New Strains Intended for the Production of Inactivated Polio Vaccine at Low-Containment After Eradication.
New Strains Intended for the Production of Inactivated Polio Vaccine at Low-Containment After Eradication.
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DOI：
10.1371/journal.ppat.1005316
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发表时间：
2015-12
期刊：
影响因子：
6.7
通讯作者：
Minor PD
中科院分区：
文献类型：
--
作者：
Knowlson S;Burlison J;Giles E;Fox H;Macadam AJ;Minor PD
通过世界卫生组织全球根除行动的努力，小儿麻痹症几乎被根除，这引发了人们对在野外消灭小儿麻痹症病毒后对其进行控制的问题。目前，大多数灭活脊髓灰质炎疫苗的生产需要大量高毒力脊髓灰质炎病毒的生长，根除后从生产设施释放可能是灾难性的；因此，世卫组织建议使用减毒的沙宾毒株生产，作为一种更安全的选择，尽管人们认识到它们可以恢复到可传播的瘫痪形式。我们利用对沙宾疫苗毒株的分子病毒学的了解来设计基因极其稳定和高度减毒的病毒。这些病毒以3型Sabin疫苗毒株为基础，通过改变碱基对以产生一个盒，将其他血清型的衣壳区域引入到盒中，在5‘非编码区的V区域进行了基因改造。这些病毒在培养中产生令人满意的抗原性和免疫原性正确的病毒，没有可测量的神经毒力，并且在沙宾菌株能够感染非人类灵长类动物的条件下不能感染。将需要新的脊髓灰质炎疫苗来保障全球根除：已知沙宾毒株的进化填补了野生毒株留下的利基，因此它们的长期使用与根除不相容；目前大多数灭活疫苗是由野生脊髓灰质炎病毒制成的，因此生产存在重大的生物安全风险。我们已经开发了生产灭活脊髓灰质炎疫苗(IPV)的新毒株，如果它们逃脱，对人类人口的风险可以忽略不计。Sabin的减毒活疫苗是通过使用非自然细胞底物、宿主和生长条件选择的野生菌株的变体。毫不奇怪，在它们的自然宿主之间复制和传播过程中，这些变体进化回野生型属性。对这些途径的分子基础的了解使我们设计了新的疫苗株，这些疫苗株具有非常高的减毒能力，可以说不能在人体内复制，而且在细胞培养中复制期间逆转的机会受到严重限制。同时，这些毒株可以大规模生产，而且它们与目前的IPV一样具有免疫原性。这些特性允许在根除后的世界进行安全的疫苗生产。
Poliomyelitis has nearly been eradicated through the efforts of the World Health Organization’s Global Eradication Initiative raising questions on containment of the virus after it has been eliminated in the wild. Most manufacture of inactivated polio vaccines currently requires the growth of large amounts of highly virulent poliovirus, and release from a production facility after eradication could be disastrous; WHO have therefore recommended the use of the attenuated Sabin strains for production as a safer option although it is recognised that they can revert to a transmissible paralytic form. We have exploited the understanding of the molecular virology of the Sabin vaccine strains to design viruses that are extremely genetically stable and hyperattenuated. The viruses are based on the type 3 Sabin vaccine strain and have been genetically modified in domain V of the 5’ non-coding region by changing base pairs to produce a cassette into which capsid regions of other serotypes have been introduced. The viruses give satisfactory yields of antigenically and immunogenically correct viruses in culture, are without measurable neurovirulence and fail to infect non-human primates under conditions where the Sabin strains will do so. New polio vaccines will be needed to safeguard global eradication: Sabin strains are known to evolve to fill the niche left by wild-strains so their long-term use is incompatible with eradication; most current inactivated vaccine is made from wild polioviruses so that production presents a significant biosecurity risk. We have developed new strains for Inactivated Polio Vaccine (IPV) production with negligible risk to the human population should they escape. Sabin’s live-attenuated vaccines are variants of wild strains selected by the use of unnatural cell substrates, hosts and growth conditions. Unsurprisingly these variants evolve back towards wild-type properties during replication in, and transmission between, their natural hosts. An understanding of the molecular basis of these pathways led us to design novel vaccine strains that are very highly attenuated and arguably cannot replicate in people and whose opportunities for reversion during replication in cell culture are severely restricted. At the same time, the strains can feasibly be produced on a large-scale and they are as immunogenic as current IPV. These attributes allow for safe vaccine production in the post-eradication world.