VACCINE: Development and evaluation of vectored vaccines for HCV using an enhanced gene expression technology in a novel rodent hepacivirus model

疫苗：在新型啮齿动物肝炎病毒模型中使用增强基因表达技术开发和评估 HCV 载体疫苗

• 批准号: MR/P011128/1
• 负责人: Peter Simmonds
• 金额: $ 85.26万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP011128%2F1
• 关键词: VACCINE; Development; evaluation; vectored; vaccines

Hepatitis C virus (HCV) is a major pathogen worldwide, causing progressive and often severe liver disease in the estimated 160 million people infected with the virus. In the UK, a substantial proportion of the estimated 350,000 individuals chronically infected with HCV will eventually develop cirrhosis and liver cancer (hepatocellular carcinoma; HCC) if left untreated. While there is treatment available, conventional therapies based on interferon are effective in only a proportion of those treated while more recently developed antiviral therapy that directly targets the virus is expensive and its use will remain cost-limited for many years. Importantly, such treatments will not stem the spread of HCV and the large numbers of new infections recorded every year; even those who have been effectively treated remain prone to re-infection. HCV also poses a much greater medical problem worldwide where access to treatment will remain limited in much the same as HIV therapy. HCV-related deaths worldwide exceed 350,000 per year, of the same order to those attributed to AIDS, TB and malaria. Large scale immunisation with a safe and effective HCV vaccine would induce life-long immunity to HCV and prevent further spread of the virus to those currently at risk for infection. Secondly, the therapeutic use of a vaccine in which immunisation would control and clear infection in those already infected with HCV would prevent and in many cases reverse development of liver disease complications, such as cirrhosis and HCC associated with long term chronic infection. The development of such vaccines would therefore have profound effects on global health. The development of HCV vaccine has been hampered by a lack of animal models with which to test different type of vaccine. It has also proven exceptionally difficult to develop vaccines that induce long-lived protective immunity - even clearance of natural infections does not protect from subsequent re-infection, quite unlike the situation of poliovirus, measles and hepatitis A virus (as examples) for which effective vaccines have been developed. We believe the solution to the problems is to generate novel vaccines in which viral proteins, such as those from HCV, are inserted into another virus, cytomegalovirus (CMV) or adenovirus (AdV). A feature of CMV infections is that although harmless, infection leads invariably to persistent infections. Infections with CMV containing inserted HCV genes, once established, would therefore continuously immunise the body against HCV, much more so than infection with HCV itself. The most compelling evidence for the effectiveness of this method of immunisation arises from HIV vaccine research, where CMV vectors were effective at preventing infection of macaques with SIV, a monkey version of HIV. Furthermore, the CMV/SIV vaccine was able to clear infection from macaques already infected with SIV. A human version of this CMV vaccine, containing HIV genes, is currently entering human clinical trial. AdV-vectored vaccines for HCV have proven efficacy in animal models and are currently in human phase I/II clinical trial. The other development that will enable us to develop an effective HCV vaccine is the very recent discovery of a virus called rodent hepacivirus (RHV), closely related to HCV, that infects rats and causes the same pattern of liver disease and frequency of persistence as HCV in humans. In our planned project, we will develop CMV and AdV vectors containing genes from RHV to directly evaluate whether this approach can generate protective immunity and can clear RHV infection in rats that are chronically infected with the virus. Based on previous experience with CMV/SIV vaccine candidates in macaques, we believe this strategy will also prove effective for HCV and if confirmed, could translate through very rapidly into human clinical trials.

丙型肝炎病毒（HCV）是世界范围内的主要病原体，在估计1.6亿感染该病毒的人中引起进行性且通常严重的肝脏疾病。在英国，估计有350，000人慢性感染HCV，如果不及时治疗，其中很大一部分人最终会发展为肝硬化和肝癌（肝细胞癌; HCC）。虽然有可用的治疗方法，但基于干扰素的常规疗法仅对一部分治疗有效，而最近开发的直接靶向病毒的抗病毒疗法价格昂贵，并且其使用将在许多年内保持成本限制。重要的是，这种治疗方法不会阻止HCV的传播，每年都会有大量新的感染记录;即使是那些已经得到有效治疗的人仍然容易再次感染。丙型肝炎病毒还在全世界造成了一个更大的医疗问题，在那里获得治疗的机会将仍然有限，与艾滋病毒治疗大致相同。全世界每年与HCV相关的死亡人数超过35万，与艾滋病、结核病和疟疾造成的死亡人数相同。使用安全有效的HCV疫苗进行大规模免疫接种，可诱导对HCV的终身免疫力，并防止病毒进一步传播给目前有感染风险的人。其次，疫苗的治疗性使用，其中免疫将控制和清除那些已经感染HCV的人的感染，将预防并在许多情况下逆转肝病并发症的发展，如与长期慢性感染相关的肝硬化和HCC。因此，这种疫苗的开发将对全球健康产生深远影响。HCV疫苗的开发一直受到缺乏动物模型来测试不同类型疫苗的阻碍。此外，事实证明，要研制出能产生长期保护性免疫力的疫苗极为困难，即使清除了自然感染，也不能防止随后的再感染，这与脊髓灰质炎病毒、麻疹和甲型肝炎病毒的情况（例如）很不一样，这些病毒已研制出有效的疫苗。我们相信解决这些问题的方法是生产新的疫苗，其中病毒蛋白，如来自HCV的蛋白，插入另一种病毒，巨细胞病毒（CMV）或腺病毒（AdV）。CMV感染的一个特点是，虽然无害，但感染总是导致持续感染。因此，含有插入的HCV基因的CMV感染一旦建立，就会持续地使身体对HCV产生免疫，比HCV本身的感染更有效。这种免疫方法的有效性的最令人信服的证据来自HIV疫苗研究，其中CMV载体有效地预防了猕猴感染SIV，一种猴子版本的HIV。此外，CMV/SIV疫苗能够从已经感染SIV的猕猴中清除感染。这种含有HIV基因的CMV疫苗的人类版本目前正在进入人体临床试验。HCV的AdV载体疫苗已在动物模型中证明有效，目前正在进行人体I/II期临床试验。另一个使我们能够开发有效的HCV疫苗的进展是最近发现的一种称为啮齿动物肝炎病毒（RHV）的病毒，它与HCV密切相关，感染大鼠并导致与人类HCV相同的肝病模式和持续频率。在我们计划的项目中，我们将开发含有RHV基因的CMV和AdV载体，以直接评估这种方法是否可以产生保护性免疫，并可以清除慢性感染病毒的大鼠中的RHV感染。根据之前在猕猴中使用CMV/SIV候选疫苗的经验，我们相信这种策略也将证明对HCV有效，如果得到证实，可以非常迅速地转化为人类临床试验。