Zheng Allen, Sun Weina, Xiong Xiaoli, Freyn Alec W, Peukes Julia, Strohmeier Shirin, Nachbagauer Raffael, Briggs John A G, Krammer Florian, Palese Peter
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Structural Studies Division, Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom.
J Virol. 2020 Jul 30;94(16). doi: 10.1128/JVI.00742-20.
Humoral immune protection against influenza virus infection is mediated largely by antibodies against hemagglutinin (HA) and neuraminidase (NA), the two major glycoproteins on the virus surface. While influenza virus vaccination efforts have focused mainly on HA, NA-based immunity has been shown to reduce disease severity and provide heterologous protection. Current seasonal vaccines do not elicit strong anti-NA responses-in part due to the immunodominance of the HA protein. Here, we demonstrate that by swapping the 5' and 3' terminal packaging signals of the HA and NA genomic segments, which contain the RNA promoters, we are able to rescue influenza viruses that express more NA and less HA. Vaccination with formalin-inactivated "rewired" viruses significantly enhances the anti-NA antibody response compared to vaccination with unmodified viruses. Passive transfer of sera from mice immunized with rewired virus vaccines shows better protection against influenza virus challenge. Our results provide evidence that the immunodominance of HA stems in part from its abundance on the viral surface, and that rewiring viral packaging signals-thereby increasing the NA content on viral particles-is a viable strategy for improving the immunogenicity of NA in an influenza virus vaccine. Influenza virus infections are a major source of morbidity and mortality worldwide. Increasing evidence highlights neuraminidase as a potential vaccination target. This report demonstrates the efficacy of rewiring influenza virus packaging signals for creating vaccines with more neuraminidase content which provide better neuraminidase (NA)-based protection.
针对流感病毒感染的体液免疫保护主要由针对血凝素（HA）和神经氨酸酶（NA）的抗体介导，这两种是病毒表面的主要糖蛋白。虽然流感病毒疫苗接种工作主要集中在HA上，但基于NA的免疫已被证明可降低疾病严重程度并提供异源保护。目前的季节性疫苗不会引发强烈的抗NA反应，部分原因是HA蛋白的免疫显性。在这里，我们证明，通过交换HA和NA基因组片段的5'和3'末端包装信号（其中包含RNA启动子），我们能够拯救表达更多NA和更少HA的流感病毒。与用未修饰病毒接种相比，用福尔马林灭活的“重新布线”病毒接种可显著增强抗NA抗体反应。用重新布线病毒疫苗免疫的小鼠血清的被动转移显示出对流感病毒攻击的更好保护。我们的结果提供了证据，表明HA的免疫显性部分源于其在病毒表面的丰度，并且重新布线病毒包装信号——从而增加病毒颗粒上的NA含量——是提高流感病毒疫苗中NA免疫原性的可行策略。流感病毒感染是全球发病和死亡的主要来源。越来越多的证据表明神经氨酸酶是一个潜在的疫苗接种靶点。本报告证明了重新布线流感病毒包装信号以创建具有更多神经氨酸酶含量的疫苗的功效，这些疫苗可提供更好的基于神经氨酸酶（NA）的保护。
