Development of a Novel Rift Valley Fever Virus Vaccine

描述（由申请人提供）：裂谷热病毒（RVFV）是布尼亚病毒科白蛉病毒属的一种典型病毒，属于NIAID a类病原体和CDC潜在生物恐怖主义制剂清单。裂谷热是撒哈拉以南非洲的一种地方性疾病，可以蚊子传播的爆炸性流行病出现，使牛羊大批死亡，造成巨大的经济损失；人类同时被感染，他们的感染导致出血热、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，都是裂谷热病毒流行传播的有效媒介。将裂谷热病毒引入北美可能会引起一般人群的恐慌，对牲畜的影响可能会产生毁灭性的经济影响。尽管针对病毒包膜蛋白的体液免疫可引起保护性免疫，但目前还没有适合大规模人类疫苗接种计划的裂谷热病毒疫苗。由野生型RVFV ZH548连续传代12次得到的MP-12毒株对小鼠有明显的减毒作用，但仍保持免疫原性。然而，幼年小鼠腹腔注射MP-12可导致病毒在中枢神经系统内的高效复制。MP-12的神经毒性是为公众开发针对该病毒的免疫方法所关注的问题；MP-12可能在基因易感或暂时免疫受损个体的中枢神经系统中侵入并有效复制。本申请提出了一种新的RVFV疫苗策略，其中基于mp -12的伪传染性病毒（piv）在免疫后进行单周期病毒复制并产生非传染性病毒样颗粒。由于其单周期复制的特点，PIV极不可能引起全身感染和侵入免疫动物和人的中枢神经系统；然而，我们预计单周期复制PIV和释放免疫原性病毒样颗粒的联合作用将诱导对裂谷热病毒蛋白的强烈免疫反应。我们将在小鼠模型中测试PIV的免疫原性、神经侵袭性和神经毒力，并研究PIV免疫是否能保护在RVFV攻击后免疫的动物。拟议的研究将对产生高度免疫原性的RVFV候选疫苗具有价值，该疫苗具有更高的安全性，适合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.