Development of a Novel Rift Valley Fever Virus Vaccine

新型裂谷热病毒疫苗的开发

• 批准号: 8509347
• 负责人: Shinji Makino
• 金额: $ 23.18万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-15 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8509347
• 关键词: Acute; Africa South of the Sahara; Age; Agriculture; Animals; Antigens; Arthralgia; Attenuated; Attenuated Vaccines; Bioterrorism; Bunyaviridae; Categories; Cattle; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Containment; Country; Culicidae; Data; Development; Disease; Disease Outbreaks; Economics; Egypt; Encephalitis; Endemic Diseases; Epidemic; Family; Farming environment; Fever; Future; Gene Expression; General Population; Generations; Genetic; Genome; Genus Phlebovirus; Headache; Health Status; Hepatitis; Human; Humoral Immunities; Immune response; Immunity; Immunization; Immunocompromised Host; Individual; Infection; Invaded; Kenya; Laboratories; Licensing; Literature; Livestock; Madagascar; Mauritania; Methods; Movement; Mus; Mutate; Myalgia; National Institute of Allergy and Infectious Disease; Neurologic; North America; Panic; Patients; Photophobia; Population; Production; Property; Proteins; Public Health; RNA; RNA replication; Research; Retinal; Retinal Vasculitis; Rift Valley Fever; Rift Valley fever virus; Ruminants; SCID Mice; Safety; Saudi Arabia; Senegal; Serial Passage; Sheep; South Africa; Spontaneous abortion; System; Systemic infection; Testing; Time; Vaccination; Vaccines; Viral; Viral Antigens; Viral Envelope Proteins; Viral Genes; Viral Hemorrhagic Fevers; Viral Proteins; Virus; Virus Replication; Virus-like particle; Vision; Wild Animals; Yemen; base; biosecurity; cost; economic impact; env Gene Products; immunogenic; immunogenicity; intraperitoneal; macula; member; mouse model; mutant; neurovirulence; novel; pathogen; prevent; product development; programs; protective efficacy; public health relevance; safety testing; transmission process; vaccine candidate; vector; viral RNA

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.

描述（由申请方提供）：裂谷热病毒（RVFV）是布尼亚病毒科白蛉病毒属的一种原型病毒，属于NIAID A类病原体列表和CDC潜在生物恐怖主义因子列表。裂谷热是撒哈拉以南非洲的一种地方性疾病，可以在爆发性蚊媒流行病中出现，杀死羊群和牛群，造成巨大的经济损失;人类同时感染，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，是RVFV流行病传播的主管媒介。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。尽管针对病毒包膜蛋白的体液免疫增强了保护性免疫，但目前还没有适用于大规模人类疫苗接种计划的RVFV疫苗。MP-12株是由野生型RVFV株ZH 548连续传代12次而获得的，对小鼠具有显著的减毒作用，但仍具有免疫原性。然而，将MP-12腹腔接种到幼龄小鼠中导致CNS中的有效病毒复制。MP-12的神经毒力是为公众开发针对该病毒的免疫方法的一个问题; MP-12可能在遗传易感或暂时免疫功能低下个体的CNS中有效侵入和复制。本申请提出了开发新的RVFV疫苗策略，其中基于MP-12的假感染性病毒（PIV）在免疫后经历单循环病毒复制和非感染性病毒样颗粒的产生。由于单循环复制的特征，PIV极不可能引起全身性感染并侵入免疫动物和人的CNS;但我们预期PIV的单循环复制和释放免疫原性病毒样颗粒的组合效应将诱导对RVFV蛋白的强烈免疫应答。我们将测试PIV的免疫原性、神经侵袭性和神经毒力，并检查PIV免疫是否对小鼠模型中野生型RVFV攻毒后免疫的动物提供保护。所提出的研究对于产生具有增加的安全性且适合于未来产品开发和人类测试的高免疫原性RVFV疫苗候选物将是有价值的。