Preclinical development of a vaccine for Nipah virus

尼帕病毒疫苗的临床前开发

• 批准号: 10369731
• 负责人: Thomas William Geisbert
• 金额: $ 117.98万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-11 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10369731
• 关键词: Advanced Development; Aman; Animals; Awareness; Bangladesh; Biological Assay; Biological Markers; Biological Response Modifier Therapy; Biotechnology; COVID-19 pandemic; Case Fatality Rates; Category C pathogen; Cells; Centers for Disease Control and Prevention (U.S.); Cluster randomized trial; Collaborations; Complement; Containment; Data; Development; Disease; Disease Outbreaks; Dose; Ebola; Ebola Hemorrhagic Fever; Ebola virus; Effectiveness; Encephalitis; Epidemic; European Union; Fatality rate; Fever; Funding; GTP-Binding Proteins; Glycoproteins; Government Agencies; Guinea; Health Personnel; Henipavirus; Human; Human Resources; Immunity; India; Infection; Injections; Laboratories; Lassa virus; Lead; Malaysia; Mammals; Marburgvirus; Methods; Morbidity - disease rate; Mus; National Institute of Allergy and Infectious Disease; Nature; Nipah Virus; Oryctolagus cuniculus; Pathogenicity; Pathologic; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Positioning Attribute; Preventive vaccine; Process; Publications; Recombinant Vaccines; Recombinants; Recording of previous events; Regulatory Affairs; Reporting; Research; Research Personnel; Respiratory Disease; Safety; Singapore; Stomatitis; Toxicology; United States Food and Drug Administration; United States National Institutes of Health; Vaccination; Vaccines; Vesicular stomatitis Indiana virus; Viral Vaccines; Virus; Virus Diseases; Work; World Health Organization; Zoonoses; animal rule; base; cell bank; experience; improved; manufacturing process; medical countermeasure; meetings; mortality; nervous system disorder; neurotoxicity; nonhuman primate; open label; pandemic disease; pathogen; phase I trial; preclinical development; prevent; priority pathogen; product development; programs; research and development; respiratory pathogen; transmission process; vaccine development; vaccine evaluation; vaccine platform; vaccine safety; vaccine-induced antibodies; vector vaccine

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.

项目总结/摘要 尼帕病毒（NiV）在人类中引起发热性脑炎和严重呼吸道疾病， 在某些暴发中为100%（过去十年暴发的平均值约为75%）。目前没有许可的 疫苗或疗法来对抗NiV疾病。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， 传播的便利性。除了作为自然获得性感染引起发病率和死亡率外，NiV还 也被几个美国政府机构归类为C类优先病原体， 故意滥用重要的是，NiV最近被列入世界卫生组织（WHO）2018年 优先病原体列表。由于前所未有的COVID-19全球大流行， 对呼吸道病原体的关注和认识。2020年3月，美国CDC 建议将NiV添加到Tier 1 Select Agent列表中。研究制定有效对策 NiV的高致病性及其对BSL-4遏制的限制阻碍了研究。有效 预防性疫苗将在疾病暴发期间应用于医务人员和密切接触者， 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）是一种由许多高致病性病毒的糖蛋白（GP）假型化的病毒 已显示完全保护非人灵长类动物（NHP）免受埃博拉病毒、马尔堡病毒和拉沙病毒的侵害。 此外，还证明了rVSV载体疫苗在预防埃博拉病毒病方面的有效性 在2013-16年埃博拉疫情期间在几内亚进行的一项环形疫苗接种，开放标签，随机分组试验中。这 该疫苗最近被欧盟和美国FDA批准为ERVEBO。最近，我们开发了 表达NiV糖蛋白的复制限制性rVSV NiV疫苗载体。重要的是，我们发现， 这些疫苗可以完全保护NHP免受高剂量致死性孟加拉国NiV毒株攻击， 用作单次注射疫苗。这些新数据对于控制疫情至关重要， 在抑制呼吸道病原体和预防大流行方面最有效的疫苗是 在一个行政部门迅速运作。开发一个复制受限平台， 安全而不影响疗效是一个非常重要的进步，可以应用于其他病毒 有可能引发大流行该提案的主要目标是开发针对NiV的基于rVSV的疫苗 （rVSV-NiVBG），其可以提供针对最流行和最不受欢迎的病毒的快速保护和长期免疫。 孟加拉国致病性NiV毒株，并鉴定可用于预测保护的生物标志物。关于 在产品开发方面，还将建立研究细胞库和病毒疫苗库 (RVB)生产工艺和GLP-安全毒理学的实施。