Discovery and characterization of protective Influenza Type B Virus neuraminidase antibodies

项目摘要/摘要 据估计，每年有10亿例流感病例，严重病例会导致死亡 支气管肺炎，特别是在易受伤害的人群中。流感病毒粒子表达两个主要表面 糖蛋白、血凝素(HA)和神经氨酸酶(NA)，后者因其在 病毒渗出并从粘液中裂解。目前，FDA批准的唯一用于治疗流感的抗病毒药物是 神经氨酸酶抑制剂，对某些菌株无效。针对以下目标的单抗 NA提供了一种替代治疗方案。将NA单抗输送到呼吸道粘膜表面， 在病毒复制的地方，是一种新的给药方法，可以提高药物疗效和患者的依从性。 这项为期五年的研究职业发展奖将提供必要技能的培训和发展。 候选人希望建立一个独立的研究实验室，专注于了解人类是如何 抗流感抗体可用于治疗和预防动物疾病和传播 模特们。目前，候选人是一名兽医，也是范德比尔特疫苗中心的研究生实习生 将于2024年7月过渡到医生-科学家轨道上的助理教授职位。她接受的训练是 DATE的重点是从受试者中分离和鉴定人的单抗 既往有流行性感冒病史和老鼠模型的治疗。她将对这一经历进行进一步的补充 用于研究流感感染的体内雪貂和体外人体组织模型的开发培训 该病毒的自然致病机制，以及人类单抗如何结合流感以减少致病。简而言之- 拟议研究的术语目标是检验神经氨酸酶导向抗体的中心假设 在保护性免疫反应中发挥重要作用，并可通过抗体疗法加以利用。 这项培训将得到研究人类抗体的国家专家的指导(詹姆斯 人类呼吸道上皮细胞培养(蒂莫西·布莱克韦尔)，流感疫苗学 (Spyros Kalams)，以及病毒感染和病理的小动物模型(凯瑟琳·吉布森-科利)。这个 申请者的目标是：1)阐明针对B型流感病毒(IBV)的单抗抑制IBV的机制 神经氨酸酶(NA)糖蛋白，以检验NA抗体发挥不同机制的假设 保护，2)使用IBV感染的人类呼吸道模型来确定在粘液存在的情况下NA单抗如何 在鼻腔给药的雪貂模型中测试这些单抗，以测试NA单抗的假设 外用可以减少病毒载量和脱落。总体而言，这些研究将有助于确定IBV NA的作用 抗体和单抗传递到呼吸道粘膜表面的机制。行业组织是 开发作为人类治疗剂的候选保护性单抗。因此，这些研究直接 翻译人类健康的重要性，有助于更根本地了解这种疾病。

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.