Feasibility of reconstructed ancestral H5N1 influenza viruses for cross-clade protective vaccine development
Feasibility of reconstructed ancestral H5N1 influenza viruses for cross-clade protective vaccine development
复制标题
DOI：
10.1073/pnas.1012457108
复制
发表时间：
2011-01-04
影响因子：
11.1
通讯作者：
Webby, Richard J.
中科院分区：
文献类型：
--
作者：
Ducatez, Mariette F.;Bahl, Justin;Webby, Richard J.
自2003年人类再次出现高致病性H5N1流感病毒以来，这些病毒已在亚洲、欧洲和非洲的禽类物种中传播。它们的持续循环导致了遗传多样性谱系的进化。来自这些谱系的病毒显示出相当大的抗原变异，这混淆了疫苗规划工作。我们重建了代表不同H5N1病毒进化枝祖先的血凝素（HA）和神经氨酸酶（NA）基因同源性的几个节点处的祖先蛋白质序列。通过使用已经用于产生目前许可的灭活H5N1疫苗的相同方法，我们能够产生一组具有复制能力的流感病毒，其含有代表重建的祖先蛋白的合成的HA和NA基因。我们确定了这些病毒中的两种，它们与进化枝1、2.1、2.2、2.3.4和4病毒显示出有希望的体外交叉反应性。为了证实这些病毒衍生的疫苗抗原能够在免疫后引发功能性抗体，我们创建了全病毒疫苗，并将其保护效力与来自阳性对照、天然存在和广泛反应性H5N1病毒的抗原的保护效力进行了比较。祖先病毒的疫苗提供了强大的保护，防止发病率和死亡率与H5N1毒株从进化枝1，2.1和2.2的挑战，以类似的方式对控制株。这些发现提供了原理证明，即可以在当前许可的疫苗平台的背景下构建可行的计算衍生疫苗种子病毒。应探索这类技术，以提高H5N1流感疫苗的交叉反应性和可用性。
Since the reemergence of highly pathogenic H5N1 influenza viruses in humans in 2003, these viruses have spread throughout avian species in Asia, Europe, and Africa. Their sustained circulation has resulted in the evolution of phylogenetically diverse lineages. Viruses from these lineages show considerable antigenic variation, which has confounded vaccine planning efforts. We reconstructed ancestral protein sequences at several nodes of the hemagglutinin (HA) and neuraminidase (NA) gene phylogenies that represent ancestors to diverse H5N1 virus clades. By using the same methods that have been used to generate currently licensed inactivated H5N1 vaccines, we were able to produce a panel of replication competent influenza viruses containing synthesized HA and NA genes representing the reconstructed ancestral proteins. We identified two of these viruses that showed promising in vitro cross-reactivity with clade 1, 2.1, 2.2, 2.3.4, and 4 viruses. To confirm that vaccine antigens derived from these viruses were able to elicit functional antibodies following immunization, we created whole-virus vaccines and compared their protective efficacy versus that of antigens from positive control, naturally occurring, and broadly reactive H5N1 viruses. The ancestral viruses' vaccines provided robust protection against morbidity and mortality in ferrets challenged with H5N1 strains from clades 1, 2.1, and 2.2 in a manner similar to those based on the control strains. These findings provide proof of principle that viable, computationally derived vaccine seed viruses can be constructed within the context of currently licensed vaccine platforms. Such technologies should be explored to enhance the cross reactivity and availability of H5N1 influenza vaccines.