NASVAC合并乙型肝炎病毒表面核心抗原治疗疫苗

StephenW

Hepatol Int (2013) 7:981–989
DOI 10.1007/s12072-013-9486-
Therapeutic potential of a combined hepatitis B virus surface
and core antigen vaccine in patients with chronic hepatitis B

Mamun Al-Mahtab • Sheikh Mohammad Fazle Akbar •
Julio Cesar Aguilar • Md. Helal Uddin •
Md. Sakirul Islam Khan • Salimur Rahman

Mamun Al-Mahtab and Sheikh Mohammad Fazle Akbar contributed
equally to this study.
M. Al-Mahtab  S. Rahman
Department of Hepatology, Bangabandhu Sheikh Mujib Medical
University, Dhaka, Bangladesh
e-mail: [email protected]
S. Rahman
e-mail: [email protected]
S. M. F. Akbar (&)
Department of Medical Sciences, Toshiba General Hospital,
Higashi Oi 6-3-22, Tokyo 140-8522, Japan
e-mail: [email protected]
J. C. Aguilar
Center for Genetic Engineering and Biotechnology, Havana,
Cuba
e-mail: [email protected]
Md. H. Uddin
Clinical Research Organization, Dhaka, Bangladesh
e-mail: [email protected]
Md. S. I. Khan
Bangladesh Agricultural University, Mymensign, Bangladesh
e-mail: [email protected]
123
Received: 24 March 2013 / Accepted: 21 October 2013 / Published online: 9 November 2013
 Asian Pacific Association for the Study of the Liver 2013
Abstract
Purpose The safety and clinical efficacy of a vaccine
containing both hepatitis B surface antigen (HBsAg) and
hepatitis B core antigen (HBcAg) (HBsAg/HBcAg) were
evaluated in patients with chronic hepatitis B (CHB).
Methods Eighteen patients with CHB were administered
a vaccine containing 100 lg of HBsAg and 100 lg of
HBcAg. The vaccine was administered ten times at
2-weekly intervals, the first five times via the nasal route
only and the subsequent five times via both nasal and
subcutaneous routes. The safety and efficacy of this
therapeutic approach were assessed by periodic assessment
of the patients’ general condition, viral kinetics, and biochemical
parameters during treatment and 24 and 48 weeks
after therapy. The production of cytokines by peripheral
blood mononuclear cells (PBMC) and antigen-pulsed
dendritic cells (DC) was evaluated to assess the immunomodulatory
effects of the HBsAg/HBcAg vaccine in CHB
patients.
Results The HBsAg/HBcAg vaccine was safe in all
patients. No flare of HBV DNA or alanine aminotransferase
(ALT) was recorded in any patient. Sustained HBV
DNA negativity and persistently normalized ALT were
detected in 9 (50 %) and 18 (100 %) patients with CHB,
respectively. PBMC and HBsAg/HBcAg-pulsed DCs from
HBsAg/HBcAg-vaccinated CHB patients produced significantly
higher levels of various cytokines [interleukin 1b
(IL-1b), IL-6, IL-8, IL-12, and tumor necrosis factor a
(TNF-a)] than those from control unvaccinated CHB
patients (p\0.05) after stimulation with HBsAg/HBcAg
in vitro.
Conclusion HBsAg/HBcAg vaccine seems a safe and
efficient therapeutic approach for patients with CHB

StephenW

肝脏病诠释（ 2013 ） 7:981-989
DOI 10.1007/s12072-013-9486-
合并乙型肝炎病毒表面的治疗潜力
而在慢性乙型肝炎核心抗原疫苗
马蒙的Al- Mahtab •谢赫·穆罕默德·阿克巴Fazle •
胡利奥·塞萨尔·阿吉拉尔•马里兰州希拉勒乌丁•
马里兰州Sakirul伊斯兰汗• Salimur拉赫曼

