Development of Safer,Live Attenuated Rift Valley Fever Vaccines

开发更安全的裂谷热减毒活疫苗

• 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
• 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

 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.

 描述（由申请方提供）：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类病原体列表和CDC潜在生物恐怖主义因子列表。RVFV在撒哈拉以南非洲地区引起一种地方性疾病，并可能以爆炸性的蚊媒流行病出现，大量牛羊死亡，造成巨大的经济损失。在人类中，RVFV感染可引起出血热、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传播的有效载体。因此，将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产生毁灭性的经济影响。诱导针对病毒包膜蛋白的体液免疫应答对于提供针对RVFV的保护是必要且足够的。目前，没有适用于大规模人类疫苗接种计划的RVFV疫苗。在5-氟尿嘧啶存在下，通过野生型RVFV毒株ZH 548的12次连续传代获得的MP-12毒株在小鼠中显著减毒，但保留其免疫原性。然而，将MP-12腹膜内接种到幼龄小鼠或SCID小鼠中导致动物中枢神经系统中的有效病毒复制。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，当考虑大规模接种疫苗的一般公众，特别是在免疫功能低下的个人。本申请提出了通过在病毒包膜糖蛋白Gc和毒力因子NS中引入突变来开发新的且更安全的MP-12衍生疫苗候选物。这种突变选择性地消除了这些蛋白质的特定功能，并产生了一种“残废”的MP-12。我们将检验这一假设，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，但仍保留其免疫原性和保护效力。在本研究中，我们将检测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，免疫原性和保护效力。