Rational Design of Live Attenuated Influenza A Vaccine Candidates

描述(申请人提供)：尽管有流感疫苗可用，但仅在美国每年就有大约35,000人死于流感和流感相关并发症。流感的临床影响促使人们寻找能够快速设计和容易生产的新的、更有效的疫苗。我们已经开发了一种合理的、计算机辅助的方法来构建有效的减毒(弱)流感病毒疫苗候选疫苗。这一过程被称为合成减毒病毒工程(SAVE)，(Coleman等人，2008年。科学320(5884)：1784-7)SAVE技术中使用的定制设计的衰减通过基因组规模的密码子对偏差的变化来运作(Mueller等人，2010)。自然生物技术28：723-727)。在这项提案中，我们将扩展我们的技术，该技术在实验室毒株A/PR8/3/34(Mueller等人)中成功地创造了一种减毒活疫苗。A/California/07/2009(CA07)。CA07是导致2009年H1N1(“猪流感”)大流行的毒株。这些保存减毒(减毒)的CA07病毒将在小鼠模型中测试它们的安全性水平和作为活疫苗候选者的潜力。我们系统中的衰减是通过在整个病毒基因组中设计数百个同义核苷酸变化来实现的。这种合理的基因设计方法使Codagenix Inc.能够保持氨基酸序列与所有病毒蛋白质100%相同。这数百种突变通过高度的遗传稳定性为候选疫苗提供了广泛的安全边际。此外，保持与疫苗目标100%的氨基酸序列匹配，提供了目前任何可用的疫苗技术中不存在的节省减毒疫苗的特征。通过将SAVE扩展到临床重要的菌株，以及构建各种合成设计，我们将展示 我们独特的计算机算法使我们能够构建可行的候选疫苗，并具有额外的能力来调整衰减的量，类似于汽车收音机上的体积。鉴于SAVE是一种计算机辅助方法，该方法可以迅速应用于任何新出现的流感病毒的整体。该项目的成果是A/California/07/2009系的改良减毒活疫苗株，其氨基酸与目标株具有100%的同源性。这种候选疫苗将在第二阶段进行进一步的临床开发。

DESCRIPTION (provided by applicant): Despite the availability of influenza vaccines, approximately 35,000 individuals die each year in the US alone from influenza, and influenza-related complications. The clinical impact of Influenza motivates the search for new, more effective vaccines that can be rapidly designed and easily produced. We have developed a rational, computer-aided approach to construct efficacious live attenuated (weakened) influenza virus vaccine candidates. The process is termed Synthetic Attenuated Virus Engineering (SAVE), (Coleman et al., 2008. Science 320(5884):1784-7) The custom designed attenuation used in the SAVE technology operates through genome-scale changes in codon pair bias (Mueller et al., 2010. Nature Biotechnology 28:723-727). In this proposal, we will extend our technology, which successfully created a live-attenuated vaccine in the laboratory strain A/PR8/3/34 (Mueller et al. 2010), to a clinically significant pandemic influenza strain, A/California/07/2009 (CA07). CA07 was the strain responsible for the 2009 H1N1 ("swine flu") pandemic. These SAVE-attenuated (weakened) CA07 viruses will be tested for their level of safety and their potential as live vaccine candidates in a mouse model. Attenuation in our system is achieved via designing hundreds of synonymous nucleotide changes across the viral genome. This rational gene design approach allows Codagenix Inc. to maintain the amino acid sequences to have 100% identity to all viral proteins. These hundreds of mutations offers a wide margin of safety for vaccine candidates via high genetic stability. Also maintaining a 100% amino acid sequence match to the vaccine target, provides a characteristic of SAVE-attenuated vaccines that is not present in any currently available vaccine technology. By extending SAVE to a strain of clinical importance, as well as constructing various synthetic designs, we will show that our unique computer algorithms allow us construct viable vaccine candidates with the additional ability to tune the amount of attenuation predictably, similar to the volume on a car radio. Given that SAVE is a computer-aided approach the method can be applied rapidly to any emerging influenza virus in its entirety. The deliverable of this project is an improved live attenuated vaccine strain of the A/California/07/2009 lineage that has 100% amino acid identity to the target strain. This vaccine candidate will be taken into further clinical development in Phase II.