评估功能性治愈小鼠慢性乙型肝炎的抗病毒-被动-主动免疫（

StephenW

EBioMedicine. 2019 Nov 1. pii: S2352-3964(19)30713-3. doi: 10.1016/j.ebiom.2019.10.043. [Epub ahead of print]
Evaluation of antiviral-_ passive - active immunization ("sandwich") therapeutic strategy for functional cure of chronic hepatitis B in mice.
Shi B1, Wu Y2, Wang C2, Li X2, Yu F2, Wang B2, Yang Z3, Li J2, Liang M4, Wen Y5, Ying T6, Yuan Z7.
Author information

1
    MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, 138 Dong'an Rd, Xuhui District, Shanghai, PR China; Shanghai Public Health Clinical Center, Fudan University, 2901 Caolang Rd, Jinshan District, Shanghai, PR China.
2
    MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, 138 Dong'an Rd, Xuhui District, Shanghai, PR China.
3
    MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, 138 Dong'an Rd, Xuhui District, Shanghai, PR China; Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Rd, Xuhui District, Shanghai, PR China.
4
    National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, PR China.
5
    MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, 138 Dong'an Rd, Xuhui District, Shanghai, PR China. Electronic address: [email protected].
6
    MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, 138 Dong'an Rd, Xuhui District, Shanghai, PR China. Electronic address: [email protected].
7
    MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, 138 Dong'an Rd, Xuhui District, Shanghai, PR China. Electronic address: [email protected].

Abstract
BACKGROUND:

Chronic Hepatitis B (CHB) remains a major problem for global public health. Viral persistence and immune defects are the two major reasons for CHB, and it was hypothesized that based on a transient clearance of serum viral DNA and HBsAg "window stage", active immunization against hepatitis B virus (HBV) might initiate effective host immune responses versus HBV to achieve functional cure of CHB.
METHODS:

Two experimental mouse models that mice hydrodynamic injected HBV DNA or infected with recombinant AAV/HBV were used. The "sandwich" therapeutic effect by using a potent human anti-HBsAg neutralizing monoclonal antibody (G12) in combination with antiviral drug tenofovir disoproxil fumarate (TDF), followed by active immunization with HBsAg-HBsAb (mYIC) was evaluated.
FINDINGS:

A single G12 injection rapidly cleared serum HBsAg in HDI-HBV carrier mice, with a synergistic effect in decreasing viral DNA load when TDF was given orally. When both serum viral DNA and HBsAg load became low or undetectable, mYIC was administered. A more effective clearance of viral DNA and HBsAg was observed and serum HBsAb was developed only in these "sandwich"-treated mice. Efficient intrahepatic anti-HBV immune responses were also observed in these mice, including the formation of aggregates of myeloid cells with CD8+T cells and increased TNF-α, granzyme B production.
INTERPRETATION:

The "sandwich" combination therapy not only efficiently decreased HBsAg and HBV DNA levels but also induced effective cellular and humoral immunity, which may result in functional cure of CHB.

Copyright © 2019. Published by Elsevier B.V.
KEYWORDS:

Chronic hepatitis B; HBsAb; HBsAg-HBsAb immune complex; Liver CD8(+) T cells; TDF

PMID:
    31680000
DOI:
    10.1016/j.ebiom.2019.10.043

StephenW

EBioMedicine。 2019年11月1日.pii：S2352-3964（19）30713-3。 doi：10.1016 / j.ebiom.2019.10.043。 [Epub提前发布]
评估功能性治愈小鼠慢性乙型肝炎的抗病毒-被动-主动免疫（“三明治”）治疗策略。
施B1，吴Y2，王C2，李X2，于F2，王B2，杨Z3，李J2，梁M4，温Y5，英T6，袁Z7。
作者信息

