Developing recombinant coronavirus vaccines for SARS

开发针对 SARS 的重组冠状病毒疫苗

• 批准号: 6818308
• 负责人: Xuming Zhang
• 金额: $ 51.77万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6818308
• 关键词: Coronaviridae; Macaca fascicularis; SDS polyacrylamide gel electrophoresis; cooperative study; cow; cytotoxic T lymphocyte; enzyme linked immunosorbent assay; flow cytometry; immune response; polymerase chain reaction; recombinant virus; severe acute respiratory syndrome; tissue /cell culture; vaccine development; vector vaccine; virus protein

DESCRIPTION (provided by applicant): The recent epidemic of the severe acute respiratory syndrome (SARS) is caused by a novel coronavirus, SARS-CoV. During the epidemic, more than 8,000 SARS cases and 812 deaths have been reported worldwide. With an ease of transmission and severity of the disease, SARS poses a great threat to public health and causes significant economic loss. It also presents a serious biodefense risk to the United States. To date, no effective anti-SARS drugs or vaccines are available. The long-term goal of this proposed research is to develop an efficacious vaccine for preventing future SARS epidemic. Current information obtained from studies on animal coronaviruses and their respective hosts suggests that the most promising vaccine for SARS would be a coronavirus-based live vaccine. However, the development of an attenuated, live SARS-CoV vaccine, though possible, is a long-term approach with an unpredictable outcome. Previously, the P.I. has isolated an enteric coronavirus from humans (termed HECoV), which is associated with acute, mild diarrhea but with no other severe clinical symptoms in children. Recent sequence analysis of the entire genome from our laboratory revealed that the HECoV isolate is most closely related to bovine coronavirus. Based on the tenet of a common mucosal immune system, antigenic stimulation by oral immunization is often very effective in inducing immunity to respiratory pathogens. Therefore, the P.I. proposes to develop a recombinant enteric HECoV expressing the antigenic proteins of the SARS-CoV as oral vaccines for SARS. Five aims are proposed: (1) to develop recombinant enteric HECoV expressing the ectodomain of the spike and other proteins of the SARS-CoV; (2) to characterize the biologic and genetic properties of the recombinant vaccines in cell culture; (3) to evaluate the safety and immunogenicity of the recombinant vaccines in germ-free calves; (4) to evaluate the safety, immunogenicity, and efficacy of the recombinant vaccines in non-human primates; (5) to develop a cell culture process for production of vaccines for human clinic trial (GMP).These studies will provide critical information for the development of an efficacious vaccine for SARS. The development of such a reverse genetic system will facilitate studies on molecular pathogenesis of coronaviruses and may provide potential avenues for development of vaccines for other severe infectious diseases such as AIDS.

描述（由申请人提供）：严重急性呼吸综合征（SARS）最近的流行病是由新型冠状病毒SARS-COV引起的。在流行病期间，全世界已有8,000多例SARS病例和812例死亡。 SARS易于传播和严重性，对公共卫生构成了巨大威胁，并造成了巨大的经济损失。它还给美国带来了严重的生物危险风险。迄今为止，尚无有效的抗SARS药物或疫苗。这项拟议研究的长期目标是开发一种有效的疫苗，以防止未来的SARS流行。从动物冠状病毒及其各自宿主的研究中获得的当前信息表明，SARS最有希望的疫苗是基于冠状病毒的活疫苗。但是，衰减，活体SARS-COV疫苗的发展是一种长期的方法，其结果是无法预测的。以前是P.I.已经从人类（称为Hecov）中分离出肠道冠状病毒，该病毒与急性，轻度腹泻有关，但没有其他严重的临床症状。对我们实验室的整个基因组的最新序列分析表明，Hecov分离株与牛冠状病毒最密切相关。基于常见的粘膜免疫系统的原则，口服免疫刺激通常非常有效地诱导对呼吸道病原体的免疫。因此，P.I.提议开发一种重组肠Hecov，以表达SARS-COV的抗原蛋白作为SARS的口服疫苗。提出了五个目的：（1）开发重组肠Hecov表达SARS-COV的尖峰和其他蛋白质的外生域； （2）表征重组疫苗在细胞培养中的生物学和遗传特性； （3）评估无菌犊牛重组疫苗的安全性和免疫原性； （4）评估重组疫苗在非人类灵长类动物中的安全性，免疫原性和功效； （5）为人类临床试验（GMP）开发生产疫苗的细胞培养过程。这些研究将为开发SAR的有效疫苗提供关键信息。这种反向遗传系统的发展将促进冠状病毒分子发病机理的研究，并可能为其他严重的传染病（如艾滋病）提供疫苗开发的潜在途径。