Development of a Novel Rift Valley Fever Virus Vaccine

描述(由申请人提供)：裂谷热病毒(RVFV)是布尼亚病毒科白喉病毒属的典型病毒，属于NIAID A类病原体和CDC潜在生物恐怖主义病原体名单。裂谷热是撒哈拉以南非洲的一种地方性疾病，可通过蚊子传播的爆炸性疫情出现，导致成群的羊和牛死亡，并造成巨大的经济损失；人类同时感染，他们的感染会导致出血热、脑炎和视网膜血管炎。许多不同的蚊子，包括几种原产于北美的蚊子，都是RVFV疫情传播的合格媒介。RVFV引入北美可能会在普通人群中引起恐慌，对牲畜的影响可能会对经济产生毁灭性的影响。尽管针对病毒包膜蛋白的体液免疫可引起保护性免疫，但目前尚无适用于大规模人类疫苗接种的RVFV疫苗。MP-12株是由野生型RVFV ZH548株连续传代12代而成，对小鼠有明显的减毒作用，但仍具有免疫原性。然而，在幼鼠体内接种MP-12后，病毒在中枢神经系统得到了有效的复制。MP-12的神经毒力是为公众开发针对这种病毒的免疫方法的一个问题；MP-12可能会在遗传易感或暂时免疫受损的个人的中枢神经系统中有效地入侵和复制。本申请提出了一种新的RVFV疫苗策略的开发，其中基于MP-12的伪传染病病毒(PIV)在免疫后经历单周期病毒复制和产生非传染性的病毒样颗粒。由于PIV的单循环复制特征，PIV不太可能引起全身感染并入侵免疫动物和人的中枢神经系统；但我们预计，PIV的单循环复制和免疫原性病毒样颗粒的释放将联合作用，诱导对RVFV蛋白的强烈免疫反应。我们将测试PIV的免疫原性、神经侵袭性和神经毒力，并在小鼠模型上检查PIV免疫是否对Wt RVFV攻击后免疫的动物提供保护。建议的研究将对产生高免疫原性RVFV候选疫苗有价值，该候选疫苗具有更高的安全性，并适用于未来的产品开发和人体试验。

DESCRIPTION (provided by applicant): Rift Valley fever virus (RVFV) is a prototypical virus of the genus Phlebovirus, family Bunyaviridae, and belongs to the NIAID Category A list pathogens and the CDC list of potential bioterrorism agents. Rift Valley fever is an endemic disease of sub-Saharan Africa that can emerge in explosive mosquito-borne epidemics, decimating herds of sheep and cattle and resulting in enormous economic losses; humans are infected concurrently, and their infection results in hemorrhagic fever, encephalitis, and retinal vasculitis. Many different mosquitoes, including several native to North America, are competent vectors for RVFV epidemic transmission. The introduction of RVFV into North America would likely cause panic in the general population, and the effects on livestock could have a devastating economic impact. Although humoral immunity against the viral envelope proteins elicits protective immunity, there is currently no RVFV vaccine suitable for massive human vaccination programs. MP-12 strain, which was developed by 12 times serial passage of the wild-type RVFV strain ZH548, is markedly attenuated for mice, yet retains immunogenicity. However, the intraperitoneal inoculation of MP-12 into young mice resulted in efficient virus replication in the CNS. The neurovirulence of MP-12 is a concern in developing an immunization method against this virus for the general public; it is possible that MP-12 may invade and replicate efficiently in the CNS of genetically predisposed or temporarily immuno-compromised individuals. The present application proposes development of a novel RVFV vaccine strategy, in which MP-12-based pseudo infectious viruses (PIVs) undergo single-cycle virus replication and production of non- infectious, virus-like particles after immunization. Due to a feature of single-cycle replication, the PIV is highly unlikely to cause systemic infection and invade the CNS of immunized animals and people; yet we expect that a combined effect of single-cycle replication of the PIV and release of immunogenic, virus-like particles will induce a strong immune response to RVFV proteins. We will test the immunogenicity, neuroinvasiveness and neurovirulence of the PIV and examine whether PIV immunization confers protection to animals immunized following wt RVFV challenge in mouse models. The proposed studies will be valuable for generation of a highly immunogenic RVFV vaccine candidate with increased safety and suitable for future product development and human testing.