Fusion of HCV Nonstructural Antigen to MHC Class II-associated Invariant Chain Enhances T-cell Responses Induced by Vectored Vaccines in Nonhuman Primates
Fusion of HCV Nonstructural Antigen to MHC Class II-associated Invariant Chain Enhances T-cell Responses Induced by Vectored Vaccines in Nonhuman Primates
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DOI：
10.1038/mt.2014.15
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发表时间：
2014-05-01
影响因子：
12.4
通讯作者：
Folgori, Antonella
中科院分区：
文献类型：
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作者：
Capone, Stefania;Naddeo, Mariarosaria;Folgori, Antonella
尽管病毒载体是抗原特异性T细胞的有效诱导剂，但仍积极寻求进一步改善其免疫原性的策略。在研究的众多方法中，已报道编码抗原与主要组织相容性复合物II类相关不变链（Ii）的融合可增强CD 8（+）T细胞应答。我们以前已经证明，腺病毒疫苗编码的非结构（NS）丙型肝炎病毒（HCV）蛋白诱导人体有效的T细胞反应。然而，可能需要甚至更高的T细胞应答来实现针对不同HCV基因型的功效或在慢性感染的HCV患者中的治疗效果。在这项研究中，我们评估了融合的HCV NS抗原小鼠和人类Ii表达的黑猩猩腺病毒载体ChAd 3或重组修饰的牛痘安卡拉在小鼠和非人灵长类动物（NHP）。在远交系小鼠中观察到显著增加，其中用表达融合抗原的ChAd 3接种导致干扰素-γ（+）CD 8（+）T细胞增加10倍。在NHP中，CD 8（+）T细胞应答被编码Ii融合抗原的载体增强和加速。这些数据首次表明，由编码融合抗原的载体疫苗诱导的增强不是种属特异性的，并且可以从小鼠转化为NHP，从而为在人类中进行测试开辟了道路。
Despite viral vectors being potent inducers of antigen-specific T cells, strategies to further improve their immunogenicity are actively pursued. Of the numerous approaches investigated, fusion of the encoded antigen to major histocompatibility complex class II associated invariant chain (Ii) has been reported to enhance CD8(+) T-cell responses. We have previously shown that adenovirus vaccine encoding nonstructural (NS) hepatitis C virus (HCV) proteins induces potent T-cell responses in humans. However, even higher T-cell responses might be required to achieve efficacy against different HCV genotypes or therapeutic effect in chronically infected HCV patients. In this study, we assessed fusion of the HCV NS antigen to murine and human Ii expressed by the chimpanzee adenovirus vector ChAd3 or recombinant modified vaccinia Ankara in mice and nonhuman primates (NHPs). A dramatic increase was observed in outbred mice in which vaccination with ChAd3 expressing the fusion antigen resulted in a 10-fold increase in interferon-gamma(+) CD8(+) T cells. In NHPs, CD8(+) T-cell responses were enhanced and accelerated with vectors encoding the li-fused antigen. These data show for the first time that the enhancement induced by vector vaccines encoding li-fused antigen was not species specific and can be translated from mice to NHPs, opening the way for testing in humans.