Development of Safer,Live Attenuated Rift Valley Fever Vaccines

 描述(申请人提供)：裂谷热病毒(RVFV)是一种典型的白喉病毒(布尼亚病毒科)，属于NIAID A类病原体名单和CDC潜在生物恐怖主义因素名单。RVFV导致一种在撒哈拉以南非洲流行的疾病，并可在蚊媒传播的爆炸性流行病中出现，导致成群的羊和牛死亡，造成巨大的经济损失。在人类中，RVFV感染可能会导致出血热、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传播的合格媒介。因此，将RVFV引入北美可能会在普通民众中引起恐慌，对牲畜的影响可能会对经济产生毁灭性的影响。诱导针对病毒包膜蛋白的体液免疫反应是必要和充分的，以提供对RVFV的保护。目前，还没有适合大规模人类接种计划的RVFV疫苗。MP-12株是野生型RVFV ZH548株在5-氟尿嘧啶存在下连续12代获得的，在小鼠体内有明显的减毒作用，但仍保持其免疫原性。然而，将MP-12接种到幼鼠或SCID小鼠体内，可以在动物的中枢神经系统中有效地复制病毒。MP-12的神经侵袭性和神经毒力潜力是一个令人担忧的问题，当考虑到普通公众的大规模疫苗接种，特别是在免疫受损的个人。本申请建议通过在病毒包膜糖蛋白GC和毒力因子NSS中引入突变来开发一种新的、更安全的MP-12衍生疫苗候选。这种突变选择性地取消了这些蛋白质的特定功能，并产生了一种“残缺的”MP-12。我们将测试这一假设，即这种基于MP-12的候选疫苗在小鼠身上表现出比MP-12更好的安全性，但仍然保持其免疫原性和保护效力。在这项建议中，我们将检测其在培养细胞中的遗传稳定性，并通过使用小鼠模型来评估其安全性、免疫原性和保护效果。

 DESCRIPTION (provided by applicant): Rift Valley fever virus (RVFV), a prototypical Phlebovirus (family Bunyaviridae), belongs to the NIAID Category A list of pathogens and the CDC list of potential bioterrorism agents. RVFV causes a disease that is endemic in sub-Saharan Africa and can emerge in explosive, mosquito-borne epidemics decimating herds of sheep and cattle, resulting in enormous economic losses. In humans, RVFV infection may cause hemorrhagic fever, encephalitis, and retinal vasculitis. Many different mosquitoes, including several native to North America, are competent vectors for RVFV transmission. Thus, 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. Induction of a humoral immune response against the viral envelope proteins is necessary and sufficient to provide protection against RVFV. Currently, there is no RVFV vaccine suitable for mass human vaccination programs. The MP-12 strain, which was obtained by 12 serial passages of the wild-type RVFV strain ZH548 in the presence of 5-fluorouracil, is markedly attenuated in mice but retains its immunogenicity. However, intraperitoneal inoculation of MP-12 into young mice or SCID mice results in efficient virus replication in the animals' central nervous system. The neuroinvasiveness and neurovirulence potential of MP-12 is a matter of concern when considering the mass vaccination of the general public, especially, in immunocompromised individuals. The present application proposes the development of a novel and safer MP-12-derived vaccine candidate by introducing mutations in the viral envelope glycoprotein, Gc, and the virulence factor, NSs. The mutation selectively abolishes specific functions of these proteins and creates a "crippled" MP-12. We will test the hypothesis that this MP-12-based vaccine candidate exhibits a better safety profile than MP-12 in mice but still retains its immunogenicity and protective efficacy. In this proposal, we will examine its genetic stability in cultured cells nd assess its safety, immunogenicity, and protective efficacy by using mouse models.