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(丙型肝炎病毒)是世界范围内的一种主要病原体，在约1.6亿感染该病毒的人中导致进行性且往往是严重的肝病。在英国，如果不进行治疗，估计350,000名慢性丙型肝炎感染者中的相当大一部分人最终将发展为肝硬变和肝癌(肝细胞癌)。虽然有可用的治疗方法，但基于干扰素的传统疗法只对一部分接受治疗的人有效，而最近开发的直接针对病毒的抗病毒疗法价格昂贵，其使用在许多年内仍将是成本有限的。重要的是，这种治疗方法无法阻止丙型肝炎病毒的传播和每年记录的大量新感染病例；即使那些已经得到有效治疗的人仍然容易再次感染。丙型肝炎病毒还在世界范围内造成了更大的医疗问题，在那里获得治疗的机会仍将受到与艾滋病毒治疗大致相同的限制。全世界每年与丙型肝炎病毒有关的死亡人数超过350,000人，与艾滋病、结核病和疟疾死亡人数相同。使用安全有效的丙型肝炎病毒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，疫苗的治疗性使用将控制和清除已感染丙型肝炎病毒的人的感染，将防止并在许多情况下逆转肝病并发症的发展，如与长期慢性感染有关的肝硬变和肝癌。因此，此类疫苗的开发将对全球健康产生深远影响。由于缺乏测试不同类型疫苗的动物模型，丙型肝炎疫苗的发展一直受到阻碍。事实也证明，开发能诱导长期保护性免疫的疫苗极其困难--即使清除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的情况非常不同。我们认为，解决问题的办法是制造新型疫苗，将病毒蛋白(如来自丙型肝炎病毒的蛋白)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，但感染总是会导致持续感染。因此，一旦感染含有插入的丙型肝炎病毒基因的巨细胞病毒，就会不断地使身体对丙型肝炎病毒产生免疫，这比感染丙型肝炎病毒本身要强得多。这种免疫方法有效性的最令人信服的证据来自HIV疫苗研究，在这些研究中，CMV载体有效地防止了猕猴感染SIV，SIV是一种猴子版本的HIV。此外，CMV/SIV疫苗能够清除已经感染SIV的猕猴的感染。这种含有艾滋病毒基因的人用巨细胞病毒疫苗目前正在进入人体临床试验。丙型肝炎病毒AdV载体疫苗已经在动物模型中证明了有效性，目前正在进行人类I/II期临床试验。另一个使我们能够开发有效的丙型肝炎病毒疫苗的发展是最近发现的一种名为啮齿类肝炎病毒(RHV)的病毒，它与丙型肝炎病毒密切相关，它感染老鼠，并导致与人类丙型肝炎病毒相同的肝病模式和持久性频率。在我们计划的项目中，我们将开发包含RHV基因的CMV和ADV载体，以直接评估这种方法是否能产生保护性免疫，并能清除慢性感染病毒的大鼠的RHV感染。根据以前在猕猴身上接种CMV/SIV候选疫苗的经验，我们相信这一策略也将被证明对丙型肝炎有效，如果得到证实，可能很快就会转化为人类临床试验。

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.