Developing RNA Vaccines to Treat Peanut Hypersensitivity

项目摘要/摘要：PALFORZIA®口服免疫疗法是FDA最近批准的一种治疗方法 治疗花生过敏。这种疗法需要每天口服特定剂量的花生蛋白来治疗 花生过敏症患者。PALFORZIA®疗法的一个主要限制是发病的可能性 过敏反应和可能的过敏反应是由于花生特异性IgE包被的肥大细胞的激活引起的。 缺乏IgE介导的粒细胞激活潜能的低过敏性花生蛋白的开发可能 解决PALFORZIA®治疗的已知安全限制。SARS-CoV-2大流行的兴起和 信使冠状病毒疫苗的快速生产和传播凸显了信使疫苗的益处 来预防传染病。本项目的目标是利用mrna疫苗技术表达 缺乏和/或干扰已知的IgE表位的花生蛋白提供一种不具有 在宿主中引起对本地变应原过敏的过敏反应。这项提议将利用占主导地位的 花生过敏原，Ara h 2，被大多数花生过敏患者识别并足以诱导 小鼠的超敏反应，以开发产生天然的arah2或突变的arah2的mRNA疫苗 在已知的线性IgE表位中。这项提案中描述的研究将评估体外蛋白质生产，在 体外IgE介导的粒细胞活化、体内免疫原性和体内变态反应性疾病的宿主激活 对当地的过敏原敏感。该提案的结果将生成概念验证初步数据 为了支持未来的研究，开发表达多种花生蛋白的mRNA疫苗来治疗花生- 过敏宿主中的超敏反应。

Project Summary/Abstract: Oral immunotherapy with PALFORZIA® is a recently FDA-approved therapy to treat peanut allergy. This therapy requires daily doses of characterized peanut proteins administered orally to peanut hypersensitive individuals. A major limitation of the PALFORZIA® therapy is the potential for the onset of allergic responses and possibly anaphylaxis due to activation of peanut-specific IgE coated mast cells. Development of hypoallergenic peanut proteins devoid of IgE-mediated granulocyte activation potential may address the known safety limitations of therapy with PALFORZIA®. The rise of the SARS-CoV-2 pandemic and rapid production and dissemination of mRNA COVID vaccines has highlighted the benefits of mRNA vaccines to protect against infectious diseases. The goal of this project is to utilize mRNA vaccine technology to express peanut proteins that lack and/or disrupt known IgE epitopes to provide a peanut allergen vaccine that does not induce allergic reactions in hosts hypersensitive to the native allergen. This proposal will utilize the dominant peanut allergen, Ara h 2, which is recognized by majority of peanut allergic individuals and is sufficient to induce hypersensitivity in mice, to develop mRNA vaccines that produce native Ara h 2 or mutant Ara h 2 with mutations in known linear IgE epitopes. The studies described in this proposal will evaluate in vitro protein production, in vitro IgE-mediated granulocyte activation, in vivo immunogenicity, and in vivo allergic disease activation in hosts sensitized to the native allergen. The results from this proposal will generate proof-of-concept preliminary data to support future studies to develop mRNA vaccines expressing multiple peanut proteins to treat peanut- hypersensitivity in allergic hosts.