Jiang Wenbo, Wang Shuangshuang, Chen Honglin, Ren Huanhuan, Huang Xun, Wang Guiqin, Chen Ze, Chen Ling, Chen Zhiwei, Zhou Paul
Unit of Antiviral Immunity and Genetic Therapy, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
Shanghai Tech University, Shanghai, China.
J Virol. 2017 Apr 13;91(9). doi: 10.1128/JVI.02052-16. Print 2017 May 1.
Current seasonal influenza vaccines are efficacious when vaccine strains are matched with circulating strains. However, they do not protect antigenic variants and newly emerging pandemic and outbreak strains. Thus, there is a critical need for developing so-called "universal" vaccines that protect against all influenza viruses. In the present study, we developed a bivalent heterologous DNA virus-like particle prime-boost vaccine strategy. We show that mice immunized with this vaccine were broadly protected against lethal challenge from group 1 (H1, H5, and H9) and group 2 (H3 and H7) viruses, with 94% aggregate survival. To determine the immune correlates of protection, we performed passive immunizations and assays. We show that this vaccine elicited antibody responses that bound HA from group 1 (H1, H2, H5, H6, H8, H9, H11, and H12) and group 2 (H3, H4, H7, H10, H14, and H15) and neutralized homologous and intrasubtypic H5 and H7 and heterosubtypic H1 viruses and hemagglutinin-specific CD4 and CD8 T cell responses. As a result, passive immunization with immune sera fully protected mice against H5, H7, and H1 challenge, whereas with both immune sera and T cells the mice survived heterosubtypic H3 and H9 challenge. Thus, it appears that (i) neutralizing antibodies alone fully protect against homologous and intrasubtypic H5 and H7 and (ii) neutralizing and binding antibodies are sufficient to protect against heterosubtypic H1, (iii) but against heterosubtypic H3 and H9, binding antibodies and T cells are required for complete survival. We believe that this vaccine regimen could potentially be a candidate for a "universal" influenza vaccine. Influenza virus infection is global health problem. Current seasonal influenza vaccines are efficacious only when vaccine strains are matched with circulating strains. However, these vaccines do not protect antigenic variants and newly emerging pandemic and outbreak strains. Because of this, there is an urgent need to develop so-called "universal" influenza vaccines that can protect against both current and future influenza strains. In the present study, we developed a bivalent heterologous prime-boost vaccine strategy. We show that a bivalent vaccine regimen elicited broad binding and neutralizing antibody and T cell responses that conferred broad protection against diverse challenge viruses in mice, suggesting that this bivalent prime-boost strategy could practically be a candidate for a "universal" influenza vaccine.
当疫苗株与流行株相匹配时，现有的季节性流感疫苗是有效的。然而，它们不能保护抗原变异体以及新出现的大流行毒株和暴发毒株。因此，迫切需要研发所谓的“通用”疫苗，以抵御所有流感病毒。在本研究中，我们开发了一种二价异源DNA病毒样颗粒初免-加强疫苗策略。我们发现，用这种疫苗免疫的小鼠对来自第1组（H1、H5和H9）和第2组（H3和H7）病毒的致死性攻击具有广泛的保护作用，总生存率为94%。为了确定保护的免疫相关性，我们进行了被动免疫和检测。我们发现，这种疫苗引发的抗体反应能结合来自第1组（H1、H2、H5、H6、H8、H9、H11和H12）和第2组（H3、H4、H7、H10、H14和H15）的血凝素，并中和同源和亚型内的H5和H7以及异源亚型的H1病毒，以及血凝素特异性的CD4和CD8 T细胞反应。结果，用免疫血清进行被动免疫能完全保护小鼠免受H5、H7和H1攻击，而同时使用免疫血清和T细胞时，小鼠能在异源亚型H3和H9攻击中存活。因此，似乎（i）单独的中和抗体能完全保护免受同源和亚型内的H5和H7攻击，（ii）中和抗体和结合抗体足以保护免受异源亚型H1攻击，（iii）但对于异源亚型H3和H9，需要结合抗体和T细胞才能完全存活。我们认为这种疫苗方案有可能成为“通用”流感疫苗的候选者。流感病毒感染是一个全球性的健康问题。现有的季节性流感疫苗只有在疫苗株与流行株相匹配时才有效。然而，这些疫苗不能保护抗原变异体以及新出现的大流行毒株和暴发毒株。因此，迫切需要研发所谓的“通用”流感疫苗，以抵御当前和未来的流感毒株。在本研究中，我们开发了一种二价异源初免-加强疫苗策略。我们发现，一种二价疫苗方案能引发广泛的结合和中和抗体以及T细胞反应，从而在小鼠中对多种攻击病毒提供广泛的保护，这表明这种二价初免-加强策略实际上有可能成为“通用”流感疫苗的候选者。
