Project 1: Panbetacoronavirus vaccines

项目一：泛β冠状病毒疫苗

• 批准号: 10842502
• 负责人: Barton F. Haynes
• 金额: $ 109.21万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-16 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10842502
• 关键词: 2019-nCoV; Acute Respiratory Distress Syndrome; Alphavirus; Antibody Repertoire; Antibody titer measurement; Antigens; Antiviral Agents; Attenuated; Blood Coagulation Disorders; COVID-19; Cellular Immunity; Cessation of life; China; Chiroptera; Clinical; Coronavirus; Country; Data; Development; Disease; Epidemic; Epitopes; Family; Foundations; Future; Generations; Goals; Gold; Hamsters; Human; Humoral Immunities; Immune; Immune response; Immunity; Immunologics; Inactivated Vaccines; Individual; Infection; Inflammatory; Inflammatory Infiltrate; Laboratories; Laboratory mice; Location; Lung diseases; Maps; Measures; Merbecovirus; Messenger RNA; Middle East Respiratory Syndrome; Middle East Respiratory Syndrome Coronavirus; Modeling; Mus; Outcome; Pathogenesis; Pathogenicity; Pathologic; Pathology; Performance; Phase; Phenotype; Pneumonia; Population; Primates; Recombinants; Replicon; Reporter; Reporting; SARS coronavirus; Sarbecovirus; Severe Acute Respiratory Syndrome; Shock; Stroke; Structure; Syndrome; T-Lymphocyte; Testing; Vaccination; Vaccine Design; Vaccines; Variant; Viral; Virulent; Virus; Virus Diseases; Work; Zoonoses; aged; betacoronavirus; betacoronavirus vaccine; coronavirus vaccine; cytokine; design; disease phenotype; human disease; human model; in vivo; mosaic; mouse model; neutralizing antibody; novel; novel coronavirus; pandemic disease; particle; programs; response; universal coronavirus vaccine; vaccine candidate; vaccine development; vaccine formulation; vaccine immunogenicity; vaccine platform; vaccinology; vector; zoonotic coronavirus

Abstract - Project 1 Zoonotic coronaviruses (CoV) are responsible for three major epidemics/pandemics in the 21st century, including Severe Acute Respiratory Coronavirus (SARS-CoV) in 2003 and Middle East Respiratory coronavirus (MERS- CoV) in 2012. In Dec 2019, a third novel coronavirus (CoV) designated SARS-CoV-2 emerged in Wuhan China and in the space of 11 months, has caused over 85 million cases, >1.8 million deaths in >217 countries. Over 1/5 of these total cases have been reported in the US, resulting in over 350,000 deaths. In humans, virus infection results in COVID-19 disease, characterized by pneumonia and severe acute respiratory distress syndrome (ARDS), an often-fatal end-stage lung disease. In addition to SARS-CoV2, multiple other SARS-like and MERS-like CoV strains reside in bats and other species and are poised to emerge at some point in the future. The threat posed by these viruses creates a need for the development of broadly efficacious antivirals and vaccines that will protect against this heterogeneous family of highly pathogenic emerging viruses. In response, our assembled team in this P01 of leading virologists with complementary expertise in viral immunity, CoV pathogenesis, antibody repertoire mapping, vaccinology and structure-based vaccine design have developed an integrated program designed to develop panbetaCoV vaccines that protect against the Merbecoviruses (MERS-like group 2c) and Sarbecoviruses (SARS-like group 2b CoV). Project 1, led by the Baric and Heise laboratories at UNC, will develop and test panels of wildtype and chimeric vaccines developed in the context of a well-established alphavirus replicon particle (VRP) vaccine platform. They will interface with other projects and cores to map the location of broadly neutralizing antibody epitopes that will inform panCoV vaccine design. They will also produce killed and live attenuated viruses as vaccine gold standards and models for vaccine induced immune pathology phenotypes (VARED). Project 1 also provides mouse models of human disease, including the first lethal mouse adapted SARS-CoV-2 MA10 variant that replicates efficiently and produces ARDS like disease phenotypes in standard laboratory mice. They also provide novel mouse models of human disease for other SARS-like and MERS-like CoV. Project 1 also provides reporter viruses expressing nLUC, that span the group 2 and group 1 CoV that provide precise measures of neutralizing antibody titer, breadth and magnitude following natural infection and vaccination. Finally, they provide robust heterologous challenge models for evaluating the breadth and performance of emerging coronavirus vaccines. The overall goal is to develop a panCoV vaccine that will universally protect against group 2b and 2c CoV. Aim 1 deciphers the antigenic structure of the BetaCoV. Aim 2 measures group 2b and 2c vaccine performance after virus challenge. Aim 3 develops and tests panbetaCoV vaccine candidates.

