Unlocking the promise of DNA vaccines

基于核酸的疫苗是一种非常有希望的抗击流行病的工具1。它们廉价、安全、对新出现的病原体快速反应。该应用程序的合作伙伴公司Touchlight Genetics拥有一个支持GMP的、可轻松扩展的完全合成DNA平台。限制是，到目前为止，DNA疫苗在人类临床试验中表现不佳。有大量的变量可能限制DNA疫苗的效力，迫切需要进行系统的基础研究，以确定这些限制因素并开发克服它们的方法，以开发临床有效的DNA疫苗。该项目将专注于开发一种DNA编码的流感疫苗。这不仅具有商业价值--2013年季节性流感疫苗的销售额约为31亿美元，而且在开发可预防大流行性流感的疫苗方面也具有相当大的社会价值，因为流感是全球大流行的主要风险。特雷贡实验室还拥有成熟的流感感染模型2，可用于测试任何已开发疫苗的效力。该项目的假设是DNA疫苗的免疫原性可以显著增强，从而更好地转化为临床产品。学生将与Touchlight Genetics密切合作，生产具有最佳免疫原性的合成DNA流感候选疫苗。在Touchlight Genetics之前的工作中，我们已经证明了他们的线性DNA平台与质粒DNA 3相当，改变给药途径改变了诱导的免疫反应类型4，诱导肺部常驻T细胞提高了对病毒感染的保护5。项目的目标是：第一年：使用Touchlight的技术平台在体内改变DNA疫苗的表达和免疫原性。第二年：设计和测试具有更大广度和覆盖率的新型流感DNA疫苗。第三年：研究DNA免疫如何启动免疫系统，使其对其他疫苗平台有更好的反应。

Nucleic acid based vaccines are an extremely promising tool to combat pandemics 1. They are cheap, safe and rapidly responsive to novel emerging pathogens. The partner company for this application, Touchlight Genetics, has a GMP ready, completely synthetic DNA platform that is easily scalable. The limitation is that DNA vaccines have underperformed in human clinical trials to date. There are a large number of variables that may limit the efficacy of DNA vaccines and there is an urgent need to perform systematic underpinning research to identify these limiting factors and develop approaches to overcome them in order to develop clinically effective DNA vaccines. The project will focus on developing a DNA encoded influenza vaccine. This has both commercial value - the sales of seasonal influenza vaccine were approximately $3.1 billion in 2013, and also considerable societal value in the development of vaccines that could prevent pandemic influenza, with flu being the major risk of global pandemics. The Tregoning lab also has well established models of influenza infection 2, that can be used to test the efficacy of any vaccine developed.The hypothesis of the project is that the immunogenicity of DNA vaccines can be dramatically enhanced, leading to better translation into a clinical product.The student will work closely with Touchlight Genetics to generate a synthetic DNA influenza vaccine candidate with optimised immunogenicity. In previous work with Touchlight Genetics, we have shown that their linear DNA platform is comparable to plasmid DNA 3, that altering the route of administration alters the type of immune response induced 4 and that the induction of lung resident T cells improves protection against viral infection 5.The objectives of the project are:Year 1: Use Touchlight's technology platforms to alter the expression and immunogenicity of DNA vaccines in vivo.Year 2: Design and test novel influenza DNA vaccines with increased breadth and coverage.Year 3: Investigate how DNA immunisation can prime the immune system to respond better to other vaccine platforms.