A novel strategy for developing a SARS-CoV vaccine

开发 SARS-CoV 疫苗的新策略

• 批准号: 7904591
• 负责人: Stanley Perlman
• 金额: $ 40.33万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-12 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7904591
• 关键词: ADP-Ribosylation Factors; Academia; Animals; Attenuated; Attenuated Live Virus Vaccine; Biological; Biology; Bioterrorism; Cells; China; Chiroptera; Clinical; Collaborations; Coronavirus; Data; Development; Disease; Disease Outbreaks; E protein; Engineering; Environment; Epidemic; Future; Gene Expression; Generations; Genes; Genetic; Genetic Recombination; Genome; Goals; Hamsters; Human; Immune; Immunocompetent; Immunology; Infection; Infectious Agent; Ion Channel; Joints; Laboratories; Laboratory Research; Life; Lung diseases; Modeling; Modification; Morbidity - disease rate; Mus; Mutate; Pathogenesis; Patients; Peptidyl-Dipeptidase A; Platelet Factor 4; Population; Private Sector; Proteins; Publications; Recombinants; Recurrence; Research; Risk; Safety; Severe Acute Respiratory Syndrome; System; Testing; Transgenic Mice; Vaccine Therapy; Vaccines; Viral; Virulence; Virus; Virus Diseases; Vision; Wild Animals; Wild Type Mouse; abstracting; aged; base; design; immunogenic; immunogenicity; in vivo; interest; mortality; novel; novel strategies; positional cloning; premature; protein expression; protein function; receptor; recombinant virus; success; tissue culture; tissue/cell culture; trafficking; vaccine candidate; vaccine development; weapons

PROJECT SUMMARY/ABSTRACT Project Summary: The Severe Acute Respiratory Syndrome, caused by a novel coronavirus (SARS-CoV), resulted in substantial morbidity and mortality in 2002-2003. With the lack of recurrence of SARS, research efforts to develop an effective vaccine have largely halted. However, coronaviruses similar to SARS-CoV have been identified in bats and other animal populations in China, making recurrence of SARS a possibility. Thus, we believe that cessation of efforts to develop a vaccine is premature. Our goal in this proposal is to develop a safe and immunogenic live attenuated vaccine for SARS-CoV. In preliminary results, we describe what we believe is the first candidate live attenuated vaccine. This recombinant virus lacks expression of the envelope (E) protein, which results in an attenuated virus that causes no disease in either hamsters or mice transgenic for expression of the SARS-CoV receptor (human angiotensin converting enzyme, hACE2) but when used to immunize these animals, provided partial protection against challenge with wild type SARS-CoV. The central objective of this proposal is to develop novel live attenuated SARS-CoV vaccines that express mutated E protein so that they are more immunogenic than E-deleted virus but remain as safe. This objective will be achieved in the following specific aims: 1) To optimize immunogenicity of rSARS-CoV-¿E virus by mutating rather than deleting the E protein. In this aim, we will delineate different regions of the E protein responsible for its various biological activities. 2) To develop a mouse- adapted rSARS-CoV with modified E protein expression, to develop rSARS-CoV-¿E lacking expression of one or more accessory proteins and to determine the basis of enhanced protective ability of rSARS-CoV-¿E after tissue culture passage. Mouse- adapted SARS-CoV causes pulmonary disease. We will develop recombinant viruses that express mutated E protein on this background. We will also optimize the vaccine by mutating other parts of the genome. 3) To test SARS-CoV-¿E and viruses expressing mutated E as vaccine candidates. As part of this aim, immune correlates of protection will be determined. We will also introduce additional modifications to the virus to make recombination with coronaviruses in the environment unlikely.

项目概要/摘要 项目摘要：由新型冠状病毒引起的严重急性呼吸系统综合症 （SARS-CoV）在 2002 年至 2003 年期间导致了很高的发病率和死亡率。随着缺乏 SARS复发后，开发有效疫苗的研究工作基本上停止了。 然而，在蝙蝠和其他动物中发现了与 SARS-CoV 类似的冠状病毒 中国的人口数量增加，使得SARS有可能再次发生。因此，我们认为停止 努力开发疫苗还为时过早。我们在该提案中的目标是开发一个安全且 SARS-CoV 免疫原性减毒活疫苗。在初步结果中，我们描述了什么 我们相信这是第一个候选减毒活疫苗。该重组病毒缺乏 包膜 (E) 蛋白的表达，产生减毒病毒，不会引起任何症状 表达 SARS-CoV 受体（人类）的转基因仓鼠或小鼠患有疾病 血管紧张素转换酶，hACE2），但当用于免疫这些动物时，提供 部分保护免受野生型 SARS-CoV 的攻击。本次活动的中心目标 建议开发表达突变 E 蛋白的新型 SARS-CoV 减毒活疫苗 因此它们比 E 删除病毒更具免疫原性，但仍然安全。这一目标将 可以实现以下具体目标：1）优化rSARS-CoV-¿E的免疫原性 通过突变而不是删除E蛋白来对抗病毒。为了这个目标，我们将划定不同的 E 蛋白的区域负责其各种生物活性。 2）开发鼠标- 改造 rSARS-CoV 并修饰 E 蛋白表达，开发 rSARS-CoV-¿ 缺乏一种或多种辅助蛋白的表达并确定其基础 组织培养传代后 rSARS-CoV-¿E 的保护能力增强。老鼠- 适应的 SARS-CoV 会引起肺部疾病。我们将开发重组病毒 在此背景下表达突变的E蛋白。我们还将通过变异来优化疫苗 基因组的其他部分。 3) 测试 SARS-CoV-¿E 和表达突变 E 的病毒 候选疫苗。作为该目标的一部分，将确定保护的免疫相关性。 我们还将对该病毒进行额外的修饰，以与 环境中不太可能存在冠状病毒。