Synthetic Viral Genome Design for Rapid Vaccine Development

用于快速疫苗开发的合成病毒基因组设计

• 批准号: 8048029
• 负责人: Eckard Wimmer
• 金额: $ 55.32万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8048029
• 关键词: Attenuated; Base Sequence; Biological Models; Capsid; Chimera organism; Code; Codon Nucleotides; Computational algorithm; Cultured Cells; Data Analyses; Development; Dinucleoside Phosphates; Engineering; Generations; Genetic; Genome; Goals; Human; Human poliovirus; Immune response; In Vitro; Influenza; Influenza A virus; Medical; Methods; Modeling; Modification; Molecular; Mus; Nucleic Acids; Nucleic acid sequencing; Oligonucleotides; Poliomyelitis; Polioviruses; Proteins; RNA; RNA Stability; Scanning; Screening procedure; Software Design; Structure; System; Testing; Translations; Vaccination; Vaccines; Variant; Viral; Viral Genome; Viral Physiology; Viral Vaccines; Virion; Virulence; Virus; Virus Diseases; attenuation; base; design; experience; fitness; influenzavirus; novel; novel vaccines; public health relevance; rapid technique; vaccine candidate; vaccine development

DESCRIPTION (provided by applicant): Using modern methods for synthesizing long DNAs, and using computer algorithms, we have recently synthesized several totally novel variants of polio virus in vitro from oligonucleotides, and we have converted these nucleic acids into infectious virus. These viruses preserve the exact protein coding capacity of wild- type polio, but use synonymous codons in various ways to target translation. Two of the viruses were designed to have poor codon bias, or poor codon pair bias, respectively, and both of these viruses were inviable (i.e., cannot form plaques on cultured cells). Here, we seek to understand exactly why the altered viruses are attenuated; to find ways of generating still other, novel polio viruses attenuated to predictable extents; and to extend this approach of synthesizing predictably-attenuated viruses to other classes of viruses. The most important longer term implication of these studies is that the predictable synthesis of attenuated virus should provide a rapid, safe, inexpensive, general and reliable method of creating the raw material for viral vaccines. In principle, vaccines could be created quickly even for very poorly characterized viruses, as long as a nucleic acid sequence is available. PUBLIC HEALTH RELEVANCE: Vaccination has been humankind's main most robust defense against viral disease. We describe an entirely novel and rapid method to generate anti-virus vaccine candidates that might prove applicable to most if not all human pathogenic viral systems.

描述（由申请人提供）：使用合成长DNA的现代方法，并使用计算机算法，我们最近在体外从寡核苷酸合成了几种全新的脊髓灰质炎病毒变体，并将这些核酸转化为感染性病毒。这些病毒保留了野生型脊髓灰质炎的确切蛋白质编码能力，但以各种方式使用同义密码子来靶向翻译。其中两种病毒被设计为分别具有差的密码子偏好性或差的密码子对偏好性，并且这两种病毒都是不可存活的（即，不能在培养的细胞上形成噬斑）。在这里，我们试图确切地理解为什么改变的病毒是减毒的;找到产生其他新的脊髓灰质炎病毒的方法，减毒到可预测的程度;并将这种合成可预测减毒病毒的方法扩展到其他类型的病毒。这些研究最重要的长期意义是，减毒病毒的可预测合成应该提供一种快速、安全、廉价、通用和可靠的方法来生产病毒疫苗的原材料。原则上，只要有核酸序列，即使是特征非常不明确的病毒，也可以快速制备疫苗。 公共卫生相关性：疫苗接种一直是人类对抗病毒性疾病的主要最强大的防御手段。我们描述了一种全新的、快速的方法来产生抗病毒候选疫苗，这种方法可能适用于大多数（如果不是所有的话）人类致病病毒系统。