Abstract：
Current seasonal influenza vaccines have suboptimal effectiveness, especially in seasons dominated by viruses that do not match the vaccine. Therefore, finding new approaches to improve the immunogenicity and efficacy of traditional influenza vaccines is of high priority for public health. Licensed live attenuated influenza vaccine (LAIV) is a promising platform for designing broadly protective vaccines due to its ability to induce cross-reactive T-cell immunity. In this study, we tested the hypothesis that truncation of the nonstructural protein 1 (NS1) and the replacement of the nucleoprotein (NP) of the A/Leningrad/17 master donor virus with a recent NP, i.e., switching to 5:3 genome composition, could improve the cross-protective potential of the LAIV virus. We generated a panel of LAIV candidates differing from the classical vaccine by the source of NP gene and/or by the length of NS1 protein. We showed that NS1-modified LAIV viruses had reduced viral replication in the respiratory tract of mice, indicating a more attenuated phenotype compared to the LAIVs with full-length NS1. Most importantly, the LAIV candidate with both NP and NS genes modified induced a robust systemic and lung-localized memory CD8 T-cell response targeting more recent viruses, and better protected immunized mice against lethal challenge with a heterosubtypic influenza virus than the control LAIV variant. Overall, these data indicate that the 5:3 LAIVs with truncated NS1 may be beneficial for protection against heterologous influenza viruses and warrant further preclinical and clinical development.
摘要：
目前的季节性流感疫苗效果欠佳，尤其是在病毒与疫苗不匹配的季节。因此,寻找新的方法来改善传统流感疫苗的免疫原性和功效是公共卫生的高度优先事项.许可的减毒活疫苗（LAIV）是设计广泛保护性疫苗的有前途的平台，因为它能够诱导交叉反应性T细胞免疫。在这项研究中,我们测试了非结构蛋白1（NS1）的截短和A/列宁格勒/17主供体病毒的核蛋白（NP）的替代最近的NP的假设，即，切换到5:3的基因组组成，可以提高LAIV病毒的交叉保护潜力。我们产生了一组与经典疫苗不同的LAIV候选物,其区别在于NP基因的来源和/或NS1蛋白的长度。我们表明NS1修饰的LAIV病毒在小鼠呼吸道中减少了病毒复制，表明与具有全长NS1的LAIV相比，表型更减弱。最重要的是,具有NP和NS基因修饰的LAIV候选物诱导了针对最新病毒的强大的系统性和肺定位记忆CD8T细胞应答，与对照LAIV变体相比，更好地保护免疫小鼠免受异亚型流感病毒的致命攻击。总的来说,这些数据表明,具有截短的NS1的5:3LAIV可能有利于针对异源流感病毒的保护,并需要进一步的临床前和临床开发.
