Adenoviruses vectored hepatitis C virus vaccine cocktails induce broadly specific immune responses against multi-genotypic HCV in mice
Adenoviruses vectored hepatitis C virus vaccine cocktails induce broadly specific immune responses against multi-genotypic HCV in mice
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DOI：
10.1016/j.biopha.2023.115901
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发表时间：
2023-12-06
影响因子：
7.5
通讯作者：
Li，Chengyao
中科院分区：
文献类型：
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作者：
Luo，Shengxue;Zhang，Panli;Li，Chengyao
背景丙型肝炎病毒（HCV）疫苗是预防丙型肝炎及其肝细胞癌进一步进展的迫切需要。由于有前途的基于T细胞的黑猩猩腺病毒和改良痘苗病毒安卡拉载体HCV疫苗在临床II期试验中失败，因此提出了针对多基因型HCV的假设，旨在提高细胞免疫和体液免疫相结合的保护功效的疫苗设计。方法用编码HCV基因型E1E2或NS3-5B蛋白的两种新型腺病毒载体（Sad23L和Ad49L）构建8株HCV疫苗株(Gt) 1b 和 6a 分离株，涵盖华南和东南亚流行的 80% HCV 毒株。将8株HCV疫苗株分别分为基于Sad23L的疫苗鸡尾酒1和基于Ad49L的疫苗鸡尾酒2，用于接种小鼠。结果单剂量107-1010PFU HCV个体疫苗在小鼠中的免疫原性评估显示，对E1和E2蛋白的特异性抗体较弱，但对E1E2/NS3-5B肽的T细胞反应呈剂量依赖性，通过替代载体加强可显着增强这种反应携带同源抗原的疫苗。使用疫苗cocktail-1和cocktail-2进行初免加强疫苗接种可诱导显着更高的交叉反应抗体和更强的针对HCV GT-1b/6a的T细胞反应。鉴定出脾内和肝内 NS31629–1637CD8+T 细胞反应频率较高，其中高比例的 TRM 和 TEM 细胞可能在抵抗肝脏 HCV 感染中发挥重要作用。结论 HCV 疫苗混合物的初免方案在小鼠中引发了针对多基因型 HCV 的广泛交叉反应抗体和强大的 T 细胞反应。
BackgroundHepatitis C virus (HCV) vaccines are an urgent need to prevent hepatitis C and its further progression of hepatocellular carcinoma. Since the promising T cell based chimpanzee adenovirus and modified vaccinia virus Ankara vectorial HCV vaccines were failed in clinical phase II trial, the vaccine designs to improve protection efficacy in combination of cellular and humoral immunity have been hypothesized against multi-genotypic HCV.MethodsEight HCV vaccine strains were constructed with two novel adenovirus vectors (Sad23L and Ad49L) encoding E1E2 or NS3–5B proteins of HCV genotype (Gt) 1b and 6a isolates, covering 80 % HCV strains prevalent in south China and south-east Asia. Eight HCV vaccine strains were grouped into Sad23L-based vaccine cocktail-1 and Ad49L-based vaccine cocktail-2 for vaccinating mice, respectively.ResultsThe immunogenicity of a single dose of 107-1010PFU HCV individual vaccines was evaluated in mice, showing weak specific antibody to E1 and E2 protein but a dose-dependent T cell response to E1E2/NS3–5B peptides, which could be significantly enhanced by boosting with an alternative vector vaccine carrying homologous antigen. Prime-boost vaccinations with vaccine cocktail-1 and cocktail-2 induced significantly higher cross-reactive antibody and stronger T cell responses to HCV Gt-1b/6a. The high frequency of intrasplenic and intrahepatic NS31629–1637CD8+T cell responses were identified, in which the high proportion of TRMand TEMcells might play an important role against HCV infection in liver.ConclusionsPrime-boost regimens with HCV vaccine cocktails elicited the broad cross-reactive antibody and robust T cell responses against multi-genotypic HCV in mice.