A Sindbis virus-based Vaccine Against RVFV Infection

描述(申请人提供)：布尼亚病毒科的白喉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，以多种动物为主要宿主。目前已知的50多个定义这一组的成员广泛分布在两个半球。白喉病毒属包含一系列重要的病原体，可导致人类和家畜的致命疾病。我们的研究计划重点是创造一种针对裂谷热病毒(RVFV)的疫苗。这种病毒可以通过多种蚊子传播，并传播到遥远的地理位置，从而引发家禽流行性感冒。最近，RVFV于1997-98年在撒哈拉以南非洲地区引发大规模疫情，并跨越红海蔓延至沙特阿拉伯和也门，在羊和牛中造成毁灭性的疾病暴发。RVFV具有用于生物恐怖主义的潜力，预计它对美国农业利益的影响可能是巨大的。目前还没有针对人类的治疗方法，也没有针对家畜的疫苗，因为它们是病毒的如此重要的传播者。目前已有一种用于人类的实验性疫苗，但剂量有限，未来也没有制造的前景。我们建议基于表达RVFV结构蛋白的Sindbis病毒复制子，开发一种针对RVFV感染的重组疫苗原型。复制子将被包装成由Sindbis和其他阿尔法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预防RVFV感染，并将有可能在工业规模生产这种疫苗。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。在这项建议中，我们将确定1)重组辛德比斯病毒表达RVFV结构蛋白的最佳策略，2)将重组基因组输送到抗原提呈细胞的系统，以及3)大规模生产重组病毒的制造程序。这项研究将对制定针对新出现感染的疫苗开发的总体战略具有重要意义，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.