J HEPATOL：复旦大学闻玉梅院士等发现治疗性乙肝疫苗过度刺激可致疗效下降

尽管目前已报道了多种慢性乙型肝炎（CHB）感染的实验性治疗方法，但鲜有通过临床试验对这些方法进行确证。我国自主开发了一种以明矾为佐剂的治疗性乙肝疫苗（YIC），该疫苗由抗原-抗体（HBsAg[乙型肝炎病毒表面抗原]-HBIG[乙型肝炎免疫球蛋白]）免疫原性复合物组成，旨在通过改变机体对乙型肝炎病毒（HBV）抗原的加工和呈递方式，从而消除免疫耐受。

先前已有研究报道了YIC的双盲安慰剂对照II B期临床试验结果，而《肝脏病学杂志》（Journal of Hepatology）杂志也于2013年5月13日在线发表了我国复旦大学闻玉梅院士等人在450例患者中开展的III期临床试验结果。研究发现，当YIC疫苗的接种剂数由6剂增加至12剂时，疫苗针对慢性乙型肝炎患者的有效性反而降低。

在III期临床试验中，450例CHB患者随机接受12剂YIC或安慰剂（只含明矾）治疗，并在完成免疫治疗后进行为期24周的随访。试验的主要终点是出现HBeAg血清转换，次要终点是病毒载量下降，肝功能及肝组织学改善。

先前II B期临床试验采取的治疗方案是注射6剂YIC或安慰剂（明矾），在该基础上，III期临床试验又额外增加6剂YIC或明矾。然而，与II B期试验结果相反，YIC组的HBeAg血清转变率由21.8%降至14.0%，而明矾组则从9%增加至21.9%。两个组别的血清HBV DNA水平及标准化后的肝功能相当（p>0.05）。

作者发现，使用YIC过度刺激并不能增加其有效性，反而会造成宿主免疫疲劳而导致有效性下降。对于治疗性疫苗的开发来说，找到适度的免疫治疗方案是至关重要的。单独注射明矾多次可能会刺激产生强烈的炎症反应及先天性免疫应答，从而出现一定的治疗效果，这一点需要进一步研究加以确证。

Results of a Phase III Clinical Trial with an HBsAg-HBIG Immunogenic Complex Therapeutic Vaccine for Chronic Hepatitis B Patients: Experiences and Findings.
BACKGROUND AND AIMS
Though, various experimental therapeutic approaches for chronic hepatitis B infection have been reported, few have been verified by clinical trials. We have developed an antigen-antibody (HBsAg-HBIG) immunogenic complex therapeutic vaccine candidate with alum as adjuvant (YIC), aimed at breaking immune tolerance to HBV by modulating viral antigen processing and presentation. A double-blind placebo controlled phase II B clinical trial of YIC has been reported previously, and herein results of phase III clinical trial among 450 patients are presented.
METHODS
Twelve doses of either YIC or alum alone as the placebo was administrated randomly to 450 CHB patients and followed for 24 weeks after the completion of immunization. The primary endpoint was HBeAg seroconversion, and the secondary endpoints were decrease in viral load, improvement of liver function and histology.
RESULTS
In contrast to previous phase II B trial using six doses of YIC and alum as placebo, six more injections of YIC or alum resulted in decrease of HBeAg seroconversion rate from 21.8% to 14.0% in YIC group, but increase from 9% to 21.9% in the alum group. Decrease in serum HBV DNA and normalization of liver function were similar in both groups (p>0.05).
CONCLUSIONS
Over stimulation with YIC did not increase but decreased its efficacy due to immune fatigue in hosts. Appropriate immunization protocol should be explored and is crucial for therapeutic vaccination. Multiple injections of alum alone could have stimulated potent inflammatory and innate immune responses contributing to its therapeutic efficacy, and needs further investigation。 FUNDING: Supported by China National Science and Technology Major Project (grant No.: 2008ZX10002-003).