Vaccines Expressing the Innate Immune Modulator EAT-2 Elicit Potent Effector Memory T Lymphocyte Responses despite Pre-Existing Vaccine Immunity
Vaccines Expressing the Innate Immune Modulator EAT-2 Elicit Potent Effector Memory T Lymphocyte Responses despite Pre-Existing Vaccine Immunity
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DOI：
10.4049/jimmunol.1200736
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发表时间：
2012-08-01
影响因子：
4.4
通讯作者：
Amalfitano, Andrea
中科院分区：
文献类型：
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作者：
Aldhamen, Yasser Ali;Seregin, Sergey S.;Amalfitano, Andrea
最近针对 HIV-1 的疫苗临床试验的结果好坏参半，证明有必要增强 HIV-1 疫苗平台的总体效力。使用第一代重组腺病毒血清型 5 (rAd5) 平台未能保护疫苗接种者免受 HIV-1 感染。一种假设是，基于 rAd5 的疫苗失败是因为许多疫苗中存在预先存在的 Ad5 免疫力。我们最近证实，表达 EAT-2 的 rAd5 载体独特地激活先天免疫系统，并改善针对 rAd5 表达的 Ag（包括 HIV/Gag）的细胞免疫反应。在这项研究中，我们报告说，尽管存在 Ad5 特异性免疫，但使用 rAd5-EAT-2 疫苗也可以诱导针对 HIV-1 Ag 的有效细胞免疫反应。与表达 EAT-2 突变体 SH2 结构域形式的对照相比，接种 rAd5 野生型 EAT-2 HIV/Gag 特异性疫苗制剂的 Ad5 免疫小鼠显着促进了先天免疫系统多个臂的诱导。尽管预先存在抗 Ad5 免疫力，但这些反应与疫苗诱导针对共表达 Ag 的更强的效应记忆 T 细胞偏向细胞免疫反应的能力提高呈正相关。此外，疫苗混合物中包含EAT-2可改善多功能溶细胞CD8+T细胞反应的产生，其特征是IFN-γ、TNF-α的产生增强、细胞毒性脱颗粒和体内溶细胞活性增加。这些数据提出了一种新方法，将 EAT-2 表达纳入严格的人类疫苗接种应用中，可以提供更有效的 HIV-1 疫苗，特别是在 Ad5 免疫受试者中。免疫学杂志，2012，189：1349-1359。
The mixed results from recent vaccine clinical trials targeting HIV-1 justify the need to enhance the potency of HIV-1 vaccine platforms in general. Use of first-generation recombinant adenovirus serotype 5 (rAd5) platforms failed to protect vaccinees from HIV-1 infection. One hypothesis is that the rAd5-based vaccine failed due to the presence of pre-existing Ad5 immunity in many vaccines. We recently confirmed that EAT-2-expressing rAd5 vectors uniquely activate the innate immune system and improve cellular immune responses against rAd5-expressed Ags, inclusive of HIV/Gag. In this study, we report that use of the rAd5-EAT-2 vaccine can also induce potent cellular immune responses to HIV-1 Ags despite the presence of Ad5-specific immunity. Compared to controls expressing a mutant SH2 domain form of EAT-2, Ad5 immune mice vaccinated with an rAd5-wild-type EAT-2 HIV/Gag-specific vaccine formulation significantly facilitated the induction of several arms of the innate immune system. These responses positively correlated with an improved ability of the vaccine to induce stronger effector memory T cell-biased, cellular immune responses to a coexpressed Ag despite pre-existing anti-Ad5 immunity. Moreover, inclusion of EAT-2 in the vaccine mixture improves the generation of polyfunctional cytolytic CD8(+) T cell responses as characterized by enhanced production of IFN-gamma, TNF-alpha, cytotoxic degranulation, and increased in vivo cytolytic activity. These data suggest a new approach whereby inclusion of EAT-2 expression in stringent human vaccination applications can provide a more effective vaccine against HIV-1 specifically in Ad5 immune subjects. The Journal of Immunology, 2012, 189: 1349-1359.