Project 1: Panbetacoronavirus vaccines

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年的严重急性呼吸道冠状病毒(SARS-CoV)和中东呼吸冠状病毒(MERS- Cov)在2012年。2019年12月，武汉出现第三种新型冠状病毒，命名为SARS-CoV-2中国 在11个月的时间里，它已经在217个国家造成了8500多万个病例，180万人死亡。完毕 这些病例中有五分之一是在美国报告的，导致超过35万人死亡。在人类身上，病毒 感染导致新冠肺炎病，特征是肺炎和严重的急性呼吸窘迫 综合征(ARDS)，一种通常致命的终末期肺部疾病。除了SARS-CoV2，还有许多其他类似SARS的病毒 而类似MERS的冠状病毒株存在于蝙蝠和其他物种中，并准备在未来的某个时候出现 未来。这些病毒构成的威胁需要开发广谱有效的抗病毒药物。 以及将保护免受这种异质高致病性新兴病毒家族影响的疫苗。在……里面 响应，我们在P01中集结的团队由领先的病毒学家组成，在病毒免疫方面具有互补的专业知识， 冠状病毒的发病机制、抗体谱图、疫苗学和基于结构的疫苗设计 开发了一个综合计划，旨在开发泛美冠状病毒疫苗，以防止 MerbecoVirus(MERS-like Group 2c)和SarbecoVirus(SARS-like Group 2b CoV)。项目1，由 北卡罗来纳大学的巴里克和海斯实验室将开发和测试开发的野生型和嵌合疫苗面板 在建立良好的甲型病毒复制粒子(VRP)疫苗平台的背景下。它们将与 其他项目和核心，以绘制将告知PanCoV的广泛中和抗体表位的位置 疫苗设计。他们还将生产灭活和活的减毒病毒，作为疫苗的黄金标准和模型 疫苗诱导免疫病理表型(VARED)。项目1还提供了人类的鼠标模型 疾病，包括第一个致命的小鼠适应的SARS-CoV-2 MA10变种，它有效地复制和 在标准的实验室小鼠身上产生类似ARDS的疾病表型。他们还提供了新的老鼠模型 人类疾病对其他类似SARS和MERS的冠状病毒的影响。项目1还提供了报告病毒，表达 NLUC，跨越第2组和第1组冠状病毒，提供中和抗体滴度的精确测量， 自然感染和接种疫苗后的广度和幅度。最后，它们提供了健壮的异源 评估新出现的冠状病毒疫苗广度和性能的挑战模型。整体而言 目标是开发一种对2b和2c组冠状病毒具有普遍保护作用的泛冠状病毒疫苗。目标1 破译贝塔冠状病毒的抗原结构。目的2检测2b组和2c组疫苗接种后的效果 病毒挑战。目标3开发和测试PanbetaCoV候选疫苗。

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.