Vaccines and Therapeutics for Nipah and Hendra virus

性状（由申请方提供）：广泛的种嗜性和在动物和人类中引起致死性疾病的能力将亨德拉病毒、尼帕病毒（NiV）和亨德拉病毒（HeV）与所有其他已知副粘病毒区分开来。这些病毒可以扩增并在动物中引起疾病，并传播给人类，感染表现为严重的呼吸道疾病和/或发热性脑炎。它们被归类为BSL-4选择剂，具有使其高度适用于用作生物恐怖剂的若干特性。HeV于1994年首次在澳大利亚出现，并从受感染的马传播给人类; NiV于1998-99年在马来西亚出现，主要是从受感染的猪传播给人类，但也有几种动物物种被感染。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年在同一地区的另一次爆发夺去了12人的生命，2007年在印度最近出现的一次爆发夺去了5人的生命。HeV在1999年、2004年和2006年在澳大利亚再次出现，有马的致命感染病例和一例非致命的血清转化人类病例。公共卫生相关性：在最近的NiV疫情中，重要的观察结果是急性呼吸窘迫综合征的发病率较高，人际传播，病死率较高（约75%），与受感染的牲畜或家畜无关。现在，治疗和疫苗策略的发展很重要。在过去的几年中，我们已经进行了广泛的病毒包膜糖蛋白（F和G），病毒装配机制的表征，开发病毒融合抑制剂，并确定了HeV和NiV（ephrinB 2）的细胞受体。最近，我们已经表征了可溶性G糖蛋白（sG）作为亚单位疫苗，NiV感染的猫模型，并已证明sG可以保护免受NiV攻击。我们还分离和鉴定了有效的中和性全人抗G单克隆抗体，并绘制了G受体结合位点。该提案的目的是：充分表征尼帕病毒感染的雪貂模型，并评估现有的和发现新的治疗尼帕和亨德拉病毒感染的治疗方法。具体目的是：1）建立雪貂模型中NiV的病毒感染、致死剂量和检测参数。2)评价sG作为NiV亚单位疫苗在雪貂中的保护效力。3)确定中和、抗G、全人源单克隆抗体治疗猫和雪貂NiV感染的被动保护效力。4)确定NiV sG与其受体ephrinB 2复合物的溶液结构，并进行G-受体相互作用的小分子抑制剂的结构依赖性设计和结构非依赖性高通量筛选发现。

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.