利用马赛克策略设计靶向神经氨酸酶抗原的广谱流感疫苗

Development of A Broad-spectrum Influenza Vaccine Targeting Neuraminidase Antigen with A “Mosaic” Strategy

季节性流感病毒仍对全球公共卫生安全构成巨大威胁,对老人、儿童以及免疫功能低下人群的危害尤其严重。疫苗接种是目前应对季节性流感疫情重要手段,然而由于抗原转换和抗原漂移,常出现疫苗株与实际病毒流行株的不匹配现象,因此迫切需要开发一种安全高效的广谱流感疫苗来对抗季节性流感病毒和潜在的流感大流行。抗原设计是研发新型疫苗的关键前提,我们利用马赛克(mosaic)遗传算法设计研发了一种具有广谱抗原表位覆盖率的靶向流感病毒神经氨酸酶(Neuraminidase,NA)的新型抗原(Mosaic-NA)。该抗原在最大程度上涵盖了所有已报道甲型流感病毒的NA1蛋白与NA2蛋白序列中的细胞毒性T淋巴细胞(Cytotoxic T lymphocyte,CTL)抗原表位,并保留了天然蛋白空间构象。因此,这种新型抗原预期可有效诱导出靶向保守表位的CTL反应和抗体反应,从而为研发通用流感疫苗提供新思路和理论基础。

Seasonal influenza viruses still pose a huge threat to global public health security. They are particularly harmful to the elderly,children and people with immune deficiency. Vaccination is currently an important method to counter seasonal influenza epidemics. However,due to conversion and drift of antigens,there is often a mismatch between vaccine strains and actual circulating virus strains. Therefore,development of a safe,efficient and broad-spectrum influenza vaccine is important. Antigen design is a key prerequisite for development of novel vaccines. We designed a new type of antigen targeting influenza virus neuraminidase(NA)in influenza viruses with broad-spectrum epitope coverage using mosaic genetic algorithms(“Mosaic-NA”). This antigen contained,to the greatest extent,conserved cytotoxic T lymphocyte(CTL)epitopes in the natural viral sequence. This antigen covered all the CTL epitopes of the NA1 and NA2 proteins of influenza A viruses that had been reported. Mosaic-NA retained the native protein conformation to the greatest extent.This novel antigen is expected to effectively induce CTL responses and antibody responses against conserved epitopes. Our data lay a theoretical foundation and reference for development of universal influenza vaccines.