Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, New York, NY 14642, USA.
Medical Scientist Training Program, University of Rochester School of Medicine and Dentistry, Rochester, New York, NY 14642, USA.
Viruses. 2020 Oct 31;12(11):1246. doi: 10.3390/v12111246.
Current influenza vaccines have modest efficacy. This is especially true for current live attenuated influenza vaccines (LAIV), which have been inferior to the inactivated versions in recent years. Therefore, a new generation of live vaccines may be needed. We previously showed that a mutation at PB1 residue 319 confers enhanced temperature sensitivity and attenuation in an LAIV constructed in the genetic background of the mouse-adapted Influenza A Virus (IAV) strain A/PR/8/34 (PR8). Here, we describe the origin/discovery of this unique mutation and demonstrate that, when combined with the PB2 N265S mutation of LAIV, it conveys an even greater level of temperature sensitivity and attenuation on PR8 than the complete set of attenuating mutations from LAIV. Furthermore, we show that the combined PB1 L319Q and PB2 N265S mutations confer temperature sensitivity on IAV polymerase activity in two different genetic backgrounds, PR8 and A/Cal/04/09. Collectively, these findings show that the PB2 LAIV mutation synergizes with a mutation in PB1 and may have potential utility for improving LAIVs.
目前的流感疫苗效果有限。这在近年来的减毒活流感疫苗（LAIV）中尤为明显，其效果不如灭活疫苗。因此，可能需要新一代的活疫苗。我们之前曾表明，在遗传背景为鼠适应流感病毒（IAV）株 A/PR/8/34（PR8）的 LAIV 中，PB1 残基 319 的突变赋予了增强的温度敏感性和衰减性。在这里，我们描述了这个独特突变的起源/发现，并证明当与 LAIV 的 PB2 N265S 突变结合使用时，与 LAIV 的整套减毒突变相比，它在 PR8 上赋予了更高水平的温度敏感性和衰减性。此外，我们还表明，联合 PB1 L319Q 和 PB2 N265S 突变赋予了 PR8 和 A/Cal/04/09 两种不同遗传背景中的 IAV 聚合酶活性温度敏感性。总的来说，这些发现表明 PB2 LAIV 突变与 PB1 中的突变协同作用，可能对改进 LAIV 具有潜在的用途。
