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

丙型肝炎病毒（HCV）是世界范围内的一种主要病原体，估计有1.6亿人感染该病毒，可导致进行性且往往严重的肝脏疾病。在英国，估计有35万慢性HCV感染者，如果不及时治疗，其中很大一部分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，但基于干扰素的传统疗法仅对一部分接受治疗的患者有效，而最近开发的直接针对该病毒的抗病毒疗法价格昂贵，其使用在许多年内仍将受到成本限制。重要的是，这种治疗不能阻止丙型肝炎病毒的传播和每年记录的大量新感染；即使那些已经得到有效治疗的人仍然容易再次感染。丙型肝炎病毒在世界范围内也构成了一个更大的医疗问题，在那里获得治疗的机会与艾滋病毒治疗一样仍然有限。全世界每年与丙型肝炎相关的死亡人数超过35万，与艾滋病、结核病和疟疾的死亡人数相同。使用安全有效的丙型肝炎疫苗进行大规模免疫接种将诱导对丙型肝炎病毒的终身免疫，并防止病毒进一步传播给目前有感染风险的人。其次，治疗性使用一种疫苗，通过免疫控制和清除已经感染HCV的人的感染，可以预防并在许多情况下逆转肝脏疾病并发症的发展，如与长期慢性感染相关的肝硬化和HCC。因此，开发这类疫苗将对全球健康产生深远影响。由于缺乏动物模型来测试不同类型的疫苗，丙型肝炎疫苗的开发受到了阻碍。事实也证明，开发能诱发长期保护性免疫的疫苗异常困难——即使清除了自然感染，也不能防止随后的再次感染，这与已开发出有效疫苗的脊髓灰质炎病毒、麻疹和甲型肝炎病毒（例如）的情况完全不同。我们认为，解决这些问题的办法是制造新型疫苗，将病毒蛋白（如丙型肝炎病毒）插入另一种病毒，巨细胞病毒（CMV）或腺病毒（AdV）。巨细胞病毒感染的一个特点是，虽然无害，但感染总是导致持续感染。因此，含有插入HCV基因的巨细胞病毒感染一旦建立，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艾滋病毒疫苗研究，其中巨细胞病毒载体有效地防止猕猴感染SIV， SIV是一种猴子版的艾滋病毒。此外，CMV/SIV疫苗能够清除已经感染SIV的猕猴的感染。含有HIV基因的人类巨细胞病毒疫苗目前正在进入人体临床试验。针对丙型肝炎病毒的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。使我们能够开发有效的丙型肝炎疫苗的另一项进展是最近发现的一种称为啮齿动物肝炎病毒（RHV）的病毒，与丙型肝炎病毒密切相关，它感染大鼠并引起与人类丙型肝炎病毒相同的肝脏疾病模式和持续频率。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，直接评估这种方法是否能产生保护性免疫，并能清除慢性感染RHV病毒的大鼠的RHV感染。根据以前在猕猴身上使用巨细胞病毒/SIV候选疫苗的经验，我们相信这一策略也将被证明对丙肝病毒有效，如果得到证实，可以非常迅速地转化为人体临床试验。

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.