Characterization of seasonal CoV immunity and operationalization of a novel controlled human infection model for the betacoronavirus OC43

β冠状病毒 OC43 的季节性 CoV 免疫特征和新型受控人类感染模型的操作

• 批准号: 10663727
• 负责人: Meagan Elise Deming
• 金额: $ 16.14万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-25 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10663727
• 关键词: 2019-nCoV; Adult; Advanced Development; Affect; Antibodies; Assessment tool; Binding; Bioinformatics; Biological Assay; Biological Models; Cell Culture Techniques; Clinical; Clinical Protocols; Complex; Coronavirus; Coronavirus Infections; Development; Dose; Elements; Ensure; Epitopes; Ethics; Evolution; Exclusion Criteria; Foundations; Future; Genotype; Glycoproteins; Goals; Growth; Human; Humoral Immunities; Immune response; Immunity; Immunologic Memory; Immunologics; Immunology; Individual; Infection; Influenza; Innate Immune Response; Integration Host Factors; Intervention; Leadership; Learning; Maryland; Mediator; Mentors; Mentorship; Modeling; Mutation; Nature; Participant; Pathogenicity; Population; Predisposition; Preparation; Process; Productivity; Protocols documentation; RNA Viruses; Readiness; Research; Research Design; Research Personnel; Residual state; Resources; Role; SARS-CoV-2 immunity; SARS-CoV-2 variant; Safety; Sampling; Seasons; Specificity; Specimen; System; Time; Training; Uncertainty; Universities; Vaccine Design; Validation; Variant; Viral; Viral Genome; Viral Pathogenesis; Viral Respiratory Tract Infection; Virus; Virus Replication; Virus Shedding; assay development; betacoronavirus; career; coronavirus therapeutics; coronavirus vaccine; cross-species transmission; cytokine; design; follow-up; future outbreak; genome analysis; human coronavirus; inclusion criteria; influenza infection; influenzavirus; next generation sequencing; novel; novel coronavirus; outbreak preparedness; outbreak response; pressure; protocol development; respiratory; screening; seasonal coronavirus; skills; therapeutic development; tool; universal coronavirus vaccine; vaccine development; vaccine efficacy; vaccinology; virology

Project Summary Coronaviruses (CoVs) are large RNA viruses with a well-demonstrated potential for jumping host species. The persistent threat of novel emergent CoVs necessitates a thorough understanding of CoV immunity and preparedness for outbreak response. Four CoVs circulate seasonally, and SARS-CoV-2 has further demonstrated the ability of coronaviruses to re-infect the same individual multiple times over a lifetime. Whether CoV reinfections occur due to evolving viral epitopes or waning immunologic memory, and the role of within host immunity for selection of novel variants remains a critical gap in understanding CoV immunity. My long-term career goal is to become an independent and productive investigator in CoV and influenza vaccinology, with a focus on controlled human infection models (CHIMs). A CHIM using the seasonal CoV OC43, with low pathogenicity and structural similarity to the severe CoVs, will advance our understanding of CoV immunology and provide a foundation for pan-CoV vaccine and therapeutic development in preparation for future outbreaks. Under the mentorship of Dr. Frieman, an expert in coronaviruses, and Dr. Neuzil, an expert in vaccine development and controlled human infection models, I will pursue this goal of developing a CHIM with the seasonal CoV OC43. A 2022 isolate of OC43 is undergoing ongoing development for use in a CHIM. However, the assays to evaluate immunity to seasonal CoVs such as OC43 have historically been limited by relatively poor growth in cell culture and lack of specificity by binding assays. Therefore, in Aim 1 I will use pseudoviruses to develop a functional neutralization assay to assess immunity to seasonal CoVs, evaluating the ability of sera from the past four decades to neutralize both recent and older OC43 pseudotyped viruses. This will provide a mechanism to rapidly evaluate seasonal CoV neutralization with greater accuracy than antibody binding alone. In Aim 2 I will build on a recent influenza CHIM conducted at the University of Maryland to explore the diversity of influenza mutations occurring within individuals after a controlled infection, providing novel explorations of the host factors that affect viral diversity. The viral genome analysis platform that we develop in aim 2 will be essential for evaluating the viral diversity that develops during an OC43 CHIM. In Aim 3 I will develop the protocol for a seasonal CoV CHIM, with careful consideration for safety and endpoints that will allow us to evaluate the effect of pre-existing immunity on symptomatic infection, viral shedding, and duration of immune response. A seasonal CoV CHIM has not been conducted for over 40 years, and today would allow us to characterize the cellular and humoral correlates of protection, define host mediators of susceptibility, and directly assess durability of immunity. This model system will be an essential tool for assessing variant-proof pan-coronavirus interventions and will provide preparedness for the emergence of future novel coronaviruses.

项目摘要 冠状病毒（COVS）是大的RNA病毒，具有跳跃宿主物种的潜力。这 持续存在的新兴COV威胁需要对COV免疫和 准备爆发反应。四个COV季节性循环，SARS-COV-2进一步 证明了冠状病毒在一生中多次重新感染相同个体的能力。 COV是由于不断发展的病毒表位或免疫记忆减弱而发生的，以及 在宿主免疫中，选择新型变体仍然是理解COV免疫力的关键差距。 我的长期职业目标是成为COV和流感的独立和富有成效的调查员 疫苗科学，重点是受控的人类感染模型（CHIMS）。使用季节性COV的辣椒 与严重COV的致病性和结构相似性低的OC43将提高我们对 COV免疫学并为准备泛池疫苗和治疗性开发提供基础 对于将来的爆发。 在冠状病毒专家Frieman博士和疫苗专家Neuzil博士的指导下 开发和受控的人类感染模型，我将追求这个目标，即与 季节性COV OC43。 2022年OC43的分离株正在进行中，以用于CHIM中。然而， 评估对季节性COV（例如OC43）免疫力的测定在历史上受到相对限制 通过结合测定，细胞培养的生长不良和缺乏特异性。因此，在AIM 1中我会使用 伪病毒开发功能中和测定法以评估对季节性COV的免疫力，评估 从过去的四十年中，血清近期和旧的OC43伪型病毒的能力。 这将提供一种机制，可以快速评估季节性COV中和的精度 抗体结合。在AIM 2中，我将以最近在马里兰大学进行的流感chim为基础 探索受控感染后个体内发生的流感突变的多样性，提供 对影响病毒多样性的宿主因素的新探索。我们的病毒基因组分析平台 在AIM 2中开发对于评估OC43 CHIM期间发展的病毒多样性至关重要。目标 3我将为季节性COV CHIM制定协议，并仔细考虑安全性和终点 将使我们能够评估预先存在免疫对症状感染，病毒脱落和的影响 免疫反应的持续时间。 季节性的COV Chim已经40多年没有进行，今天使我们能够描述 细胞和体液保护的相关性，定义易感性的宿主介质，并直接评估 免疫力的耐用性。该型号系统将是评估可变化的泛盘病毒的重要工具 干预措施，并将为未来新型冠状病毒的出现提供准备。