马蒙铝Mahtab和谢赫·穆罕默德·阿克巴Fazle贡献
同样对这项研究。
M.铝Mahtab ？ S.拉赫曼
肝脏病学系，班加班谢赫·穆吉布医科大学
大学，达卡，孟加拉国
电子邮件： [email protected]
S.拉赫曼
电子邮件： [email protected]
S. M，F，阿克巴（ ＆ ）
医学科学部，东芝公司总医院，
东爱22年6月3日，东京140-8522 ，日本
电子邮件： sheikh.akbar @ po.toshiba.co.jp
J. C.阿吉拉尔
中心遗传工程和生物技术，哈瓦那，
古巴
电子邮件： julio.aguilar @ cigb.edu.cu
马里兰州H.乌丁
临床研究组织，达卡，孟加拉国
电子邮件： [email protected]
马里兰州学导汗
孟加拉国农业大学， Mymensign ，孟加拉国
电子邮件： sakirul.khan @ gmail.com
123
收稿日期： 2013年3月24日/接受日期： 2013年10月21日在线/发布时间： 2013年11月9日
？亚太肝脏研究协会2013年研究
摘要
目的的安全性和疫苗的临床疗效
同时含有乙肝表面抗原（HBsAg）和
乙型肝炎核心抗原（HBcAg ）（乙肝表面抗原/核心抗原）为
评估在慢性乙型肝炎（CHB ） 。
方法18例CHB患者服用
含有乙肝表面抗原LG 100和100 LG的疫苗
乙肝病毒核心抗原。疫苗给药10次
2 ，每周一班，经鼻途径的第一个五次
只和其后五年同时通过鼻腔和时间
皮下路线。这样做的安全性和有效性
治疗方法是通过定期评估评估
患者的一般状况，病毒动力学，生化
治疗和24时的参数周和48周
治疗后。细胞因子通过外设生产
血单核细胞（PBMC）和抗原 - 脉冲
树突状细胞（DC ）进行了评估，以评估免疫调节
乙肝表面抗原/核心抗原疫苗的慢性乙肝效果
患者。
结果的HBsAg / HBcAg的疫苗是安全的，所有的
患者。 HBV-DNA或丙氨酸氨基转移酶的无眩光
（ ALT）录得任何病人。乙肝病毒持续
DNA阴转，坚持规范化ALT均
9例（ 50 ％ ）检出18例（ 100 ％ ）慢性乙肝患者，
分别。外周血单个核细胞与HBsAg /从HBcAg的冲激的DC
的HBsAg / HBcAg的接种CHB患者显著制作
较高水平的各种细胞因子[白介素1b中
（IL -1β ），IL- 6，IL- 8，IL- 12和肿瘤坏死因子a
（ TNF - a）条]比对照未接种乙肝
患者（P \ 0.05 ）刺激的HBsAg / HBcAg的后
体外。
结论的HBsAg / HBcAg的疫苗似乎是一个安全，
对于慢性乙肝患者有效的治疗方法

StephenW

非常好的消息!
"你会很高兴知道，我们已经完成了III期研究头对头这种治疗性疫苗和聚乙二醇化干扰素之间。该患者在治疗免费随访一年多了。结果是非常令人鼓舞的，我们期待与您今年的共享数据。"

咬牙硬挺

是古巴的那个疫苗吗？效果很好吗？

StephenW

回复 咬牙硬挺 的帖子

是古巴的那个疫苗吗？Yes 效果很好吗？Yes

tonychant

没有表面抗原定量是否下降的数据啊，能治愈吗？

StephenW

回复 tonychant 的帖子

上述论文是关于第一阶段的临床试验。我只刚才收到了论文，我会明天读。好消息是关于第3阶段临床试验，结果似乎是不错的。这是治疗性的，但我不认为它会100％治愈，希望比干扰素好.

