Modification Of Antigenicity & Virulence Of Rotaviruses

抗原性修饰

• 批准号: 7196633
• 负责人: JOHN PATTON
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7196633
• 关键词: Rotavirus; biotechnology; cell line; diarrhea; enzyme linked immunosorbent assay; host organism interaction; immunogenetics; interferons; microorganism immunology; pediatric pharmacology; polymerase chain reaction; positional cloning; recombinant virus; rotavirus vaccines; transcription factor; transfection /expression vector; vaccine development; vaccinia virus; virulence; virus antigen; virus genetics; virus infection mechanism; virus protein

Rotaviruses are the primary cause of acute dehydrating diarrhea in infants and young children and are responsible for ~440,000 deaths worldwide per year. Their impact on human health has stimulated extensive efforts towards the development of rotavirus vaccines by the Laboratory of Infectious Diseases (LID). Large scale phase III trials have shown that a rhesus-based rotavirus tetravalent vaccine developed by the LID is highly effective in protecting against the severe and life-threatening dehydrating diarrhea caused by these viruses. The tetravalent vaccine was approved for use in humans by the FDA, marketed by as Rotashield, and administered to approximately one million children. However, because of concerns that the vaccine may infrequently induce intussusception, the use of the vaccine at the present time has been discontinued. Due to the great impact that rotavirus illness continues to have on human mortality and morbidity, it remains a goal of the Laboratory to develop vaccines against these agents that are effective and safe. The primary goal of this project is the development of a reverse genetics system that can be used to alter the genetic information of the rotavirus genome. Such a system can be used to identify loci within the genome that define the growth characteristics, antigenic properties, and virulence of rotaviruses. With this knowledge, the system can be used to create a new generation of vaccines by the introduction of mutations into the genome of virulent isolates of human rotaviruses. Secondary goals of this project include (i) identification of viral gene products that interfere with innate cellular immune responses, and thereby affect the virulence of the virus, and (ii) analysis of the impact that host cell lines have on the protein coding capacity of vaccine strains of rotavirus. In the past year, progress was made in understanding the mechanism by which rotavirus subverts the innate immune response of the host.

轮状病毒是婴儿和幼儿急性脱水腹泻的主要原因，全球造成约440,000人死亡。它们对人类健康的影响激发了传染病实验室（LID）实验室开发轮状病毒疫苗的广泛努力。大规模III期试验表明，由盖子开发的基于恒河猴的轮状病毒四重病毒疫苗在防止这些病毒引起的严重且威胁生命的脱水腹泻方面非常有效。四载疫苗已被FDA批准在人类中使用，该疫苗由rotashield销售，并给予了大约一百万儿童。但是，由于担心该疫苗可能很少会诱导肠套，因此目前已经停止使用疫苗。由于轮状病毒疾病继续对人类死亡率和发病率产生巨大影响，因此实验室仍是针对这些有效且安全的药物开发疫苗的目标。该项目的主要目标是开发反向遗传系统，该系统可用于改变轮状病毒基因组的遗传信息。这样的系统可用于识别定义生长特征，抗原特性和轮状病毒毒力的基因组中的基因组。有了这些知识，该系统可用于通过将突变引入人轮状病毒的毒物分离株的基因组中来创建新一代疫苗。该项目的次要目标包括（i）识别干扰先天细胞免疫反应的病毒基因产物，从而影响病毒的毒力，以及（ii）宿主细胞系对旋转病毒疫苗菌株蛋白质编码能力的影响。在过去的一年中，在理解轮状病毒颠覆宿主先天免疫反应的机制方面取得了进展。