Discovery and characterization of protective Influenza Type B Virus neuraminidase antibodies

项目总结/摘要 据估计，流感每年造成10亿例病例，严重病例会导致死亡。 支气管肺炎，特别是在弱势群体中。流感病毒体表达两种主要的表面 糖蛋白、血凝素（HA）和神经氨酸酶（NA），后者由于其在免疫调节中的作用而受到关注。 病毒从粘液中排出和裂解。目前，FDA批准的用于治疗流感的抗病毒药物只有 神经氨酸酶抑制剂，其对某些菌株无效。单克隆抗体（mAb），针对 NA提供了替代的治疗候选物。将NA mAb递送至呼吸道粘膜表面， 在病毒复制的地方，是一种新的输送方法，可以提高药物疗效和病人的依从性。 这个为期五年的研究职业发展奖将提供必要的技能培训和发展 候选人建立一个独立的研究实验室，专注于了解人类如何 抗流感抗体可用于治疗和预防疾病及其在动物中的传播 模型目前，候选人是一名兽医和范德比尔特疫苗中心的研究生实习生， 将于2024年7月过渡到物理学家-科学家轨道上的助理教授职位。她的训练， 迄今为止，已集中于从受试者中分离和表征人单克隆抗体（mAb 既往流感病史和治疗的小鼠模型。她将进一步补充这一经验， 在开发用于研究的流感感染的体内雪貂和离体人类组织模型方面的培训 这种病毒的自然发病机制以及人单克隆抗体如何结合流感病毒以减少发病机制。短- 所提议的研究的长期目标是检验神经氨酸酶导向抗体 在保护性免疫反应中发挥重要作用，并可与抗体疗法一起利用。 这项培训将得到国家人类抗体研究专家的指导（James 小克罗，Ivelin Georgiev）、人气道上皮细胞培养物（Timothy Blackwell）、流感疫苗学 （Spyros Kalams）和病毒感染和病理学的小动物模型（凯瑟琳吉布森-科利（Gibson-Corley））。的 申请人的目的是：1）阐明特异于流感病毒的mAb抑制B型流感病毒（IBV）的机制， 神经氨酸酶（NA）糖蛋白，以测试NA抗体发挥不同机制的假设， 保护，2）使用IBV感染的人气道模型来确定NA mAb在粘液存在下 行为，3）并在鼻内递送的雪貂模型中测试这些mAb，以测试NA mAb的假设 局部递送可减少病毒载量和脱落。总的来说，这些研究将有助于确定IBV NA的作用， 抗体和将mAb递送至呼吸道粘膜表面的机制。行业组织正在 开发由候选人制备的保护性mAb作为人类治疗剂。这些研究直接 翻译人类健康的重要性，并有助于更根本地了解疾病。

Project Summary/Abstract Influenza causes an estimated 1 billion cases yearly, with severe cases leading to fatal bronchopneumonia, particularly in vulnerable populations. Influenza virions express two major surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA), the latter of which is of interest due to its role in viral egress and cleavage from mucus. Currently, the only FDA-approved antivirals used to treat influenza are neuraminidase inhibitors, which are ineffective against some strains. Monoclonal antibodies (mAbs) directed at NA provide an alternative therapeutic candidate. Delivering NA mAbs to the respiratory mucosal surface, where the virus replicates, is a novel delivery method that could improve drug efficacy and patient compliance. This five-year research career development award will provide training and development of the skills necessary for the candidate to establish an independent research laboratory focused on understanding how human antibodies against influenza can be harnessed to treat and prevent disease and transmission in animal models. Currently, the candidate is a veterinarian and a graduate trainee at the Vanderbilt Vaccine Center who will transition to an assistant professor position on the physician-scientist track in July 2024. Her training to date has focused on the isolation and characterization of human monoclonal antibodies (mAbs) from subjects with prior influenza history and mouse models of therapy. She will supplement this experience with further training in developing in vivo ferret and ex vivo human tissue models of influenza infection with which to study the natural pathogenesis of this virus and how human mAbs bind influenza to reduce pathogenesis. The short- term goals of the proposed studies are to test the central hypothesis that neuraminidase-directed antibodies play a significant role in the protective immune response and can be harnessed with antibody therapeutics. This training will be supported by mentoring from national experts in the study of human antibodies (James Crowe, Jr., Ivelin Georgiev), human airway epithelial cultures (Timothy Blackwell), influenza vaccinology (Spyros Kalams), and small animal models of virus infection and pathology (Katherine Gibson-Corley). The applicant aims to 1) elucidate the mechanisms of influenza type B (IBV) inhibition by mAbs specific to the neuraminidase (NA) glycoprotein to test the hypotheses that NA antibodies exert distinct mechanisms of protection, 2) use a human airway model of IBV infection to determine how NA mAbs in the presence of mucus behave, 3) and test these mAbs in a ferret model of intranasal delivery to test the hypothesis that NA mAbs delivered topically can reduce viral load and shedding. Overall, these studies will help define the role of IBV NA antibodies and the mechanism of delivering mAbs to the respiratory mucosal surface. Industry groups are developing protective mAbs made by the candidate as human therapeutic agents. Thus, these studies directly translate the importance of human health and contribute to a more fundamental understanding of the disease.