Development of Safer,Live Attenuated Rift Valley Fever Vaccines

开发更安全的裂谷热减毒活疫苗

基本信息

批准号：
9091408
负责人：
Shinji Makino
金额：
$ 19.38万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-17 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9091408
关键词：
Acute Africa South of the Sahara Age Agriculture Amino Acids Animals Antiviral Response Arthralgia Attenuated Attenuated Vaccines Bioterrorism Bunyaviridae Categories Cattle Cell Culture Techniques Cell membrane Centers for Disease Control and Prevention (U.S.)Cessation of life Containment Country Culicidae Cultured Cells Data Development Disease Disease Outbreaks Double-Stranded RNA Economics Egypt Encephalitis Endemic Diseases Epidemic Exhibits Family Farming environment Fever Fluorouracil General Population Genetic Genetic Transcription Genome Genus Phlebovirus Glycoproteins Headache Health Health Status Hepatitis Human Humoral Immunities Immune response Immunity Immunization Immunocompromised Host Individual Infection Inflammatory Interferons Invaded Kenya Laboratories Licensing Life Literature Livestock Madagascar Mass Vaccinations Mauritania Mediating Membrane Fusion Messenger RNA Movement Mus Mutate Mutation Myalgia National Institute of Allergy and Infectious Disease Neuraxis Neurologic North America Panic Patients Photophobia Play Population Production Property Proteins Public Health RNA RNA chemical synthesis Research Retinal Retinal Vasculitis Rift Valley Fever Rift Valley fever virus Role Ruminants SCID Mice Safety Saudi Arabia Senegal Serial Passage Sheep South Africa Spontaneous abortion Systemic infection Testing Time Vaccination Vaccines Viral Viral Envelope Proteins Viral Hemorrhagic Fevers Viral Nonstructural Proteins Viral Proteins Virion Virulence Factors Virus Virus Assembly Virus Diseases Virus Replication Visual impairment Wild Animals Yemen base biosecurity chemokine cytokine eIF-2 Kinase economic impact immunogenic immunogenicity improved innate immune function intraperitoneal macula member mouse model mutant neurovirulence novel pathogen prevent programs promoter protective efficacy protein function safety testing vaccine candidate vector viral transmission

项目摘要

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.

说明（由申请人提供）：裂谷热病毒 (RVFV) 是一种典型的白蛉病毒（布尼亚病毒科），属于 NIAID A 类病原体清单和 CDC 潜在生物恐怖主义病原体清单，RVFV 会导致亚种流行疾病。 - 撒哈拉非洲地区可能会出现爆发性、蚊媒损失的流行病，导致羊群和牛群大量死亡，给人类带来巨大的经济损失。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 传播的有效媒介。因此，RVFV 传入北美可能会引起普通人群的恐慌，并对牲畜造成影响。诱导针对病毒包膜蛋白的体液免疫反应对于提供针对 RVFV 的保护是必要且充分的，目前还没有适合大规模人类疫苗接种计划的 RVFV 疫苗。 MP-12株是通过野生型RVFV株ZH548在5-氟尿嘧啶存在下连续传代获得的，在小鼠中明显减毒，但保留了其免疫原性。然而，将MP-12腹膜内接种到幼鼠或小鼠中。 SCID 小鼠导致病毒在动物中枢神经系统中有效复制在考虑大规模疫苗接种时，MP-12 的神经侵袭性和神经毒力潜力是一个值得关注的问题。本申请提出通过在病毒包膜糖蛋白Gc和毒力因子NS中选择性地引入突变来开发新型且更安全的MP-12衍生疫苗候选物。废除这些蛋白质的特定功能并产生“残缺的”MP-12 我们将测试这一假设，即这种基于 MP-12 的候选疫苗在小鼠中表现出比 MP-12 更好的安全性，但仍保留其特性。在本提案中，我们将检查其在培养细胞中的遗传稳定性，并使用小鼠模型评估其安全性、免疫原性和保护功效。