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: 10490881
• 负责人: Ivan Zanoni
• 金额: $ 75.19万
• 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/10490881
• 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; 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; Respiratory Disease; 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.

项目摘要 疫苗代表了一种高效的公共卫生措施，以保护个人免受传染病的侵害。许多 疫苗通过诱导中和病原体或其产物中和抗原特异性抗体并促进疫苗来起作用 他们的清理。基于蛋白质抗原的疫苗通常需要添加佐剂才能增强 抗原特异性适应性免疫反应的效力，宽度和持续时间。佐剂促进疫苗 抗原免疫原性通过激活先天免疫系统的受体称为模式识别受体 （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，包括针对特定PRR的佐剂在内的疫苗，特别是类似Toll样的疫苗 FDA也批准了受体（TLR）4和TLR9，为发展铺平了道路 分子定义的佐剂。研究其他PRR作为辅助目标的潜力至关重要 重要的是要扩大我们的疫苗工具箱和探测不同的先天免疫细胞激活方式的不同方式 影响适应性免疫反应。在这里，我们建议使用严重的急性呼吸综合症 冠状病毒2（SARS-COV-2）SPIKE蛋白作为模型抗原，以测试包含的新辅助配方 靶向PRR Dectin-2的真菌配体。我们的初步结果表明Mannans（真菌细胞壁 单独从白色念珠菌分离的多糖或用氢氧化铝配制的多糖增强了 融合前融合的免疫原性稳定在小鼠免疫模型中。特别是曼南 与氢氧化铝相比，配方可诱导抗尖峰抗体水平的早期增加， 增强SARS-COV-2中和抗体的诱导，扩大针对的尖峰表位 并有利于转向与较高效应子功能相关的免疫球蛋白亚类并降低 与疫苗相关的呼吸道疾病（VAERD）的风险。在这里，我们假设曼南斯 用铝制制造的诱导对SARS-COV-2尖峰的有效耐用的自适应免疫反应 通过诱导特定的先天免疫途径和激活程序。通过结合详细的内容 免疫原性和机械分析，我们的建议将定义一种新颖的辅助配方 SARS-COV-2尖峰以及潜在的其他病毒糖蛋白以及对生物学的新灯 dectin-2。