Luo Shengxue, Deng Qitao, Liang Chaolan, Zhang Panli, Zou Peng, Deng Shikai, Zhang Meng, Zeng Feifeng, Zhang Ling, Fu Yongshui, Li Chengyao, Li Tingting
Institute of Clinical Blood Transfusion, Guangzhou Blood Center, Guangzhou, China.
Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China.
Liver Int. 2025 Apr;45(4):e70045. doi: 10.1111/liv.70045.
Hepatitis C virus (HCV) vaccines are urgently needed to achieve WHO's goal for the elimination of viral hepatitis by 2030. The lack of suitable animal models for evaluating vaccine efficacy has greatly hindered the development of HCV vaccines. By using the rat model chronically infected with rodent hepacivirus from Rattus norvegicus (RHV-rn1), a hepacivirus homologously close to HCV as a surrogate model of HCV infection, we assessed the protective effectiveness of the RHV-rn1 vaccine Sad23L-RHVns.
Sad23L-RHVns vaccine was constructed with the nonstructural proteins (NS) 3-5B genes of RHV-rn1. SD rats were immunised with Sad23L-RHVns by prime or prime-boost regimen via intramuscular injection, then challenged 4 weeks post vaccination by RHV-rn1. A part of the rats were rechallenged with a variant 15 weeks post the first challenge of RHV-rn1.
The specific T-cell responses to NS3-5B antigens were induced by prime immunisation, which were significantly enhanced by boost vaccination. The inoculated rats and controls were challenged by wild-type RHV-rn1, of all the primed and control rats having persistently high levels of viremia, whereas 7 of 9 (77.8%) boosted rats cleared RHV-rn1 infection. Interestingly, the resolver acquired immune protection against re-challenging with variant and showed significantly higher T-cell responses than the nonresolver in 25 weeks post rechallenge.
Sad23L-RHVns with prime-boost regimen protected 77.8% of rats against wild-type RHV-rn1 infection, and resolvers showed high levels and maintenance of T cell immunity against the variant. Our findings that maintenance of effective T cell immunity is required for RHV-rn1 resolution may provide insight to develop the HCV vaccine in humans.
为实现世界卫生组织在2030年消除病毒性肝炎的目标，迫切需要丙型肝炎病毒（HCV）疫苗。缺乏用于评估疫苗效力的合适动物模型极大地阻碍了HCV疫苗的研发。通过使用慢性感染来自褐家鼠的啮齿动物肝炎病毒（RHV-rn1）的大鼠模型，RHV-rn1是一种与HCV同源性相近的肝炎病毒，作为HCV感染的替代模型，我们评估了RHV-rn1疫苗Sad23L-RHVns的保护效力。
用RHV-rn1的非结构蛋白（NS）3-5B基因构建Sad23L-RHVns疫苗。将SD大鼠通过肌肉注射采用初免或初免-加强免疫方案接种Sad23L-RHVns，然后在接种疫苗4周后用RHV-rn1进行攻击。一部分大鼠在首次受到RHV-rn1攻击15周后再次受到变异株攻击。
初免诱导了对NS3-5B抗原的特异性T细胞反应，加强免疫显著增强了该反应。接种疫苗的大鼠和对照大鼠受到野生型RHV-rn1攻击，所有初免和对照大鼠的病毒血症水平持续较高，而9只加强免疫大鼠中有7只（77.8%）清除了RHV-rn1感染。有趣的是，清除病毒者获得了针对变异株再次攻击的免疫保护，并且在再次攻击后25周时显示出比未清除病毒者显著更高的T细胞反应。
采用初免-加强免疫方案的Sad23L-RHVns保护了77.8%的大鼠免受野生型RHV-rn1感染，清除病毒者对变异株显示出高水平且持久的T细胞免疫。我们的研究结果表明，RHV-rn1的清除需要维持有效的T细胞免疫，这可能为开发人类HCV疫苗提供思路。