1个
    中国上海市徐汇区东安路138号，复旦大学上海医学院基础医学教育部，医学分子病毒学重点实验室，MOE / NHC / CAMS；复旦大学上海公共卫生临床中心，上海市金山区草浪路2901号。
2
    中国上海市徐汇区东安路138号，复旦大学上海医学院基础医学学院，MOE / NHC / CAMS医学分子病毒学重点实验室。
3
    中国上海市徐汇区东安路138号，复旦大学上海医学院基础医学教育部，医学分子病毒学重点实验室，MOE / NHC / CAMS；上海市徐汇区枫林路180号复旦大学附属中山医院肺科。
4
    中国疾病预防控制中心国家病毒疾病预防控制所，中国北京。
5
    中国上海市徐汇区东安路138号，复旦大学上海医学院基础医学学院，MOE / NHC / CAMS医学分子病毒学重点实验室。电子地址：[email protected]。
6
    中国上海市徐汇区东安路138号，复旦大学上海医学院基础医学学院，MOE / NHC / CAMS医学分子病毒学重点实验室。电子地址：[email protected]。
7
    中国上海市徐汇区东安路138号，复旦大学上海医学院基础医学学院，MOE / NHC / CAMS医学分子病毒学重点实验室。电子地址：[email protected]。

抽象
背景：

慢性乙型肝炎（CHB）仍然是全球公共卫生的主要问题。病毒的持久性和免疫缺陷是导致CHB的两个主要原因，并假设基于瞬时清除血清病毒DNA和HBsAg“窗口期”，针对乙型肝炎病毒（HBV）的主动免疫可能会引发有效的宿主免疫应答HBV可实现CHB的功能性治愈。
方法：

使用了两种实验小鼠模型，它们是小鼠动液注射的HBV DNA或感染了重组AAV / HBV。通过使用有效的人抗HBsAg中和性单克隆抗体（G12）与抗病毒药物替诺福韦二富马酸富马酸酯（TDF）联合使用HBsAg-HBsAb（mYIC）进行主动免疫，评估了“三明治”治疗效果。
发现：

一次G12注射快速清除了HDI-HBV携带者小鼠的血清HBsAg，口服TDF时具有降低病毒DNA负荷的协同作用。当血清病毒DNA和HBsAg载量都变低或无法检测到时，则使用mYIC。观察到病毒DNA和HBsAg的更有效清除，并且仅在这些“三明治”治疗的小鼠中产生了血清HBsAb。在这些小鼠中还观察到有效的肝内抗HBV免疫应答，包括与CD8 + T细胞形成的髓样细胞聚集体的形成以及TNF-α和颗粒酶B产量的增加。
解释：

“三明治”联合疗法不仅可以有效降低HBsAg和HBV DNA水平，还可以诱导有效的细胞和体液免疫，从而可能导致CHB的功能性治愈。

版权所有©2019.由Elsevier B.V.发布
关键字：

慢性乙型肝炎；乙肝抗体HBsAg-HBsAb免疫复合物；肝CD8（+）T细胞； TDF

PMID：
    31680000
DOI：
    10.1016 / j.ebiom.2019.10.043

StephenW

https://www.ebiomedicine.com/article/S2352-3964(19)30713-3/pdf

hunterpt

这个实验怎么没人讨论？  什么药剂这么厉害

hunterpt

这个实验怎么没人讨论？  什么药剂这么厉害

平凡之路123

回复 hunterpt 的帖子

厉害个毛线，有多少药物在小白鼠身上好用，到人体上不行？

治好小白鼠，跟治愈人体，差一百个银河系那么远。

齐欢畅

StephenW

回复 平凡之路123 的帖子

这是闻玉梅“三明治”联合治疗的 假设:
"并假设基于瞬时清除血清病毒DNA和HBsAg“窗口期”，针对乙型肝炎病毒（HBV）的主动免疫可能会引发有效的宿主免疫应答HBV可实现CHB的功能性治愈。"

所以她在老鼠模型中证明了这一点. 接下来将在人体模型中进行测试.这不是新药的测试.

平凡之路123

回复 StephenW 的帖子

我也听过这个“三明治”，问题是提出多少年了，还是没什么进展，发这种论文不就是刷经验，骗经费的吗？

乙克发展到现在，都没人提了，而乙克的目标只不过是银牌。

平凡之路123

拿着个小白鼠，就号称能治愈，有一个算一个，都是胡扯