MHC class II invariant chain-adjuvanted viral vectored vaccines enhances T cell responses in humans.
MHC class II invariant chain-adjuvanted viral vectored vaccines enhances T cell responses in humans.
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DOI：
10.1126/scitranslmed.aaz7715
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发表时间：
2020-06-17
影响因子：
17.1
通讯作者：
PEACHI Consortium
中科院分区：
文献类型：
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作者：
Esposito I;Cicconi P;D'Alise AM;Brown A;Esposito M;Swadling L;Holst PJ;Bassi MR;Stornaiuolo M;Mori F;Vassilev V;Li W;Donnison T;Gentile C;Turner B;von Delft A;Del Sorbo M;Barra F;Contino AM;Abbate A;Novellino E;Thomsen AR;Christensen JP;Lahm A;Grazioli F;Ammendola V;Siani L;Colloca S;Klenerman P;Nicosia A;Dorrell L;Folgori A;Capone S;Barnes E;PEACHI Consortium
迫切需要通过疫苗接种来增强高强度T细胞应答的诱导的策略。MHC II类相关不变链（Ii）在抗原呈递中起关键作用，形成用于产生CD 4 + T细胞应答的MHC II类肽复合物。评价Ii与载体递送系统中编码的抗原融合的临床前研究已经表明，这种策略可以增强对编码抗原的T细胞免疫应答。我们现在评估这种策略在人类中，使用黑猩猩腺病毒3（ChAd 3）和修饰的牛痘安卡拉载体（MVA）编码的人Ii融合到丙型肝炎病毒（HCV）的非结构性抗原（NS）在异源初免/加强方案。与非Ii疫苗相比，疫苗接种具有良好的耐受性，并增强了抗HCV T细胞应答的峰值、宽度和增殖能力。HCV特异性T细胞在人类中的频率非常高。多功能HCV特异性CD 8+和CD 4+应答由高达30%的靶向单个HCV表位的CD 3 + CD 8+细胞诱导;这些细胞主要是效应记忆细胞，具有高比例表达T细胞活化和细胞溶解标志物。没有志愿者产生抗Ii T细胞或抗体应答。使用小鼠模型和体外实验，我们表明，Ii融合NS增加HCV免疫反应，通过增强泛素化和蛋白酶体降解。这一策略可用于开发更有效的HCV疫苗，可能有助于HCV消除目标，并为开发针对癌症和其他感染的II类Ii疫苗铺平道路。
Strategies to enhance the induction of high magnitude T cell responses through vaccination are urgently needed. MHC class II associated invariant chain (Ii) plays a critical role in antigen presentation, forming MHC class II peptide complexes for the generation of CD4+ T cell responses. Pre-clinical studies evaluating the fusion of Ii to antigens encoded in vector delivery systems have shown that this strategy may enhance T cell immune responses to the encoded antigen. We now assess this strategy in humans, using chimpanzee adenovirus 3 (ChAd3) and modified vaccinia Ankara vectors (MVA) encoding human Ii fused to the non-structural antigens (NS) of hepatitis C virus (HCV) in a heterologous prime/boost regimen. Vaccination was well tolerated and enhanced the peak magnitude, breadth, and proliferative capacity of anti-HCV T cell responses compared to non-Ii vaccines in humans. Very high frequencies of HCV-specific T cells were elicited in humans. Polyfunctional HCV specific CD8+ and CD4+ responses were induced with up to 30% of CD3+CD8+ cells targeting single HCV epitopes; these were mostly effector memory cells with a high proportion expressing T cell activation and cytolytic markers. No volunteers developed anti Ii T cell or antibody responses. Using a mouse model and in vitro experiments, we show that Ii fused to NS increases HCV immune responses through enhanced ubiquitination and proteasomal degradation. This strategy could be used to develop more potent HCV vaccines that may contribute to the HCV elimination targets, and paves the way for developing class-II Ii vaccines against cancer and other infections.
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影响因子：
12.4
作者：
Capone, Stefania;Naddeo, Mariarosaria;Folgori, Antonella
通讯作者：
Folgori, Antonella
影响因子：
3.8
作者：
Hahn, Judith A.;Wylie, Dennis;Getz, Wayne M.
通讯作者：
Getz, Wayne M.
影响因子：
82.9
作者：
Folgori, A;Capone, S;Nicosia, A
通讯作者：
Nicosia, A
影响因子：
4.4
作者：
Holst, Peter Johannes;Sorensen, Maria Rathmann;Christensen, Jan Piravsgaard
通讯作者：
Christensen, Jan Piravsgaard
DOI：
10.1038/mt.2013.284
发表时间：
2014-03
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
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作者：
通讯作者：
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