A West Nile virus recombinant protein vaccine that coactivates innate and adaptive immunity
A West Nile virus recombinant protein vaccine that coactivates innate and adaptive immunity
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DOI：
10.1086/517613
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发表时间：
2007-06-01
影响因子：
6.4
通讯作者：
Powell, T. J.
中科院分区：
文献类型：
--
作者：
McDonald, William F.;Huleatt, James W.;Powell, T. J.
通过将细菌鞭毛蛋白（STF 2 δ）的修饰形式融合到西尼罗河病毒（WNV）包膜蛋白的EIII结构域，设计了能够递送先天性和适应性免疫信号的嵌合蛋白质WNV疫苗。该融合蛋白以Toll样受体（TLR）5依赖性方式刺激白细胞介素-8产生，证实了适当的体外TLR 5生物活性，并且还保留了关键的WNV-E特异性构象依赖性中和表位，如通过酶联免疫吸附测定所测量的。当在没有佐剂的情况下向C3 H/HeN小鼠施用时，融合蛋白引起强烈的WNV-E特异性免疫球蛋白G抗体应答，其中和病毒感染性并赋予针对致死性WNV攻击的保护。这种有效的EIII特异性免疫应答需要EIII与STF 2D的直接连接，因为两种组分的简单混合物不能诱导抗体应答或提供针对病毒攻击的保护。体内功能性TLR 5基因的存在也是必需的-TLR 5缺陷小鼠仅引起最小的抗原特异性应答。这些结果证实，设计用于协调调节先天性和适应性免疫应答的疫苗可以诱导保护性免疫应答，而不需要潜在的毒性佐剂。他们还支持进一步开发有效的西尼罗河病毒疫苗以及针对相关黄病毒的新型单价和多价疫苗。
A chimeric protein West Nile virus (WNV) vaccine capable of delivering both innate and adaptive immune signals was designed by fusing a modified version of bacterial flagellin (STF2 Delta) to the EIII domain of the WNV envelope protein. This fusion protein stimulated interleukin-8 production in a Toll- like receptor ( TLR) 5 -dependent fashion, confirming appropriate in vitro TLR5 bioactivity, and also retained critical WNV-E specific conformation- dependent neutralizing epitopes as measured by enzyme-linked immunosorbent assay. When administered without adjuvant to C3H/HeN mice, the fusion protein elicited a strong WNV-E-specific immunoglobulin G antibody response that neutralized viral infectivity and conferred protection against a lethal WNV challenge. This potent EIII-specific immune response requires a direct linkage of EIII to STF2D, given that a simple mixture of the 2 components failed to induce an antibody response or to provide protection against virus challenge. The presence of a functional TLR5 gene in vivo is also required -TLR5-deficient mice elicited only a minimal antigen- specific response. These results confirm that vaccines designed to coordinately regulate the innate and adaptive immune responses can induce protective immune responses without the need for potentially toxic adjuvants. They also support the further development of an effective WNV vaccine and novel monovalent and multivalent vaccines for related flaviviruses.