Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, USA.
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, USA.
Vaccine. 2019 Sep 3;37(37):5567-5577. doi: 10.1016/j.vaccine.2019.07.095. Epub 2019 Aug 6.
Seasonal influenza virus infections cause significant morbidity and mortality every year. Annual influenza virus vaccines are effective but only when well matched with circulating strains. Therefore, there is an urgent need for better vaccines that induce broad protection against drifted seasonal and emerging pandemic influenza viruses. One approach to design such vaccines is based on targeting conserved regions of the influenza virus hemagglutinin. Sequential vaccination with chimeric hemagglutinin constructs can refocus antibody responses towards the conserved immunosubdominant stalk domain of the hemagglutinin, rather than the variable immunodominant head. A complementary approach for a universal influenza A virus vaccine is to induce T-cell responses to conserved internal influenza virus antigens. For this purpose, replication deficient recombinant viral vectors based on Chimpanzee Adenovirus Oxford 1 and Modified Vaccinia Ankara virus are used to express the viral nucleoprotein and the matrix protein 1. In this study, we combined these two strategies and evaluated the efficacy of viral vectors expressing both chimeric hemagglutinin and nucleoprotein plus matrix protein 1 in a mouse model against challenge with group 2 influenza viruses including H3N2, H7N9 and H10N8. We found that vectored vaccines expressing both sets of antigens provided enhanced protection against H3N2 virus challenge when compared to vaccination with viral vectors expressing only one set of antigens. Vaccine induced antibody responses against divergent group 2 hemagglutinins, nucleoprotein and matrix protein 1 as well as robust T-cell responses to the nucleoprotein and matrix protein 1 were detected. Of note, it was observed that while antibodies to the H3 stalk were already boosted to high levels after two vaccinations with chimeric hemagglutinins (cHAs), three exposures were required to induce strong reactivity across subtypes. Overall, these results show that a combinations of different universal influenza virus vaccine strategies can induce broad antibody and T-cell responses and can provide increased protection against influenza.
季节性流感病毒感染每年都会导致大量发病率和死亡率。每年的流感病毒疫苗是有效的，但只有当与流行株很好地匹配时才有效。因此，迫切需要更好的疫苗，以诱导对漂移的季节性和新兴大流行性流感病毒的广泛保护。设计此类疫苗的一种方法是基于针对流感病毒血凝素的保守区域。用嵌合血凝素构建体进行连续疫苗接种可以使抗体反应重新聚焦于血凝素的保守免疫亚结构域茎，而不是可变免疫显性头部。针对通用流感 A 病毒疫苗的另一种互补方法是诱导针对保守内部流感病毒抗原的 T 细胞反应。为此，使用基于黑猩猩腺病毒牛津 1 和改良安卡拉痘苗病毒的复制缺陷重组病毒载体来表达病毒核蛋白和基质蛋白 1。在这项研究中，我们结合了这两种策略，并在小鼠模型中评估了表达嵌合血凝素和核蛋白加基质蛋白 1的病毒载体在针对包括 H3N2、H7N9 和 H10N8 在内的 2 组流感病毒挑战中的功效。我们发现，与仅表达一组抗原的病毒载体疫苗相比，表达两组抗原的载体疫苗对 H3N2 病毒的挑战提供了增强的保护。疫苗诱导针对不同的 2 组血凝素、核蛋白和基质蛋白 1 的抗体反应以及对核蛋白和基质蛋白 1 的强烈 T 细胞反应。值得注意的是，观察到在用嵌合血凝素（cHA）进行两次疫苗接种后，针对 H3 茎的抗体已经被增强到很高的水平，但需要三次暴露才能诱导针对不同亚型的强烈反应。总的来说，这些结果表明，不同的通用流感病毒疫苗策略的组合可以诱导广泛的抗体和 T 细胞反应，并为流感提供增加的保护。
