Centralized Consensus Hemagglutinin Genes Induce Protective Immunity against H1, H3 and H5 Influenza Viruses

With the exception of the live attenuated influenza vaccine there have been no substantial changes in influenza vaccine strategies since the 1940’s. Here we report an alternative vaccine approach that uses Adenovirus-vectored centralized hemagglutinin (HA) genes as vaccine antigens. Consensus H1-Con, H3-Con and H5-Con HA genes were computationally derived. Mice were immunized with Ad vaccines expressing the centralized genes individually. Groups of mice were vaccinated with 1 X 1010, 5 X 107 and 1 X 107 virus particles per mouse to represent high, intermediate and low doses, respectively. 100% of the mice that were vaccinated with the high dose vaccine were protected from heterologous lethal challenges within each subtype. In addition to 100% survival, there were no signs of weight loss and disease in 7 out of 8 groups of high dose vaccinated mice. Lower doses of vaccine showed a reduction of protection in a dose-dependent manner. However, even the lowest dose of vaccine provided significant levels of protection against the divergent influenza strains, especially considering the stringency of the challenge virus. In addition, we found that all doses of H5-Con vaccine were capable of providing complete protection against mortality when challenged with lethal doses of all 3 H5N1 influenza strains. This data demonstrates that centralized H1-Con, H3-Con and H5-Con genes can be effectively used to completely protect mice against many diverse strains of influenza. Therefore, we believe that these Ad-vectored centralized genes could be easily translated into new human vaccines.

自20世纪40年代以来，除减毒活流感疫苗（live attenuated influenza vaccine）外，流感疫苗研发策略未出现实质性变革。本研究报道了一种新型疫苗研发方案，该方案以腺病毒载体（Adenovirus-vectored）中心化血凝素（hemagglutinin，HA）基因作为疫苗抗原。研究通过计算方法获得了共识型H1-Con、H3-Con及H5-Con HA基因。研究将小鼠按剂量分为三组，分别以每只小鼠1×10^10、5×10^7及1×10^7病毒颗粒的剂量接种表达对应中心化基因的腺病毒（Ad）疫苗，对应高、中、低三个剂量组。各亚型高剂量疫苗接种组的小鼠均实现100%的异源致死性攻毒保护。除全部存活外，8个高剂量接种组中有7个组的小鼠未出现体重下降及疾病相关症状。较低剂量的疫苗保护效果呈剂量依赖性下降，但即便最低剂量疫苗，仍对多种不同亚型流感毒株提供了显著的保护效果，尤其考虑到本次攻毒所用病毒的高毒力。此外，研究发现无论接种剂量如何，H5-Con疫苗均能为小鼠提供完全的死亡保护，使其免受3株致死剂量H5N1流感毒株的攻击。本研究数据表明，中心化H1-Con、H3-Con及H5-Con基因可有效用于保护小鼠抵御多种不同亚型的流感毒株。因此，本研究认为这类腺病毒载体中心化基因可顺利转化为新型人类疫苗。