A Sindbis virus-based Vaccine Against RVFV Infection

描述（由申请人提供）：布尼亚病毒科的白蛉病毒属是一组节肢动物传播的病毒，通常以蚊子和苍蝇为媒介，多种动物为主要宿主。目前已知的定义这一群体的50多个成员广泛分布在两个半球。白蛉病毒属包含一系列可在人类和家畜中引起致命疾病的重要病原体。我们的研究计划侧重于研制一种对抗裂谷热病毒（RVFV）的疫苗。该病毒可通过多种蚊子传播，并传播到遥远的地理地点，从而引发动物流行病。最近，裂谷热病毒于1997- 1998年在撒哈拉以南非洲造成大规模流行，并越过红海蔓延到沙特阿拉伯和也门，在羊和牛中造成毁灭性的疾病暴发。RVFV有可能用于生物恐怖主义，它对美国农业利益的预期影响可能是巨大的。目前还没有针对人类的治疗方法，也没有针对牲畜的疫苗，而牲畜是这种病毒的重要传播者。存在一种用于人类的实验性疫苗，但剂量数量有限，而且没有未来生产的前景。我们提出以表达裂谷热病毒结构蛋白的Sindbis病毒复制子为基础，开发一种抗裂谷热病毒感染的重组疫苗原型。复制子将被包装成由Sindbis和其他α病毒的结构蛋白组成的病毒颗粒。这些颗粒的免疫将有效地防止裂谷热病毒感染，并且有可能在工业规模上生产这种疫苗。该疫苗将结合减毒活疫苗的有效性和亚单位疫苗的安全性。在本研究中，我们将确定i)重组Sindbis病毒表达RVFV结构蛋白的最佳策略，ii)将重组基因组传递到抗原呈递细胞的系统，以及iii)重组病毒大规模生产的制造过程。这项研究对于制定针对新发感染的疫苗开发的总体战略非常重要，这些疫苗需要快速设计和大规模生产以供立即使用。

DESCRIPTION (provided by applicant): The Phlebovirus genus of the Bunyaviridae family is a group of arthropod-borne viruses, having mosquitoes and flies as the usual vectors and a wide variety of animals as primary hosts. Over fifty currently known members defining this group are widely distributed in both hemispheres. The Phlebovirus genus contains a spectrum of important pathogens that can cause fatal disease in humans and domestic animals. Our research plan focuses on creating a vaccine against the Rift Valley fever virus (RVFV). This virus can be transmitted by a wide variety of mosquitoes and spread to distant geographical sites to initiate epizootics. Most recently, RVFV caused a massive epidemic in sub-Saharan Africa in 1997-98 and spread across the Red Sea to Saudi Arabia and Yemen, causing devastating disease outbreaks in sheep and cattle. The RVFV has potential for use in bioterrorism, and its projected effect on U.S. agricultural interests would likely be immense. There is no treatment for humans or vaccine for the livestock that are such important amplifiers of the virus. An experimental vaccine exists for humans, but the number of doses is limited, and there are no prospects for future manufacture. We propose to develop a prototype recombinant vaccine against RVFV infection based on Sindbis virus replicons expressing structural proteins of RVFV. Replicons will be packaged into viral particles composed by structural proteins of Sindbis and other alpha viruses. Immunization by these particles will efficiently protect against RVFV infection, and it will be possible to manufacture this vaccine on an industrial scale. This vaccine will combine the efficiency of live attenuated vaccines and safety of the subunit vaccines. In this proposal we will identify i) the optimal strategy for expression of structural proteins of RVFV by recombinant Sindbis virus, ii) a system for delivery of recombinant genomes into antigen-presenting cells, and iii) the manufacturing procedure for large-scale production of the recombinant viruses. The study will be important for creating a general strategy for development of vaccines against emerging infections, vaccines that require fast design and large-scale production for immediate use.