曹永长课题组在H7N9流感病毒广谱疫苗研究领域取得进展

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曹永长教授研究团队在H7N9流感病毒广谱疫苗研究领域取得突破性进展

中山大学生命科学学院有害生物控制与资源利用国家重点实验室曹永长教授团队近期在国际抗病毒权威期刊《Antiviral Research》上发表了题目为“A recombinant H7N9 influenza vaccine with the H7 hemagglutinin transmembrane domain replaced by the H3 domain induces increased cross-reactive antibodies and improved interclade protection in mice”的研究论文，报道了一种对血凝素蛋白（Hemagglutinin，HA）进行结构设计的H7N9流感病毒全病毒灭活疫苗，并且证明这种全病毒灭活疫苗可以刺激机体产生H7N9亚型内广谱交叉免疫反应和交叉保护。

自2013年3月，我国首次报道H7N9流感病毒感染人以来，H7N9流感病毒已经经历了5波流行，感染病例1364例（截至2017年4月1日），死亡率达30%。H7N9流感病毒不仅具有潜在大流行的威胁，也对养禽业造成了巨大的损失。跟其他流感病毒一样，H7N9流感病毒变异十分迅速，已经形成了多个基因型，因此研制具有广谱交叉保护效果的H7N9流感病毒疫苗十分必要。

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重组H7N9流感病毒的拯救

该团队之前的研究证实H3亚型HA蛋白跨膜区（Transmembrane domain，TM）与HA蛋白稳定性、HA蛋白交叉免疫原性关系密切，通过HA跨膜区置换策略可以提高三聚化H1、H5和H9亚型HA蛋白的亚型间交叉保护力。在H7N9广谱疫苗的研究中，该团队将H7N9流感病毒HA蛋白TM置换为H3亚型HA TM，并通过反向遗传技术拯救出包含TM置换的重组H7N9流感病毒。在小鼠动物模型中，重组病毒制备的全病毒灭活疫苗能够诱导机体产生针对不同分支毒株抗原的更高的HI抗体、HA特异性IgG抗体、HA特异性IFN-γ细胞因子。并且该疫苗能够对小鼠同源或异源H7N9病毒攻毒提供完全保护，经过免疫的小鼠在攻毒后检测不到肺病毒滴度、无明显肺部病变和炎症反应。

博士研究生王洋为本文第一作者，曹永长教授为本文通讯作者。

曹永长教授团队长期进行动物病毒学研究，先后获得国家自然科学基金、863项目、国家重点研发计划项目、广东省自然科学基金等科研项目的资助，发表SCI论文30余篇。目前该团队致力于流感病毒防控、冠状病毒（猪流行性腹泻病毒PEDV、鸡传染性支气管炎病毒IBV）遗传演化和免疫逃逸机制研究，已获得多项研究成果。

A recombinant H7N9 influenza vaccine with the H7 hemagglutinin transmembrane domain replaced by the H3 domain induces increased cross-reactive antibodies and improved interclade protection in mice

Abstract

Influenza A H7N9 virus is the latest emerging pandemic threat, and has rapidly diverged into three clades, demanding a H7N9 virus vaccine with broadened protection against unmatched strains. Hemagglutinin (HA)-based structural design approaches for stabilizing HA proteins have provided excitingly promising results. However, none of the HA-based structural design approaches has been applied to a recombinant replicative influenza virus. Here we report that our HA-based structural design approach is a first in the field to generate a recombinant replicative H7N9 virus (H7N9-53TM) showing broadened protection. The H7N9-53TM contains a replaced H3 HA transmembrane domain (TM) in its HA protein. In mice, the inactivated H7N9-53TM vaccine induced significantly higher HI titers, HA-specific IgG titers, and IFN-γ production than the corresponding H7N9-53WT inactivated virus vaccine containing wild-type HA. More excitingly, mice immunized with the H7N9-53TM showed full protection against homologous (H7N9-53) and interclade (H7N9-MCX) challenges with minimal weight loss, no detectable lung viral loads, and no apparent pulmonary lesions and inflammation, while mice immunized with the H7N9-53WT showed partial protection (only 60% against H7N9-MCX) with severe weight loss, detectable lung viral loads, and severe pulmonary lesions and inflammation. In summary, this study presents a better vaccine candidate (H7N9-53TM) against H7N9 pandemics. Furthermore, our HA-based structural design approach would be conceivably applicable to other subtype influenza viruses, especially the viruses from emerging pandemic and epidemic influenza viruses such as H5N1 and H1N1.

Highlights

l The recombinant H7N9-53TM virus with the H7 hemagglutinin transmembrane domain (TM) replaced by the H3 TM was rescued.

l Inactivated H7N9-53TM vaccine induces increased cross-reactive antibodies and improved interclade protection.

l The H3 TM domain replacement technology might be applicable for other subtypes of influenza viruses.

文章链接：http://doi.org/10.1016/j.antiviral.2017.03.029