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

基本信息

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
项目类别：
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

项目摘要

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。