摘要 - 项目 1 人畜共患冠状病毒 (CoV) 是 21 世纪三大流行病/大流行的罪魁祸首，包括 2003年严重急性呼吸道冠状病毒（SARS-CoV）和中东呼吸道冠状病毒（MERS- 2012 年发现的冠状病毒 (SARS-CoV)。2019 年 12 月，中国武汉出现了第三种新型冠状病毒 (CoV)，命名为 SARS-CoV-2 在 11 个月内，已在超过 217 个国家造成超过 8500 万例病例，超过 180 万人死亡。超过 其中 1/5 的病例发生在美国，导致超过 35 万人死亡。在人类中，病毒 感染导致 COVID-19 疾病，其特征为肺炎和严重急性呼吸窘迫 综合征（ARDS），一种常常致命的终末期肺部疾病。除 SARS-CoV2 外，还有多种其他类似 SARS 的病毒 和中东呼吸综合征样冠状病毒株存在于蝙蝠和其他物种中，并准备在世界的某个时刻出现。 未来。这些病毒造成的威胁需要开发广泛有效的抗病毒药物 以及能够预防这种高致病性新兴病毒异质家族的疫苗。在 响应，我们在这个 P01 中组建了领先的病毒学家团队，他们在病毒免疫方面具有互补的专业知识， 冠状病毒发病机制、抗体谱图谱、疫苗学和基于结构的疫苗设计 制定了一项综合计划，旨在开发泛β冠状病毒疫苗，以预防 Merbecoviruses（MERS 样 2c 组）和 Sarbecoviruses（SARS 样 2b 组 CoV）。项目1，由 北卡罗来纳大学的 Baric 和 Heise 实验室将开发和测试野生型和嵌合疫苗组 在完善的甲病毒复制子颗粒（VRP）疫苗平台的背景下。他们将与 其他项目和核心，以绘制广泛中和抗体表位的位置，从而为泛冠状病毒提供信息 疫苗设计。他们还将生产灭活病毒和减毒活病毒作为疫苗黄金标准和模型 用于疫苗诱导的免疫病理表型（VARED）。项目1还提供了人类的小鼠模型 疾病，包括第一个致命的小鼠适应性 SARS-CoV-2 MA10 变体，该变体可有效复制 在标准实验室小鼠中产生类似 ARDS 的疾病表型。他们还提供新颖的小鼠模型 其他类 SARS 和 MERS 类 CoV 的人类疾病。项目1还提供了表达的报告病毒 nLUC，涵盖第 2 组和第 1 组 CoV，提供中和抗体滴度的精确测量， 自然感染和疫苗接种后的广度和程度。最后，他们提供了强大的异源 用于评估新兴冠状病毒疫苗的广度和性能的挑战模型。整体 我们的目标是开发一种泛冠状病毒疫苗，能够普遍预防 2b 型和 2c 型冠状病毒。目标1 破译了 BetaCoV 的抗原结构。目标 2 衡量 2b 组和 2c 组疫苗在接种后的性能 病毒挑战。 Aim 3 开发并测试 panbetaCoV 候选疫苗。