Vaccines and Therapeutics for Nipah and Hendra virus

描述（由申请人提供）：亨尼帕病毒具有广泛的物种亲和性和在动物和人类中引起致命疾病的能力；尼帕病毒（NiV）和亨德拉病毒（HeV）从所有其他已知的副粘病毒。这些病毒可扩增并在动物中引起疾病，并可传播给人类，其感染表现为严重呼吸道疾病和/或发热性脑炎。它们被归类为BSL-4选择剂，并具有一些特性，使它们具有高度适应性，可作为生物恐怖剂使用。戊肝病毒于1994年首次在澳大利亚出现，并由受感染的马传播给人类；NiV于1998-99年在马来西亚出现，主要由受感染的猪传染给人类，但也有几种动物被感染。这两种病毒继续重新出现；2004年，孟加拉国爆发了两次NiV疫情，造成约65例人间病例。2005年在同一地区爆发的另一次疫情夺去了12人的生命，最近2007年在印度出现的疫情夺去了5人的生命。澳大利亚于1999年、2004年和2006年再次出现了戊肝病毒，出现了马的致命感染病例和一例血清转化的非致命人间病例。公共卫生相关性：在最近的NiV暴发中，重要的观察结果是急性呼吸窘迫综合征的发生率较高，人际传播，病死率较高（约75%），并且与受感染的牲畜或家畜没有联系。治疗方法和疫苗战略的发展现在很重要。在过去的几年中，我们对病毒包膜糖蛋白（F和G）、病毒组装机制进行了广泛的表征，开发了病毒融合抑制剂，并鉴定了HeV和NiV的细胞受体（ephrinB2）。最近，我们将一种可溶性G糖蛋白（sG）作为一种亚单位疫苗，作为新冠病毒感染的猫模型，并证明sG可以预防新冠病毒的侵袭。我们还分离和鉴定了强效中和的全人抗G单克隆抗体，并绘制了G受体结合位点的图谱。本提案的目标是：充分表征尼帕病毒感染的雪貂模型，评估现有的和发现治疗尼帕和亨德拉病毒感染的新治疗方式。具体目的是：1)在雪貂模型中建立NiV病毒感染、致死剂量和检测参数。2)评价sG作为雪貂新冠病毒亚单位疫苗的保护效果。3)确定中和、抗g、全人源单克隆抗体治疗猫和雪貂NiV感染的被动保护效果。4)确定NiV sG与其受体ephrinB2复合物的溶液结构，并进行结构依赖设计和结构独立的高通量筛选发现g受体相互作用的小分子抑制剂。

DESCRIPTION (provided by applicant): The broad species tropisms and the ability to cause fatal disease in both animals and humans have distinguished the Henipaviruses; Nipah virus (NiV) and Hendra virus (HeV) from all other known paramyxoviruses. These viruses can be amplified and cause disease in animals and be transmitted to humans where infection is manifested as a severe respiratory illness and/or febrile encephalitis. They are classified as BSL-4 select agents and possess several characteristics which make them highly adaptable for their use as bioterror agents. HeV appeared first in Australia in 1994 and was transmitted to humans from infected horses; NiV appeared in 1998-99 in Malaysia and was predominantly passed from infected pigs to humans, but several animal species were also infected. Both viruses continue to re-emerge; in 2004 two NiV outbreaks in Bangladesh caused some 65 human cases. Another outbreak in 2005 in the same area claimed 12 lives, and a recent emergence in India in 2007 has taken 5 lives. HeV has reappeared in Australia in 1999, 2004 and 2006, with cases of fatal infection in horses and one non-fatal, sero-converting, human case. Public health relevance: Significant observations in the most recent NiV outbreaks have been a higher incidence of acute respiratory distress syndrome, person-to-person transmission, higher case fatality rates (~75%), and no link to infected livestock or domestic animals. The development of therapeutics and vaccine strategies is now important. Over the past several years we have performed an extensive characterization of the viral envelope glycoproteins (F and G), virus assembly mechanisms, developed viral fusion inhibitors and identified the cellular receptor for both HeV and NiV (ephrinB2). Recently, we have characterized a soluble G glycoprotein (sG) as a subunit vaccine, a cat model for NiV infection and have demonstrated that sG can protect against NiV challenge. We have also isolated and characterized potent neutralizing fully-human anti- G monoclonal antibodies and have mapped the receptor binding site on G. The objectives of this proposal are to: fully characterize a ferret model of Nipah virus infection, and evaluate existing and discover new therapeutic modalities for treating Nipah and Hendra virus infection. The Specific Aims are: 1) Establish virus infection, lethal dose, and detection parameters of NiV in a ferret model. 2) Evaluate the protective efficacy of sG as a subunit vaccine for NiV in the ferret. 3) Determine the passive protective efficacy of neutralizing, anti-G, fully-human monoclonal antibody therapy for NiV infection in the cat and ferret. 4) Determine the solution structure of NiV sG in complex with its receptor ephrinB2, and perform both structure-dependent design and structure-independent High-Throughput-Screening discovery of small- molecule inhibitors of the G-receptor interaction.