Development of a novel adjuvant strategy enabled by modulation of the physical properties of fungal mannans

通过调节真菌甘露聚糖的物理特性开发新型佐剂策略

• 批准号: 10338399
• 负责人: Ivan Zanoni
• 金额: $ 77.79万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10338399
• 关键词: 2019-nCoV; Address; Adjuvant; Adjuvanticity; Aluminum; Aluminum Hydroxide; Antibodies; Antibody Formation; Antigens; Automobile Driving; Benchmarking; Biology; Bone Marrow; C Type Lectin Receptors; Cell Wall; Cells; Chimera organism; Communicable Diseases; Cytokine Receptors; DNA; Development; Drug Kinetics; Epitopes; Experimental Models; FDA approved; Formulation; Glycoproteins; Goals; Human; Immune; Immune response; Immunity; Immunization; Immunize; Immunoglobulins; In Vitro; Inbreeding; Individual; Injections; Innate Immune System; Interferons; Knockout Mice; Ligands; Light; Lung diseases; Lymphocyte; Mannans; Measures; Mediating; Modality; Modeling; Molecular; Molecular Mechanisms of Action; Mouse Strains; Mus; Mycoses; Myeloid Cells; Pathway interactions; Pattern recognition receptor; Phagocytes; Play; Polysaccharides; Process; Proteins; Public Health; Risk; SARS-CoV-2 spike protein; Salts; Site; Specificity; Spike Potential; Surface; TLR4 gene; Testing; Th1 Cells; Toll-like receptors; Vaccine Adjuvant; Vaccine Antigen; Vaccines; Viral; Work; adaptive immune response; adaptive immunity; base; beta-Glucans; dectin 1; immune activation; immunogenicity; improved; in vitro Model; in vivo; innate immune pathways; innovation; lymph nodes; microorganism antigen; mouse dectin-2; mouse model; neutralizing antibody; novel; pathogen; physical property; programs; receptor; sensor; tool

PROJECT SUMMARY Vaccines represent a highly effective public health measure to protect individuals from infectious diseases. Many vaccines work by inducing antigen-specific antibodies that neutralize the pathogen or its products and promote their clearance. Vaccines based on protein antigens usually require the addition of adjuvants to enhance potency, breadth and duration of the antigen-specific adaptive immune response. Adjuvants promote vaccine antigen immunogenicity by activating receptors of the innate immune system called pattern-recognition receptors (PRRs) and/or modulating antigen pharmacokinetics. Aluminum salts are the most common adjuvants in FDA- approved vaccines. Recently, vaccines including adjuvants that target specific PRRs, in particular toll-like receptor (TLR)4 and TLR9, have also been approved by the FDA, paving the way for the development of molecularly defined adjuvants. Investigating the potential of additional PRRs as adjuvant targets is of paramount important to expand our vaccine toolbox and probe how different modalities of innate immune cell activation impact the adaptive immune response. Here, we propose to use the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike protein as a model antigen to test a new adjuvant formulation that contains fungal ligands that target the PRR Dectin-2. Our preliminary results show that mannans (fungal cell wall polysaccharides isolated from Candia albicans) alone or formulated with aluminum hydroxide enhance the immunogenicity of pre-fusion stabilized, Spike trimers in mouse models of immunization. In particular, mannan formulations, compared to aluminum hydroxide only, induce an early increase in anti-Spike antibody levels, potentiate the induction of SARS-CoV-2 neutralizing antibodies, broaden the Spike epitopes that are targeted and favor the switch towards immunoglobulin subclasses associated with higher effector functions and reduced risk of vaccine-associated enhanced respiratory disease (VAERD). Here we hypothesize that mannans formulated with alumOH induce a potent and durable adaptive immune response to SARS-CoV-2 Spike by inducing specific innate immune pathways and activation programs. By combining detailed immunogenicity and mechanistic analyses, our proposal will define a novel adjuvant formulation for SARS-CoV-2 Spike and potentially other viral glycoproteins as well as shed new light on the biology of Dectin-2.

项目概要 疫苗是保护个人免受传染病侵害的高效公共卫生措施。许多 疫苗通过诱导抗原特异性抗体发挥作用，中和病原体或其产物并促进 他们的许可。基于蛋白质抗原的疫苗通常需要添加佐剂来增强 抗原特异性适应性免疫反应的效力、广度和持续时间。佐剂促进疫苗 通过激活先天免疫系统的受体（称为模式识别受体）来产生抗原免疫原性 (PRR) 和/或调节抗原药代动力学。铝盐是 FDA 最常见的佐剂 批准的疫苗。最近，包含针对特定 PRR 的佐剂的疫苗，特别是 Toll 样疫苗 受体（TLR）4和TLR9也已获得FDA批准，为开发铺平了道路 分子确定的佐剂。研究额外 PRR 作为辅助靶点的潜力至关重要 扩展我们的疫苗工具箱并探索先天免疫细胞激活的不同方式非常重要 影响适应性免疫反应。在这里，我们建议使用严重急性呼吸道综合症 冠状病毒 2 (SARS-CoV-2) 刺突蛋白作为模型抗原来测试包含 靶向 PRR Dectin-2 的真菌配体。我们的初步结果表明甘露聚糖（真菌细胞壁 从白色念珠菌中分离出的多糖）单独或与氢氧化铝配制可增强 小鼠免疫模型中融合前稳定的刺突三聚体的免疫原性。特别是甘露聚糖 与仅使用氢氧化铝相比，该配方可诱导抗 Spike 抗体水平的早期增加， 增强 SARS-CoV-2 中和抗体的诱导，扩大针对的 Spike 表位 并有利于转向与更高效应功能相关的免疫球蛋白亚类，并减少 疫苗相关增强呼吸道疾病 (VAERD) 的风险。在这里我们假设甘露聚糖 采用 alumOH 配制，可诱导针对 SARS-CoV-2 Spike 的有效且持久的适应性免疫反应 通过诱导特定的先天免疫途径和激活程序。通过结合详细 免疫原性和机制分析，我们的建议将定义一种新的佐剂配方 SARS-CoV-2 Spike 和潜在的其他病毒糖蛋白，并为了解 SARS-CoV-2 的生物学提供了新的线索 Dectin-2。