants. We have previously shown that we could use a combination of NKT cell and TLR7 adjuvants to produce high affinity protective anti-bacterial glycan vaccines. Our goal is now to understand the mechanisms of this cooperative effects between the two adjuvants to optimize it and produce a vaccine formulation that promotes protection after a single administration. In addition, we contend that mechanistic studies will also allow the limitation of the potential side effects of adjuvants. To this end, our proposal is built on two separate and complementary specific aims: Aim 1: Evaluate endosomal TLR ligands for their ability to enhance NKT cell responses and their B cell helper activities. We have produced nanomolar affinity anti-glycan antibodies by combining NKT cell and TLR7 agonists. This response was dependent on NKT and CD4 T cell help. We hypothesize that each endosomal TLR ligand may have a different enhancing effect in a combinatorial usage. We will investigate NKT, T follicular helper, dendritic, and B cell responses by single cell technologies for RNA and protein expression in animal models of vaccination for each TLR/NKT cell pair that we will study. B cell receptor sequencing and pathogen challenges will be used to measure the efficacy of each combination. Aim 2: Evaluate the importance of the co-delivery of the two adjuvants to particular cell types and endosomal/lysosomal compartments. We hypothesize that the physical aspects of adjuvanticity with respect to antigen uptake and delivery to processing compartments are critical. By co-delivering antigen and adjuvants to particular cells and within chosen compartments, using synthetic chemistry to control their pairing and separation, mechanisms of adjuvant activity will be examined. The biological consequences of this molecular based design of adjuvant combinations will be evaluated with respect to dosage, toxicity, and efficacy. We expect to develop robust formulations that induce protection after a single vaccine administration. Our entire proposal is focused exclusively on vaccines aimed at developing protective B cell immunity, and our model system is a conjugate vaccine against Streptococcus pneumoniae.

为了充分响应RFA-AI-20-004，我们建议研究NKT细胞和NKT细胞之间的协同机制