Chimeric Hemagglutinin Influenza Virus Vaccine Constructs Elicit Broadly Protective Stalk-Specific Antibodies
Chimeric Hemagglutinin Influenza Virus Vaccine Constructs Elicit Broadly Protective Stalk-Specific Antibodies
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DOI：
10.1128/jvi.00641-13
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发表时间：
2013-06-01
影响因子：
5.4
通讯作者：
Palese, Peter
中科院分区：
文献类型：
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作者：
Krammer, Florian;Pica, Natalie;Palese, Peter
目前的流感病毒疫苗策略刺激针对血凝素蛋白的球状头部结构域的免疫反应，以抑制病毒生命周期的关键步骤。由于该结构域在不同毒株之间差异很大，因此大多数年份都需要新的疫苗配方。在这里，我们展示了一种新的疫苗策略，通过使用表达独特的头和茎组合的嵌合血凝素构建体，产生对高度保守的茎结构域的免疫力。通过用表达相同茎但不相关头部的构建体反复免疫小鼠，我们特异性地刺激了茎定向反应，从而在小鼠中提供了广泛的异源和异亚型免疫。值得注意的是，我们的疫苗接种计划提供了一种通用的疫苗方法，可以防止 H5 亚型病毒的攻击。此外，通过使用被动转移抗体或耗竭 CD8(+) T 细胞的体内研究，我们证明了体液免疫机制在观察到的保护中发挥的关键作用。目前的数据表明，基于血凝素蛋白茎结构域的疫苗策略可用于人类，以广泛预防多种流感病毒亚型。
Current influenza virus vaccine strategies stimulate immune responses toward the globular head domain of the hemagglutinin protein in order to inhibit key steps of the virus life cycle. Because this domain is highly variable across strains, new vaccine formulations are required in most years. Here we demonstrate a novel vaccine strategy that generates immunity to the highly conserved stalk domain by using chimeric hemagglutinin constructs that express unique head and stalk combinations. By repeatedly immunizing mice with constructs that expressed the same stalk but an irrelevant head, we specifically stimulated a stalk-directed response that provided broad-based heterologous and heterosubtypicimmunity in mice. Notably, our vaccination scheme provides a universal vaccine approach that protects against challenge with an H5 subtype virus. Furthermore, through in vivo studies using passively transferred antibodies or depletion of CD8(+) T cells, we demonstrated the critical role that humoral mechanisms of immunity play in the protection observed. The present data suggest that a vaccine strategy based on the stalk domain of the hemagglutinin protein could be used in humans to broadly protect against a variety of influenza virus subtypes.