Protection of Novel Adenovirus Vectored Vaccine in Rats Against Wild-Type Hepacivirus and Variant Infections

IF 6 2区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

Liver International Pub Date : 2025-03-17 DOI:10.1111/liv.70045

Shengxue Luo, Qitao Deng, Chaolan Liang, Panli Zhang, Peng Zou, Shikai Deng, Meng Zhang, Feifeng Zeng, Ling Zhang, Yongshui Fu, Chengyao Li, Tingting Li

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Abstract

Background and Aims

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.

Methods

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.

Results

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.

Conclusions

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.

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新型腺病毒载体疫苗对大鼠野生型肝炎病毒及其变异感染的保护作用

为了实现世卫组织到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。缺乏合适的动物模型来评估疫苗的效力，极大地阻碍了丙型肝炎疫苗的发展。采用与HCV同源的鼠肝病毒褐家鼠（RHV-rn1）慢性感染的大鼠模型作为HCV感染的替代模型，评估了RHV-rn1疫苗Sad23L-RHVns的保护效果。方法利用RHV-rn1非结构蛋白（NS） 3-5B基因构建Sad23L-RHVns疫苗。SD大鼠肌肉注射Sad23L-RHVns，接种4周后再用RHV-rn1攻毒。部分大鼠在第一次感染RHV-rn1后15周再次感染一种变体。结果初免疫可诱导对NS3-5B抗原的特异性t细胞应答，强化免疫可显著增强特异性t细胞应答。接种大鼠和对照大鼠均受到野生型RHV-rn1的攻击，所有接种大鼠和对照大鼠均持续高水平病毒血症，而9只增强大鼠中有7只（77.8%）清除了RHV-rn1感染。有趣的是，在再次挑战后25周，解决者获得了免疫保护，对变体的再次挑战表现出明显高于非解决者的t细胞反应。结论Sad23L-RHVns初始强化方案可保护77.8%的大鼠免受野生型RHV-rn1感染，且解决者对该变体表现出高水平和维持的T细胞免疫。我们的研究发现，维持有效的T细胞免疫是解决RHV-rn1所需的，这可能为开发人类HCV疫苗提供见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Liver International 医学-胃肠肝病学

CiteScore

13.90

自引率

4.50%

发文量

348

审稿时长

2 months

期刊介绍： Liver International promotes all aspects of the science of hepatology from basic research to applied clinical studies. Providing an international forum for the publication of high-quality original research in hepatology, it is an essential resource for everyone working on normal and abnormal structure and function in the liver and its constituent cells, including clinicians and basic scientists involved in the multi-disciplinary field of hepatology. The journal welcomes articles from all fields of hepatology, which may be published as original articles, brief definitive reports, reviews, mini-reviews, images in hepatology and letters to the Editor.