Increasing the Safety Profile of the Master Donor Live Attenuated Influenza Vaccine
Increasing the Safety Profile of the Master Donor Live Attenuated Influenza Vaccine
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DOI：
10.3390/pathogens9020086
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发表时间：
2020-02-01
期刊：
影响因子：
3.7
通讯作者：
Martinez-Sobrido, Luis
中科院分区：
文献类型：
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作者：
Hilimire, Thomas A.;Nogales, Aitor;Martinez-Sobrido, Luis
季节性流感流行仍然是当今最大的公共卫生负担之一。迄今为止，预防流感感染的最佳和最有效的策略是全球范围内的疫苗接种运动。目前，公众可使用两种疫苗来治疗流感感染，即化学灭活流感疫苗（IIV）和减毒活流感疫苗（LAIV）。然而，不建议部分人群使用 LAIV，例如两岁以下儿童、免疫功能低下者、老年人和孕妇。为了提高减毒活疫苗的安全性并使更多人能够使用它，我们寻求进一步减毒减毒活疫苗。在这项研究中，我们证明甲型流感病毒 (IAV) 主供体病毒 (MDV) A/Ann Arbor/6/60 H2N2 LAIV 可以使用 PA-X 和 NS1 蛋白抑制宿主基因表达。此外，我们表明，通过去除 PA-X，我们可以限制 MDV LAIV 在小鼠模型中的复制，同时保持完全的保护功效。这项工作展示了一种广泛适用的策略，即调整 IAV MDV 诱导的宿主抗病毒反应量，以开发更新、更安全的 LAIV。此外，我们的结果还首次证明了对 IAV MDV 骨架进行基因操作以提高当前 IAV LAIV 功效的可行性。
Seasonal influenza epidemics remain one of the largest public health burdens nowadays. The best and most effective strategy to date in preventing influenza infection is a worldwide vaccination campaign. Currently, two vaccines are available to the public for the treatment of influenza infection, the chemically Inactivated Influenza Vaccine (IIV) and the Live Attenuated Influenza Vaccine (LAIV). However, the LAIV is not recommended for parts of the population, such as children under the age of two, immunocompromised individuals, the elderly, and pregnant adults. In order to improve the safety of the LAIV and make it available to more of the population, we sought to further attenuate the LAIV. In this study, we demonstrate that the influenza A virus (IAV) master donor virus (MDV) A/Ann Arbor/6/60 H2N2 LAIV can inhibit host gene expression using both the PA-X and NS1 proteins. Furthermore, we show that by removing PA-X, we can limit the replication of the MDV LAIV in a mouse model, while maintaining full protective efficacy. This work demonstrates a broadly applicable strategy of tuning the amount of host antiviral responses induced by the IAV MDV for the development of newer and safer LAIVs. Moreover, our results also demonstrate, for the first time, the feasibility of genetically manipulating the backbone of the IAV MDV to improve the efficacy of the current IAV LAIV.