A human vaccine strategy based on chimpanzee adenoviral and MVA vectors that primes, boosts, and sustains functional HCV-specific T cell memory.
A human vaccine strategy based on chimpanzee adenoviral and MVA vectors that primes, boosts, and sustains functional HCV-specific T cell memory.
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DOI：
10.1126/scitranslmed.3009185
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发表时间：
2014-11-05
影响因子：
17.1
通讯作者：
Barnes E
中科院分区：
文献类型：
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作者：
Swadling L;Capone S;Antrobus RD;Brown A;Richardson R;Newell EW;Halliday J;Kelly C;Bowen D;Fergusson J;Kurioka A;Ammendola V;Del Sorbo M;Grazioli F;Esposito ML;Siani L;Traboni C;Hill A;Colloca S;Davis M;Nicosia A;Cortese R;Folgori A;Klenerman P;Barnes E
针对丙型肝炎病毒（HCV）的保护性疫苗仍未满足临床需求。丙型肝炎病毒感染了全世界数百万人，是导致肝硬化和肝细胞癌的主要原因。动物激射实验、免疫遗传学研究和急性感染期间宿主免疫评估强调了有效的t细胞免疫在病毒控制中的关键作用。在这项首次人体研究中，我们诱导了抗病毒免疫，其功能特征类似于自然感染中与病毒控制相关的功能特征，并在仅基于腺病毒载体的疫苗基础上进行了改进。我们基于复制缺陷猴腺病毒载体（ChAd3）和编码HCV基因型1b的NS3、NS4、NS5A和NS5B蛋白的修饰痘苗安卡拉（MVA）载体，评估了一种异种启动-增强疫苗接种策略。分析采用单细胞大量细胞术（CyTOF）和HLA - i类肽四聚体技术。我们发现，ChAd3诱导的HCV特异性t细胞在MVA的作用下得到最佳增强，并产生非常高水平的CD8+和CD4+ HCV特异性t细胞靶向多种HCV抗原。在异种MVA增强后，持续记忆和效应t细胞群产生，t细胞记忆随着时间的推移而进化，质量（增殖和多功能性）得到改善。我们已经开发了一种HCV疫苗策略，具有持久、广泛、持续和平衡的t细胞反应，与病毒控制相关的特征，为预防性HCV疫苗的首次疗效研究铺平了道路。
A protective vaccine against hepatitis C virus (HCV) remains an unmet clinical need. HCV infects millions of people worldwide and is a leading cause of liver cirrhosis and hepatocellular cancer. Animal challenge experiments, immunogenetics studies and assessment of host immunity during acute infection highlight the critical role that effective T-cell immunity plays in viral control. In this first-in-man study we have induced antiviral immunity with functional characteristics analogous to those associated with viral control in natural infection, and improved upon a vaccine based on adenoviral vectors alone. We assessed a heterologous prime-boost vaccination strategy based on a replicative defective simian adenoviral vector (ChAd3) and modified vaccinia Ankara (MVA) vector encoding the NS3, NS4, NS5A and NS5B proteins of HCV genotype-1b. Analysis employed single cell mass cytometry (CyTOF), and HLA class-I peptide tetramer technology in healthy human volunteers. We show that HCV specific T-cells induced by ChAd3 are optimally boosted with MVA, and generate very high levels of both CD8+ and CD4+ HCV specific T-cells targeting multiple HCV antigens. Sustained memory and effector T-cell populations are generated and T-cell memory evolved over time with improvement of quality (proliferation and polyfunctionality) following heterologous MVA boost. We have developed a HCV vaccine strategy, with durable, broad, sustained and balanced T-cell responses, characteristic of those associated with viral control, paving the way for the first efficacy studies of a prophylactic HCV vaccine.