PDF(Pubmed)
Abstract：
Classic chimeric hemagglutinin (cHA) was designed to induce immune responses against the conserved stalk domain of HA. However, it is unclear whether combining more than one HA head domain onto one stalk domain is immunogenic and further induce immune responses against influenza viruses. Here, we constructed numerous novel cHAs comprising two or three fuzed head domains from different subtypes grafted onto one stalk domain, designated as cH1-H3, cH1-H7, cH1-H3-H7, and cH1-H7-H3. The three-dimensional structures of these novel cHAs were modelled using bioinformatics simulations. Structural analysis showed that the intact neutralizing epitopes were exposed in cH1-H7 and were predicted to be immunogenic. The immunogenicity of the cHAs constructs was evaluated in mice using a chimpanzee adenoviral vector (AdC68) vaccine platform. The results demonstrated that cH1-H7 expressed by AdC68 (AdC68-cH1-H7) induced the production of high levels of binding antibodies, neutralizing antibodies, and hemagglutinin inhibition antibodies against homologous pandemic H1N1, drifted seasonal H1N1, and H7N9 virus. Moreover, vaccinated mice were fully protected from a lethal challenge with the aforementioned influenza viruses. Hence, cH1-H7 cHAs with potent immunogenicity might be a potential novel vaccine to provide protection against different subtypes of influenza virus.
摘要：
摘要经典嵌合血凝素(cHA)被设计用于诱导针对HA的保守茎结构域的免疫应答。然而,尚不清楚将一个以上的HA头部结构域结合到一个茎结构域上是否具有免疫原性并进一步诱导针对流感病毒的免疫应答.这里,我们构建了许多新的cHA，它们包含来自不同亚型的两个或三个融合的头部结构域，嫁接到一个茎结构域上，命名为cH1-H3、cH1-H7、cH1-H3-H7和cH1-H7-H3。使用生物信息学模拟对这些新型cHA的三维结构进行建模。结构分析显示,完整的中和表位暴露于cH1-H7中,并预测为免疫原性的。使用黑猩猩腺病毒载体(AdC68)疫苗平台在小鼠中评估cHA构建体的免疫原性。结果表明，由AdC68表达的cH1-H7（AdC68-cH1-H7）诱导产生高水平的结合抗体，中和抗体，和血凝素抑制抗体，针对同源大流行H1N1，漂移季节性H1N1和H7N9病毒。此外，完全保护接种的小鼠免受上述流感病毒的致命攻击。因此，具有强大免疫原性的cH1-H7cHA可能是一种潜在的新型疫苗，可提供针对不同亚型流感病毒的保护作用。
