| [ISVHLD2012]HBV治疗性疫苗最新进展——Prof.Marie-Louise Michel专访 -----
来源： 作者：M.L.Michel 发布时间：2012-7-6 11:42:19 阅读：30
开始的时候我们使用预防性HBV重组疫苗并且成功地使用它做为治疗性疫苗诱导抗体和CD4+T细胞应答，但是它的作用不是足够的强。此后我们转向了其它类型的疫苗和并利用DNA重组技术，比十年前我们第一次设计DNA疫苗更容易。
Hepatology Digest: What is the latest progress with HBV therapeutic vaccines as you have presented here at ISVHLD 2012?
《国际肝病》：您在参与此次ISVHLD2012后认为在HBV治疗性疫苗中最新的进展是什么？
Dr Michel: There has been some progress but we are far from having an efficacious therapeutic vaccine. What I will stress is that we need more fundamental research to better characterize immune responses in HBV-infected livers and this is important for the design of a therapeutic vaccine.
Dr Michel:虽然有一些进展但我们离拥有有效的治疗疫苗还很远。我需要强调的是我们需要更多基础性的研究更好的描述在HBV感染肝脏中免疫应答的特征并且其对于设计治疗性疫苗非常重要。
Hepatology Digest: Specifically， in what areas do we need more research?
《国际肝病》：那您认为在哪些方面我们特别需要做更多的工作呢？
Dr Michel: If possible， analyzing the T cell response which is present in the chronically infected liver， certainly in the periphery but also in the liver itself. This is difficult because it requires a liver biopsy. This will give us important information about these T cells which are important in the clearance of the virus.
Dr Michel:如果可能的话，研究在慢性病毒感染肝脏中呈现的T细胞应答，当然不光肝脏本身，外周T细胞应答也需要重视。这一点实现很困难是由于它需要肝脏活检。这将为我们提供关于这些T细胞清除病毒的重要资料。
Hepatology Digest: So where has the progress occurred that you mentioned?
《国际肝病》：那么您在提到的这方面有哪些进展呢？
Dr Michel: In the beginning we started with the preventative HBV recombinant vaccine and we used it as a therapeutic vaccine with some success using antibodies and CD4 T cell responses but it was not strong enough. We moved to other types of vaccines and with DNA recombinant technology it was easier than ten years ago when we first designed DNA vaccines. More recently we moved toward virus vectors to derive a vaccine which means using vectors derived from adenoviruses or pox viruses in order to deliver the antigens to the patients. Just now we have had communication about a new approach based on nasal immunization which is an immunization given by the nasal route so it is an original approach and it could be interesting for countries where there are not many medical personnel to take care of vaccination. It has been shown to induce some T cell response and an antibody response and they have a clinical trial which is ongoing in Bangladesh. It is an interesting approach and they already have some encouraging results. The other approach is the one developed here in China by Professor Yumei Wen which is also an original approach based on a combination of antigens and antibodies. They are in Phase III trials so they are analyzing the results. There are some encouraging results because the vaccine is as efficacious as interferon and is cheaper but not as efficacious as expected. So we are progressing step-by-step. From each trial we learn something even if it is negative and we can improve at the next step.
Dr Michel:开始的时候我们使用预防性HBV重组疫苗并且成功地使用它做为治疗性疫苗诱导抗体和CD4+T细胞应答，但是它的作用不是足够的强。此后我们转向了其它类型的疫苗和并利用DNA重组技术，比十年前我们第一次设计DNA疫苗更容易。最近我们又转向了病毒载体衍生的疫苗。这意味着使用由腺病毒或者痘病毒产生的载体是为了将抗原传递给患者。刚刚我们做了一个关于基于鼻粘膜的免疫新方法，它通过鼻腔途径产生免疫可以有利于自然接种的免疫方法，并且可以在没有很多医疗机构来进行免疫接种的国家适用。在巴格达进行的临床研究中这种方法可以诱导一些T细胞免疫并产生抗体。这是一种很有前景的方法并且它们已经获得了令人鼓舞的效果。其他方法中如在中国由闻玉梅教授开展的基于抗原和抗体组合的原创方法正在临床III期实验并且它们分析结果有一些令人鼓舞的结果因为这种疫苗有效性类似于干扰素，但是比预期的效果还是差些。因此我们需要一步一步进展。通过每一个试验我们汲取一些经验即使是出现阴性结论，从而我们可以在下一步提高。
Hepatology Digest: If a vaccine is comparable to interferon， what is the tolerability of the vaccine? Are they causing any kinds of side effects?
《国际肝病》：如果疫苗能够和干扰素媲美，那这种疫苗的耐受性如何？它们是否会造成任何并发症？
Dr Michel: Up to this point， it has been well-tolerated and without major side effects. Initially people were a little afraid of a therapeutic vaccine but ultimately the body is well organized to preserve the liver.
Dr Michel:在这一点上，它可以很好的耐受并且没有副作用。开始人们对治疗性疫苗使用有一些担心，但是最终宿主可以被较好的组织起来保护肝脏。
Hepatology Digest: Who will be the targets of a therapeutic vaccine? Is it something that would be used in all patients?
《国际肝病》：谁将成为治疗性疫苗的靶点？是否可以使用到所有的患者身上？
Dr Michel: Probably not in all patients. There are different kinds of patients with chronic hepatitis so I think for the moment the good candidates for therapeutic vaccination would be those with chronic active hepatitis with associated liver disease and those in the reactivation or active phase of the disease and those who are treated with antiviral treatments because， as you know， the antiviral treatments are not completely successful in eliminating the virus and this is one of the main problems in that the virus can lay silent in the liver.
