Rational Design of Live Attenuated Influenza A Vaccine Candidates

描述（由申请人提供）：尽管流感疫苗可用，但仅在美国每年约有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新的、更有效的、可以快速设计和容易生产的疫苗。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活流感病毒候选疫苗。该过程被称为合成减毒病毒工程（SAVE）（科尔曼等人，2008. Science 320（5884）：1784-7）SAVE技术中使用的定制设计的减毒通过密码子对偏好的基因组规模变化来操作（Mueller等人，2010. Nature Biotechnology 28：723-727）。 在本提案中，我们将我们的技术（在实验室毒株A/PR 8/3/34中成功制备减毒活疫苗（Mueller et al. 2010））扩展至具有临床意义的大流行性流感毒株A/加州/07/2009（CA 07）。CA 07是导致2009年H1N1（“猪流感”）大流行的毒株。将在小鼠模型中检测这些SAVE减毒（减毒）CA 07病毒的安全性水平及其作为活疫苗候选物的潜力。 我们系统中的减毒是通过在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允许Codagelinc.以保持氨基酸序列与所有病毒蛋白具有100%同一性。这数百种突变通过高遗传稳定性为候选疫苗提供了广泛的安全范围。此外，保持与疫苗靶标的100%氨基酸序列匹配提供了SAVE减毒疫苗的特征，该特征在任何目前可用的疫苗技术中都不存在。通过将SAVE扩展到具有临床重要性的菌株，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，可以预测衰减量，类似于汽车收音机的音量。鉴于SAVE是一种计算机辅助方法，该方法可以快速应用于任何新出现的流感病毒的整体。 本项目的可交付成果是A/加州/07/2009谱系的改良减毒活疫苗株，其与靶菌株具有100%的氨基酸同一性。该候选疫苗将在II期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.