Generation of influenza A viruses as live but replication-incompetent virus vaccines
Generation of influenza A viruses as live but replication-incompetent virus vaccines
复制标题
产生甲型流感病毒作为活的但无法复制的病毒疫苗。
DOI：
10.1126/science.aah5869
复制
发表时间：
2016-12-02
期刊：
影响因子：
56.9
通讯作者：
Zhou, Demin
中科院分区：
文献类型：
--
作者：
Si, Longlong;Xu, Huan;Zhou, Demin
遗传密码扩展和正交翻译机制被用来产生活的、减毒的病毒疫苗。通过更改代码进行保护的减毒活疫苗可能非常有效，但它们恢复为致病形式的可能性限制了它们的使用。在试图绕过这一点时，司徒华等人。扩大了甲型流感病毒的遗传密码。他们在一种能够表达这些流感蛋白的细胞系中传播突变的病毒，编码提前终止密码子(PTCs)。尽管不能在常规细胞中复制，但含有PTC的病毒具有高度的免疫原性，并能保护小鼠、豚鼠和雪貂免受流感的攻击。科学，本期第1170页将危及生命的病毒转化为活的但无毒的疫苗代表了疫苗学上的一场革命。在一项原则验证研究中，我们通过含有正交翻译机制的转基因细胞系扩展了甲型流感病毒基因组的遗传密码。这产生了过早终止密码子(PTC)--携带病毒的病毒在常规细胞中完全具有传染性，但不具备复制能力。在全基因组范围内优化多个PTC的整合位置，在转基因细胞中产生高度繁殖和遗传稳定的后代病毒。在小鼠、雪貂和豚鼠模型中，PTC病毒疫苗能诱导出针对不同抗原性流感病毒的强大体液、粘膜和T细胞介导的免疫，甚至中和现有的感染毒株。这里提出的方法可能成为一种通用的方法，用于生产几乎可以适应任何病毒的活病毒疫苗。
Genetic code expansion and orthogonal translation machinery are used to generate live, attenuated viral vaccines. Protecting by changing the code Live attenuated vaccines can be very potent, but their potential to revert to their pathogenic form limits their use. In an attempt to get around this, Si et al. expanded the genetic code of influenza A viruses. They propagated viruses that were mutated to encode premature termination codons (PTCs) in a cell line engineered to be able to express these flu proteins. Despite not being able to replicate in conventional cells, PTC-containing viruses were highly immunogenic and protected mice, guinea pigs, and ferrets against influenza challenge. Science, this issue p. 1170 The conversion of life-threatening viruses into live but avirulent vaccines represents a revolution in vaccinology. In a proof-of-principle study, we expanded the genetic code of the genome of influenza A virus via a transgenic cell line containing orthogonal translation machinery. This generated premature termination codon (PTC)–harboring viruses that exerted full infectivity but were replication-incompetent in conventional cells. Genome-wide optimization of the sites for incorporation of multiple PTCs resulted in highly reproductive and genetically stable progeny viruses in transgenic cells. In mouse, ferret, and guinea pig models, vaccination with PTC viruses elicited robust humoral, mucosal, and T cell–mediated immunity against antigenically distinct influenza viruses and even neutralized existing infecting strains. The methods presented here may become a general approach for generating live virus vaccines that can be adapted to almost any virus.