[studyforhope] opinions on therapeutic vaccine & future treatment

StephenW

The following is from Studyforhope. As I don't know Studyforhope, please accept this is his/her opinion only. Personally, I wish to thank Studyforhope for the valuable discussions.

To Stephen and Stef

1." Antivirals typically reduce the amount of cccDNA, but nor dramatically, at best about 10 times" - This is good news. Is this a recent discovery or well known fact? No antiviral manufacturers seem to state this fact.

This has been frequently reported at the liver meetings since years now, in poster format.The effect is just not very impressive and reflects the fact that the cccDNA concentration in a single liver cell is dynamically maintained/turned over  at a very very slow rate and that a tiny part of the genomically synthesized DNA does not enter into the virions but recycles to the cccDNa pool thus less produced - by reverse transcription of the genomic RNA - genomic DNA reduces mildly the cccDNA concentration The decrease in cccDNa is reflected somewhat in the surface antigen concentration, since it is transcribed off the cccDNA, but the decrease typically stops at a new equilibrium, very rarely - up to 6% - it leads to surface antigen to Ab seroconversion.

2. The liver stem cells, do they get infected too by HBV ?
The common thinking is NO, the satellite cells are not infectable, probably due to their lack of expression of the critical surface protein receptor gene.

Finally, how do you see the future of  treatment for chronic HBV? New drugs, new types of interferons, therapeutic vaccines, combination treatments?

Therapeutic vaccines have little chance, unless combined with something like replicor, since the antigen flooding prevents any effective immune response to reach the liver. Core epitope vaccines, even particle vaccines, fail, because the core is free of class I epitopes with only one exception the 18 to 27 AA core protein epitope as was used in the classical Cytel vaccine. it failed, because in most chronic carrier of the HLA A2 type, this epitope gets mutated and inactive, so the T cells stimulated/produced by the vaccine target nothing that exists in the virus anymore. This is BTW the only class I epitope that evolution has left in the core protein, against which the virus is normally protected by the e-Antigen flooding, it is also the epitope that is typically responsible for the clearance in acute HBV. It often mutates from one sequence to another when in the eantigen neg carrier an escape mutatnt against its response arises, causing a rise of a new mutant epitope in the high titer virions, followed by a new surge of new cytotoxic Tcells against this mutated epitope, causing severe flares, mostly without final clearance, since now we are looking at a HBV quasispecies at this critical locus.
The surface protein has about 8 class I epitopes of various vigor and affinity, and many more classII epitopes.
Thus core vaccines will produce some class II response of limited effectiveness, leading to temporary increased liver inflammation with a reduction in virion production (reduced viral load) and viral protein expression. But the effect is too unspecific and will rarely lead to clearance and seroconversion. A similar picture applies to the preS type vaccines.

A combination of replicor, Myrcludex and antivirals, with therapeutic vaccines in the surface antigen negative phase to enhance the anti surface response while the surface antigen is still artificially suppressed by  replicor, should drive the SVR rate in the 80 to 90% range. Interferon, possibly more tolerable like lambda Interferon,  might also help dramatically at this stage, but it apparently gets complicated and who would compose or pay  for such a combination therapy?

to Chantou;
Replicor is an entry inhibitor for HCV but has not been tested in humans yet.It is very promising for HBV patients, but the current response SVR rate is only 50% and its currently complicated mode of application and high price for the substance will still pose substantial hurdles for its future development.We all hope it will become available through further improvements in the practicability of its use                                       



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StephenW

谷歌翻译是不是100％准确，仅供参考，使用。

以下是从Studyforhope。我不熟悉Studyforhope，请接受这是他/她的意见。就个人而言，我想感谢Studyforhope有价值的讨论。

斯蒂芬和STEF

1，“抗病毒药物通常降低cccDNA的量，但也不显着，最好的约10倍” - 这是个好消息。这是一个最近发现的或众所周知的事实？没有抗病毒厂商似乎状态这一事实。

因为多年的肝会议，这已屡有报道，poster的format.The效果是不是很令人印象深刻，并反映在一个单一的肝细胞cccDNA的浓度是动态维护/打开在一个非常缓慢的的速度合成的基因组的DNA的一小部分，没有进入到病毒颗粒，但回收到cccDNA的池，从而减少生产 - 基因组RNA逆转录 - 基因组DNA轻度的降低cccDNA的浓度在cccDNA的减少反映在表面有些抗原浓度，因为它是关闭的cccDNA的转录，但减少通常停在一个新的平衡，很少 - 高达6％ - 它导致了表面抗原抗体血清转换。

2。肝脏干细胞，他们被感染太乙型肝炎病毒？
共同的想法是没有，卫星细胞不infectable，可能是由于他们缺乏的临界表面的蛋白质受体基因的表达。

最后，你怎么看未来治疗慢性乙型肝炎的呢？新药，新类型的干扰素，治疗性疫苗，联合治疗？

治疗性疫苗的机会不大，除非与replicor这样的东西相结合，由于抗原洪水阻止任何有效的免疫反应，达到肝脏。核心抗原表位疫苗，甚至颗粒疫苗，失败，因为其核心是类我只有一个例外18日至27 AA核心蛋白抗原表位抗原，如在古典Cytel疫苗。它失败了，因为在大多数的HLA A2型的慢性携带者，这种抗原表位获得突变和非活动，使T细胞的刺激/由疫苗的目标没有病毒的存在了生产。这是顺便说一句I类抗原表位的演变中，针对该病毒通常是由e抗原水浸保护的核心蛋白左，它也通常是负责清理在急性HBV表面抗原。它经常发生变异，从一个序列到另一个eantigen NEG载体时对响应逃生mutatnt出现，造成了高滴度的病毒颗粒，由一个新的细胞毒性Tcells，对这个突变的抗原表位的新高潮兴起的一个新的突变体的抗原表位，造成严重的耀斑，大多没有最后批准，因为现在大家都在寻找一个乙肝病毒准种在这个关键的轨迹。
表面蛋白大约有8级，我的各种活力和亲和力的抗原表位，多classII抗原表位。
因此，核心的疫苗会产生一些效果有限的II级响应，导致临时增加肝脏炎症与病毒颗粒生产的减少（减少病毒载量）和病毒蛋白表达。但效果是太多的非特异性，很少会导致间隙和血清转换。一个类似的原因适用的preS型疫苗。

一个replicor，Myrcludex和抗病毒药物相结合，表面抗原阴性阶段的治疗性疫苗，增强抗表面反应而表面抗原仍然是人为地压制replicor，应在80％到90％的范围内驱动SVR率。干扰素，可能更喜欢的lambda干扰素容忍，也可能有助于显着在这个阶段，但它明显地变得复杂，并撰写或支付这样一个联合治疗？

Chantou:
Replicor是丙型肝炎病毒进入抑制剂，但尚未在人类乙肝患者yet.It是非常看好的测试，但当前的响应SVR率只有50％，目前复杂的应用和物质的高价格模式将依然构成其未来的发展。我们的实质性障碍，所有的希望，这将成为通过进一步改善其使用的可行性进行