YIC - 对慢性乙型肝炎抗乙肝病毒疫苗失败

StephenW

Anti-HBV Vaccine Fails Against Chronic Hepatitis B
Jun 05, 2013

By Will Boggs, MD

NEW YORK (Reuters Health) Jun 05 - A therapeutic vaccine candidate, aimed at breaking immune tolerance to the hepatitis B virus, failed in a recent trial, but the researchers believe the problem is that the adjuvant itself was too potent.

The vaccine consists of hepatitis B surface antigen (HBsAg) complexed to anti-HBs antibodies, with alum as an adjuvant. The idea is that antigen-presenting cells will take up the HbsAg-Ab complex, process the HBsAg, and present it to T cells, triggering an immune response against HBV.

An earlier trial had shown promise with a six-dose course. The failed trial tested the effect of 12 doses.

One of the researchers told Reuters Health that some members of the team had been afraid before the study started that overstimulating the immune system with 12 doses would lead to immune fatigue.

"I do not believe that there is lack of efficacy of (the immune complexes) in this phase III trial. I find the problem is that alum showed therapeutic efficacy," Dr. Yu-Mei Wen from Shanghai Medical College, Fudan University, Shanghai, China told Reuters Health in an email. "Based on the recent progress of the immune stimulating effects of alum alone revealed in the past few years, obviously, alum is not suitable to serve as a blank control for therapeutic vaccination."

Dr. Wen and colleagues tested the vaccine against "sham" therapy with just the alum adjuvant, in a double-blind phase III trial of 450 patients with chronic hepatitis B

Participants received 12 weekly intramuscular injections at four-week intervals, with an eight-week break between the 6th and 7th injections, and were followed up for 24 weeks after termination of immunization.

The per-protocol analysis, reported online May 13 in the Journal of Hepatology, included 303 (90.4%) vaccine recipients and 108 (93.9%) patients from the control group.

The main endpoint was the HBeAg seroconversion rate. (HBeAg is the extracellular form of the hepatitis B core antigen.) At the end of follow-up, there was no difference between the vaccine and control groups (14.0% vs 21.9%, respectively; p>0.05).

Compared to the previous IIb trial, in which patients received six doses, the seroconversion rate with the vaccine decreased by about a third (from 22.4%), whereas the seroconversion rate with alum more than doubled (from 9%).

Seroconversion rates in both groups were higher among patients with genotype B than among patients with genotype C, but there was no significant difference between vaccine and alum for either genotype.

"The therapeutic effects of alum in this clinical trial was quite surprising and we will pursue further, as this is the first vaccination with alum alone in humans," Dr. Wen said.

Serious adverse events included transient flares in alanine aminotransferase in 22 vaccine patients and four alum patients, all of whom recovered after hospitalization.

"In fact, we were not surprised by the results with 12 injections of (vaccine), but we were surprised by the results of alum," Dr. Wen explained. "Unlike antiviral drugs and interferon, the mechanism for therapeutic vaccination is to stimulate or modify host immune responses, and thus needs proper timing and schedule for vaccination."

Dr. Wen added, "Based on our prediction that overstimulation of specific immune response would lead to immune fatigue (which we had a hot debate with the principal investigator clinician, who insisted that patients should be given 12 injections instead of six injections in phase II B) we decided to do a proof of concept study in mice, which showed that indeed overstimulation with (the immune complexes) resulted in immune fatigue in specific immune responses towards (complexes), while innate immune responses towards alum remained to be enhanced."

"Therapeutic vaccination for persistent infections is a new and hopeful approach," Dr. Wen said. "Therapeutic vaccination is less expensive, easy to employ, and can be used in a large number of patients, especially among those from developing countries."

"We hope physicians will support this new approach in clinical trials, as scientists urgently need collaboration with clinicians to make real contribution to mankind," Dr. Wen added.

SOURCE: http://bit.ly/11EWJmL

J Hepatol 2013.

StephenW

2013年6月5日

由威尔·博格斯，MD

纽约（路透社健康）6月05  - ，旨在打破乙肝病毒免疫耐受的治疗性疫苗的候选，在最近的试验中失败，但研究人员认为问题是，佐剂本身太有力。

由B型肝炎表面抗原（HBsAg），抗-HBs抗体的复合物，用明矾为佐剂的疫苗。我们的想法是，抗原呈递细胞将采取乙型肝炎表面抗原抗体复合物，处理乙肝表面抗原，它呈现给T细胞，触发对HBV的免疫反应。

早期试验表明承诺六个剂量的课程。失败的试验测试12个剂量的效果。

其中一名研究人员告诉路透社记者，一些团队成员一直害怕研究开始前有12个剂量，过度刺激免疫系统，导致免疫疲劳。

“我不认为有缺乏在这个阶段III期临床试验（免疫复合物）的疗效，我发现问题是明矾表现出疗效，”博士从上海，复旦大学，上海医学院闻玉梅中国在一封电子邮件中告诉路透社健康。 “基础上的免疫刺激作用明矾独自在过去的几年中透露的最新进展，显然，明矾是不适合作为空白对照治疗性疫苗。”

文博士和他的同事测试只是明矾佐剂疫苗的“假”疗法，在一项双盲的III期临床试验的450例慢性乙型肝炎

与会者收到了四个星期的时间间隔在12周肌肉注射，用八周的休息之间的第六和第七注射，免疫结束后随访24周。

每个协议分析中华肝脏病杂志在线报道，5月13日，包括疫苗接种者303（90.4％）和108例（93.9％）与对照组。

主要终点是HBeAg血清转换率。 （大三阳是乙肝核心抗原的外形式）在随访结束，疫苗组和对照组（14.0％比21.9％，P> 0.05）之间无显着差异。

IIb试算以前相比，患者接受了6个剂量，疫苗的血清学转换率下降了约三分之一（22.4％），而用明矾转阴率增加了一倍多（从9％）。

两组患者的血清转换率较高的B基因型比C基因型患者之间的患者，但有两种基因型疫苗和明矾没有显着区别。

“明矾这项临床试验的治疗效果是相当惊人的，我们会追问下去，因为这是第一次用明矾独自一人在人类接种，温家宝说：”博士。

严重不良事件包括谷丙转氨酶22疫苗的患者和四个的明矾患者，所有的人住院后收回的瞬态耀斑。

“文博士解释说：”事实上，我们并不感到惊讶与12注射（疫苗）的结果，但我们惊讶的结果，明矾，。 “与抗病毒药物和干扰素，治疗性疫苗的机制是刺激或修改宿主的免疫反应，因此需要适当的时机和接种时间表。”

文博士补充说，“根据我们的预测，即特异性免疫反应过度刺激会导致免疫疲劳（我们有一个热议的主要研究者的临床医生，谁坚持认为，患者应给予12针，而不是在第二阶段的六个注射B）我们决定做一个概念研究证明，在小鼠体内，这表明确实过度刺激（免疫复合物）产生特异性免疫反应的免疫疲劳朝（复合），而先天免疫反应对明矾的仍是增强“。

文博士说：“持续性感染的治疗性疫苗是一个新的，充满希望的方法，”。 “治疗性疫苗接种是较便宜的，容易使用的，并且可以用在大量的患者，特别是那些来自发展中国家。”

文博士说：“我们希望医生将支持这种新方法在临床试验中，科学家们迫切需要与临床医生合作，使真正对人类的贡献，”。

来源：http://bit.ly/11EWJmL

肝2013。


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