Preclinical development of a vaccine for Nipah virus

项目摘要/摘要 尼帕病毒可引起人类发热性脑炎和严重的呼吸道疾病，致死率高。 在一些疫情中为100%(过去十年的疫情平均为~75%)。目前没有获得许可的 对抗新城疫的疫苗或疗法。NIV被归类为生物安全级别(BSL)-4病原体 由于与感染相关的高死亡率，缺乏有效的医疗对策，以及 传播的方便性。除了作为一种自然获得性感染导致发病率和死亡率外，新城疫还 也被几个美国政府机构归类为C类优先病原体 因为故意误用。重要的是，Niv最近被列入世界卫生组织(WHO)2018年 优先病原体列表。由于史无前例的全球新冠肺炎大流行， 对呼吸道病原体的关注和认识。因此，在2020年3月，美国疾控中心 建议将NIV添加到Tier 1 Select代理列表中。研究制定有效的对策 由于新城疫病毒的高致病性及其对BSL-4遏制的限制，已经受到阻碍。卓有成效的 预防性疫苗将在疫情爆发期间与医务人员和密切接触者一起应用 从事研究的实验室工作人员。基于重组G蛋白缺失(ΔG)囊泡的疫苗 口炎病毒(rVSVΔG)与多种高致病性病毒糖蛋白(GP)的假型 已被证明完全保护非人类灵长类动物(NHP)免受埃博拉、马尔堡和拉萨病毒的侵袭。 此外，rVSV载体疫苗在预防埃博拉病毒疾病方面的有效性也得到了证明。 在2013-16年埃博拉疫情期间在几内亚进行的环状疫苗接种、开放标签、集群随机试验。这 疫苗最近被欧盟和美国FDA批准为ERVEBO。最近，我们开发了 表达新城疫病毒糖蛋白的复制限制性rVSV新城疫疫苗载体。重要的是，我们展示了 这些疫苗可以完全保护NHP免受高剂量致命性新城疫孟加拉国毒株的攻击 用作单次注射疫苗。这一新数据在控制疫情的背景下至关重要，因为 在遏制呼吸道病原体和预防大流行方面最有效的疫苗是 与单一管理部门一起快速工作。开发复制受限平台，提供改进的 安全性在不影响疗效的情况下是一个非常重要的进步，可以应用于其他病毒 具有大流行的可能性。这项建议的主要目标是开发一种基于rVSV的新城疫疫苗。 (rVSV-NiVBG)，可提供快速保护和长期免疫力，抵御最流行和 致病性新城疫孟加拉国株，并鉴定可用于预测保护作用的生物标志物。在这方面 在产品开发方面，还将开展研究细胞库(RCB)和病毒疫苗库的工作 (RVB)、制造工艺和GLP-安全毒理学行为。

PROJECT SUMMARY/ABSTRACT Nipah virus (NiV) causes febrile encephalitis and severe respiratory disease in humans with fatality rates as high as 100% in some outbreaks (average ~ 75% for outbreaks over the last decade). There are currently no licensed vaccines or therapies for combating NiV disease. NiV is classified as a Biosafety Level (BSL)-4 pathogen because of the high mortality rates associated with infection, the lack of effective medical countermeasures, and the ease of transmission. In addition to causing morbidity and mortality as a naturally acquired infection, NiV is also categorized as a Category C priority pathogen by several US Government agencies because of the concern for deliberate misuse. Importantly, NiV was recently included on the World Health Organization’s (WHO) 2018 List of Priority Pathogens. As a result of the unprecedented global pandemic of COVID-19 there is heightened concern and awareness regarding respiratory pathogens. Consequently, in March of 2020 the US CDC recommended that NiV be added to the list of Tier 1 Select Agents. Studies to develop effective countermeasures have been hampered by the highly pathogenic nature of NiV and its restriction to BSL-4 containment. An effective prophylactic vaccine would find application with medical personnel and close contacts during outbreaks and with laboratory workers engaged in research. A vaccine based on recombinant G protein deleted (ΔG) vesicular stomatitis virus (rVSVΔG) pseudotyped with the glycoproteins (GP) of a number of high consequence viruses have been shown to completely protect nonhuman primates (NHP) against Ebola, Marburg, and Lassa viruses. In addition, the effectiveness of a rVSV-vectored vaccine in preventing Ebola virus disease was demonstrated in a ring vaccination, open-label, cluster-randomised trial in Guinea during the 2013-16 Ebola epidemic. This vaccine was recently licensed as ERVEBO by the European Union and US FDA. Recently, we developed replication-restricted rVSV NiV vaccine vectors expressing the NiV glycoproteins. Importantly, we showed that these vaccines can completely protect NHPs against high dose lethal NiV Bangladesh strain challenge when used as single injection vaccines. This new data is critically important in the context of containing outbreaks as the most effective vaccine in containing a respiratory pathogen and preventing a pandemic is a vaccine that works rapidly with a single administration. Development of a replication restricted platform that provides improved safety without compromising efficacy is a highly significant advancement and can be applied to other viruses with pandemic potential. The main objective of this proposal is to develop a rVSV-based vaccine against NiV (rVSV-NiVBG) that can provide both rapid protection and long term immunity against the most prevalent and pathogenic Bangladesh strain of NiV and to identify biomarkers that can be used to predict protection. In regard to product development, work will also be done to generate research cell bank (RCB) and viral vaccine bank (RVB), a manufacturing process, and conduct of GLP-safety toxicology.