Dr Michel:这可能不能使用到所有的患者身上。这些有各种类型的慢性肝炎患者我认为治疗性疫苗使用的最佳选择是一些慢性活动性肝炎以及相关肝脏疾病，并且一些在活动性或者疾病的活动阶段以及一些经过抗病毒治疗过的患者。如大家所知，抗病毒治疗不能完全成功地清除病毒并且存在一个主要的问题就是这些病毒在感染潜伏下来。
Hepatology Digest: There has been talk about how the body， at least in a transient infection in acute hepatitis， gets rid of the cccDNA. It was suggested in a talk yesterday that mitosis and cell death were necessary to remove cccDNA but that without cytokines， mitosis itself does not cause the loss of cccDNA. Wouldn’t this mean that it would be advantageous for all people who are on antiviral treatment to increase their cytokines and eliminate cccDNA even if they don’t have active liver disease?
《国际肝病》：有些讨论关于机体如何至少是在短时间感染后急性肝炎中清除cccDNA。昨天的讨论上有人认为细胞有丝分裂以及细胞死亡对于清除cccDNA，但没有细胞因子。有丝分裂本身不会导致cccDNA下降。这种方法是否对所有正在抗病毒治疗患者有利并增加它们的细胞因子产生同时清除cccDNA甚至不会发生活动性肝病？
Dr Michel: We cannot eliminate cccDNA without destroying the infected hepatocyte which is why the T cell therapy is interesting because T cells can have a cytotoxic function and kill the infected hepatocyte and after that there is the division of hepatocytes and elimination of cccDNA. The current antiviral treatments are not able to do that other than interferon which can reduce the cccDNA level by a small amount. Cytokines are also important because they act non-cytopathically but the cccDNA persists. Maybe in the future we can design some drugs to eliminate that cccDNA and this is an approach taken from HIV because there is a problem also with the persistence of the HIV virus.
Dr Michel:我们不能在不破环病毒感染肝细胞的情况下清除cccDNA，是由于T细胞治疗可以产生细胞毒功能并且杀伤受感染肝细胞并且在其后分裂肝细胞以及清除cccDNA。目前抗病毒治疗除了干扰素能少量清除cccDNA水平，其它没有能够清除cccDNA。细胞因子也是非常重要的是由于它是通过发挥非细胞病理损伤但是cccDNA持续存在。但是在将来我们可以设计出更多的药物去减少cccDNA并且这种方法从HIV获得，因为在HIV病毒持续感染中也存在这样的问题。
Hepatology Digest: Is the thinking that an HBV therapeutic vaccine would eliminate cccDNA?
《国际肝病》：是否可以认为HBV治疗性疫苗能够清除cccDNA？
Dr Michel: Yes. If we induce the right sites and with the right function with cytotoxic T cells. So there would be the killing off of infected hepatocytes. We cannot cure without a little bit of killing.
Dr Michel:是的，或许我们可以在合适的位置诱导出适合的功能细胞毒性T细胞。因此在感染病毒的肝细胞可以发生被杀伤。但没有一点点杀伤存在的情况下我们不能治愈肝炎的。
Hepatology Digest: You said that the people who would be good candidates for therapeutic vaccination would have liver disease. Why would we not want to get rid of the cccDNA in people in the earlier stages of chronic HBV infection?
《国际肝病》：您提到治疗性疫苗最佳使用人群是肝脏疾病。那么为何在HBV慢性感染的早期阶段我们不能清除患者的cccDNA呢？
Dr Michel: This is a question that needs to be studied but unfortunately we won’t have a sample from a patient at the very beginning of infection and this is the major problem. We can’t actually analyze what is happening at the very early stage. We need to find out why some patients clear the virus and others become chronic carriers. When the infection occurs in infancy or at birth it is clear that the immune response is not mature enough to eliminate the virus but we don’t know why the majority of adults clear the virus but others become chronic carriers. There is a lot of work that still needs to be done and we probably need some animal models which is another problem for HBV. We don’t have any small animal models and there are some presentations on that topic at this meeting. There is one group who have succeeded in obtaining a mouse model with humanized hepatocytes and humanized immune system and they were able to infect these mice with HBV. This is an opportunity to study the first step of infection and how the immune system controls the infection， because this is not something that is possible to study in humans.
Dr Michel:这个问题需要研究但是不幸的是我们没有获得一例患者在感染开始最早阶段的样本，因此这是一个主要的问题。我们不能够分析出在非常早的阶段机体发生了什么。我们需要发现为何一些患者清除了病毒而另一些成为慢性携带者。当病毒感染在婴幼儿或者出生时可以明确的是免疫应答尚不成熟以致不能清除病毒，但是我们不知道为何大部分成人患者可以清除病毒而有些则成为慢性病毒携带者。仍然有许多工作需要做尤其我们可能需要一些动物模型来说明，这也是研究HBV的另一个困难问题。我们没有任何小动物模型，在此次会议上关于这个话题也有一些呈现。有一个团队在小鼠模型上获得人源化肝细胞和免疫系统获得成功并且可以使这些老鼠感染HBV。这为研究HBV感染第一步以及免疫系统如何控制感染创造条件，因为在人类身上不可能进行这项实验。
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发表于 2012-7-6 16:35