tonychant

这个治疗性疫苗对哪种基因型有效？

StephenW

Therapeutic response
Virological response
The virological responses of CHB patients to the vaccine
therapy with HBsAg/HBcAg are shown in Fig. 2. After
completion of the first cycle (five nasal vaccinations), HBV
DNA levels were undetectable (\250 copies/ml) in 5 of 11
HBeAg-negative patients. At the end of the second cycle of
vaccinations, HBV DNA was undetectable in six HBeAgnegative
patients and one HBeAg-positive patient (Fig. 2).
The sera of seven HBeAg-negative patients and two
HBeAg-positive CHB patients were negative for HBV
DNA 48 weeks after the end of treatment (Fig. 2). A further
four HBeAg-positive patients were considered to be
partial responders after follow-up for 48 weeks because
their serum viral loads had declined by 2–5 log copies
(Fig. 2). Six of 12 patients with genotype C and two of five
patients with genotype D were HBV DNA negative at the
week 48 follow-up.
Biochemical response
No flare in ALT was detected during the immunizations or
during follow-up in any patient. The kinetics of ALT at the
five observation points are shown in Table 3. Fluctuations
in ALT were seen at some points between the start of
therapy and the end of the first and second cycles of vaccination.
However, ALT was below ULN in 16 patients at
the end of the second cycle and in all patients 48 weeks
after the end of treatment.
Serological response
HBeAg was eliminated from the blood in three of seven
HBeAg-positive patients at the end of the treatment, and
this response was sustained at the 48-week follow-up. Two
of these patients also developed anti-HBe antibodies in
their sera. HBV DNA was undetectable in both of these
patients.
Immunological response
To estimate the spontaneous production of cytokines,
PBMCs from patients who had received five nasal vaccinations
were stimulated with HBsAg/HBcAg or PDC, an
irrelevant antigen, or were not stimulated with any activator.
As shown in Fig. 3, the levels of IL-1b, IL-6, IL-12,
TNF-a, and IL-8 were significantly higher in the culture
supernatants from the HBsAg/HBcAg-stimulated PBMC
than in those stimulated with PDC or with no antigen
(spontaneous).
DCs were then isolated from five patients with CHB
after the first and second cycles of vaccination. DCs were
also isolated from unvaccinated control patients with CHB.
HBsAg/HBcAg-pulsed DCs produced significantly higher
levels of IL-1b, TNF-a, and IL-12 than PDC-pulsed DCs
from HBsAg/HBcAg-vaccinated CHB patients or HBsAg/
HBcAg-pulsed DCs from control CHB patients (p\0.05)
(Fig. 4).

StephenW

治疗反应
病毒学应答
CHB患者的病毒学应答的疫苗
治疗用的HBsAg / HBcAg的示于图。 2 。后
第一个周期（ 5鼻腔接种）后， HBV
DNA水平检测不到（ \ 250拷贝/ ml ） 5 11
HBeAg阴性患者。在第二周期结束
接种疫苗， HBV DNA检测不到六HBeAgnegative
患者和1例HBeAg阳性患者（图2） 。
七HBeAg阴性患者和两个血清
HBeAg阳性CHB患者均为阴性的HBV
DNA治疗48周结束时（图2）之后。进一步
4 HBeAg阳性患者被认为是
后随访48周，部分应答，因为
他们的血清病毒载量已经下降了2-5日志副本
（图2） 。六个12例C基因型和两个五
患者的基因型D组HBV DNA阴性的
48周随访。
生化反应
在免疫法检测ALT无眩光或
在随访期间任何病人。血清ALT在动力学
5个观测点示于表3中。波动
在ALT被认为在某些点的开始之间
疗法和疫苗接种的第一和第二周期的结束。
但是， ALT为正常值上限以下16例在
第二个周期，所有患者48周结束
治疗结束后。
血清学反应
大三阳是从血液中清除三个七
HBeAg阳性患者在治疗结束时，和
这种反应是维持在48周的随访。二
这些患者还开发了抗-HBe抗体
他们的血清。 HBV DNA检测不到在这两种
患者。
免疫反应
来估计细胞因子的自发生产，
从谁曾收到五鼻腔接种患者外周血单个核细胞
被刺激的HBsAg / HBcAg的或PDC ，一个
不相关的抗原，或不被刺激的任何活化剂。
如该图所示。 3，IL -1β水平，IL-6 ，IL-12 ，
TNF -α和IL- 8是显著高在培养
从乙肝表面抗原/乙肝病毒核心抗原刺激的外周血单个核细胞上清液
比在那些与PDC或无抗原刺激
（自发） 。
区议会，然后从五个CHB患者被隔离
在接种后的第一个和第二个周期。区议会是
还分离出未接种疫苗控制慢性乙肝患者。
的HBsAg / HBcAg的冲激的DC产生显著高
IL -1β ， TNF -α和IL- 12的水平比PDC-脉冲的DC
从乙肝表面抗原/乙肝病毒核心抗原接种乙肝病人或乙肝表面抗原/
从控制慢性乙肝患者乙肝病毒核心抗原冲激的DC （P \ 0.05 ）
（图4） 。