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

项目摘要 疫苗是一种非常有效的公共卫生措施，可以保护个人免受传染病的侵害。许多 疫苗通过诱导抗原特异性抗体来中和病原体或其产物， 他们的清除。基于蛋白质抗原的疫苗通常需要添加佐剂以增强免疫原性。 抗原特异性适应性免疫应答的效力、广度和持续时间。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中最常见的佐剂- 批准的疫苗。最近，包括靶向特异性PRR（特别是toll样PRR）的佐剂的疫苗已经被发现。 受体（TLR）4和TLR 9也已获得FDA批准，为开发 分子定义的佐剂。研究其他PRR作为辅助靶点的潜力至关重要 重要的是要扩大我们的疫苗工具箱，并探讨先天免疫细胞激活的不同模式， 影响适应性免疫反应。在此，我们建议使用严重急性呼吸系统综合症 冠状病毒2（SARS-CoV-2）刺突蛋白作为模型抗原，以测试一种新的佐剂制剂， 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 从白色念珠菌分离的多糖）单独或与氢氧化铝一起配制增强了 融合前稳定的刺突三聚体在小鼠免疫模型中的免疫原性。尤其是， 与仅氢氧化铝相比，制剂诱导抗刺突抗体水平的早期增加， 增强SARS-CoV-2中和抗体的诱导，拓宽靶向的刺突表位， 并有利于向与更高的效应子功能相关的免疫球蛋白亚类的转变， 疫苗相关增强性呼吸道疾病（VAERD）。我们假设甘露聚糖 与alumOH配制诱导对SARS-CoV-2刺突的有效和持久的适应性免疫应答 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 免疫原性和机制分析，我们的建议将定义一种新的佐剂制剂， SARS-CoV-2刺突蛋白和其他潜在的病毒糖蛋白，以及揭示了新的生物学， Dectin-2。

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.