Modulation of the immune response induced by gene electrotransfer of a hepatitis C virus DNA vaccine in nonhuman primates
Modulation of the immune response induced by gene electrotransfer of a hepatitis C virus DNA vaccine in nonhuman primates
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DOI：
10.4049/jimmunol.177.10.7462
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发表时间：
2006-11-15
影响因子：
4.4
通讯作者：
Folgori, Antonella
中科院分区：
文献类型：
--
作者：
Capone, Stefania;Zampaglione, Immacolata;Folgori, Antonella
诱导多特异性、功能性CD4（+）和CD8(+) T细胞是人类急性自限性丙型肝炎病毒（HCV）感染的免疫学标志。在本研究中，我们发现基因电转移（GET）编码HCV非结构区优化版本（从NS3到NS5B）的新型候选DNA疫苗比裸DNA注射在小鼠和恒河猴中诱导更有效、更广泛和更持久的CD4（+）和CD8（+）细胞免疫，这些检测包括ifn - γ ELISPOT、细胞内细胞因子染色和细胞毒性T细胞检测。与基于腺病毒6的编码相同Ag的病毒载体相比，基于三次GET DNA注射的方案诱导了明显更高的CD4(+) T细胞反应。为了更好地评估这种疫苗的免疫效力和成功的可能性，我们对两只黑猩猩进行了免疫，并将疫苗诱导的细胞介导免疫与人类急性自限性感染的免疫进行了比较。候选HCV疫苗的GET在黑猩猩中导致了强烈的、多特异性的ifn - γ (+)CD8（+）和CD4(+) T淋巴细胞反应，这与在5个自发清除HCV感染的个体中测量的结果相当。这些数据支持了一种假设，即当前策略引发的T细胞反应可能有利于预防丙肝病毒的疫苗方法。
Induction of multispecific, functional CD4(+) and CD8(+) T cells is the immunological hallmark of acute self-limiting hepatitis C virus (HCV) infection in humans. In the present study, we showed that gene electrotransfer (GET) of a novel candidate DNA vaccine encoding an optimized version of the nonstructural region of HCV (from NS3 to NS5B) induced substantially more potent, broad, and long-lasting CD4(+) and CD8(+) cellular immunity than naked DNA injection in mice and in rhesus macaques as measured by a combination of assays, including IFN-gamma ELISPOT, intracellular cytokine staining, and cytotoxic T cell assays. A protocol based on three injections of DNA with GET induced a substantially higher CD4(+) T cell response than an adenovirus 6-based viral vector encoding the same Ag. To better evaluate the immunological potency and probability of success of this vaccine, we have immunized two chimpanzees and have compared vaccine-induced cell-mediated immunity to that measured in acute self-limiting infection in humans. GET of the candidate HCV vaccine led to vigorous, multispecific IFN-gamma(+)CD8(+) and CD4(+) T lymphocyte responses in chimpanzees, which were comparable to those measured in five individuals that cleared spontaneously HCV infection. These data support the hypothesis that T cell responses elicited by the present strategy could be beneficial in prophylactic vaccine approaches against HCV.