Synthetic Viral Genome Design for Rapid Vaccine Development

描述(申请人提供)：使用现代合成长DNA的方法，并使用计算机算法，我们最近从寡核苷酸体外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传染性病毒。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。这两种病毒分别被设计成具有较差的密码子偏好性或较差的密码子对偏好性，并且这两种病毒都是无效的(即，不能在培养细胞上形成斑块)。在这里，我们试图确切地了解为什么改变的病毒被减毒；寻找产生其他新的脊髓灰质炎病毒的方法，使其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推广到其他类型的病毒。这些研究最重要的长期影响是，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创造病毒疫苗的原料。原则上，只要有核酸序列，即使是特征非常差的病毒，也可以快速制造出疫苗。 与公共卫生相关：疫苗接种一直是人类对病毒疾病最有力的主要防御措施。我们描述了一种全新而快速的方法来产生抗病毒候选疫苗，该方法可能被证明适用于大多数(如果不是全部)人类致病病毒系统。

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.