鼻途径有利于在用重组乙肝表面和核心基治疗疫苗免疫的HBV

StephenW

Antiviral Res. 2018 Mar 3. pii: S0166-3542(17)30677-0. doi: 10.1016/j.antiviral.2018.02.019. [Epub ahead of print]
Nasal route favors the induction of CD4+ T cell responses in the liver of HBV-carrier mice immunized with a recombinant hepatitis B surface- and core-based therapeutic vaccine.
Bourgine M1, Crabe S2, Lobaina Y3, Guillen G3, Aguilar JC3, Michel ML4.
Author information

1
    Unité de Virologie Moléculaire et Vaccinologie, Institut Pasteur, Paris, France. Electronic address: [email protected].
2
    ABIVAX, Montpellier, France.
3
    Vaccine Division, Biomedical Research Department, Center for Genetic Engineering and Biotechnology, Havana City, Cuba.
4
    INSERM U994, Institut Pasteur, Paris, France.

Abstract

Immunization routes and number of doses remain largely unexplored in therapeutic vaccination. The aim of the present work is to evaluate their impact on immune responses in naïve and hepatitis B virus (HBV)-carrier mouse models following immunization with a non-adjuvanted recombinant vaccine comprising the hepatitis B surface (HBsAg) and core (HBcAg) antigens. Mice were immunized either by intranasal (i.n.), subcutaneous (s.c.) or simultaneous (i.n. + s.c.) routes. Humoral immunity was detected in all the animal models with the induction of a potent antibody (Ab) response against HBcAg, which was stronger than the anti-HBs response. In the HBV-carrier mouse model, the anti-HBs response was predominantly subtype-specific and preferentially induced by the i.n. route. However, the Ab titers were not sufficient to clear the high concentration of HBsAg present in the sera of these mice. The i.n. route was the most efficacious at inducing cellular immune responses, in particular CD4+ T cells. In naïve mice, cellular responses in spleen were strong and mainly due to CD4+ T cells whereas the CD8+ T-cell response was low. In HBV-carrier mice, high frequencies of HBs-specific CD4+ T cells secreting interferon (IFN)-γ, interleukin (IL)-2 and tumor necrosis factor (TNF)-α were found in liver only after i.n. immunization. Increased frequencies of CD4+ T cells expressing the integrin CD49a in liver suggests a role of nasal route in the cellular homing process. Multiple dose schedules appear to be a prerequisite for protein-based immunization in order to overcome immunotolerance in HBV-carrier mice. These findings provide new avenues for further preclinical and clinical development.
KEYWORDS:

Chronic hepatitis B; Hepatitis B virus; Nasal route; Therapeutic vaccine

PMID:
    29510155
DOI:
    10.1016/j.antiviral.2018.02.019

StephenW

抗病毒研究。 2018年3月3日。pii：S0166-3542（17）30677-0。 doi：10.1016 / j.antiviral.2018.02.019。 [电子版提前打印]
鼻途径有利于在用重组乙肝表面和核心基治疗疫苗免疫的HBV携带小鼠的肝脏中诱导CD4 + T细胞应答。
Bourgine M1，Crabe S2，Lobaina Y3，Guillen G3，Aguilar JC3，Michel ML4。
作者信息

1
    Unitéde VirologieMoléculaireet Vaccinologie，Institut Pasteur，Paris，France。电子地址：[email protected]。
2
    ABIVAX，法国蒙彼利埃。
3
    疫苗司，生物医学研究部，古巴哈瓦那市基因工程和生物技术中心。
4
    INSERM U994，法国巴黎巴斯德研究所。

抽象

在治疗性疫苗接种中，免疫途径和剂量数目在很大程度上仍未探索。目前工作的目的是评估它们在用包含乙型肝炎表面（HBsAg）和核心（HBcAg）抗原的非佐剂化重组疫苗免疫后幼稚和乙型肝炎病毒（HBV） - 载体小鼠模型中对免疫应答的影响。通过鼻内（i.n.），皮下（s.c.）或同时（i.n. + s.c.）途径免疫小鼠。在所有动物模型中检测到体液免疫，其中诱导针对HBcAg的强效抗体（Ab）应答，其比抗HBs应答更强。在HBV携带者小鼠模型中，抗-HBs应答主要是亚型特异性的并且优先由i.n.路线。然而，Ab滴度不足以清除存在于这些小鼠血清中的高浓度HBsAg。 i.n.途径对于诱导细胞免疫应答，特别是CD4 + T细胞是最有效的。在幼稚的小鼠中，脾脏中的细胞应答强烈且主要由于CD4 + T细胞而CD8 + T细胞应答低。在HBV携带小鼠中，仅在肝脏发现肝脏后才发现分泌干扰素（IFN）-γ，白细胞介素（IL）-2和肿瘤坏死因子（TNF）-α的高频率HBs特异性CD4 + T细胞。免疫。在肝脏中表达整合素CD49a的CD4 + T细胞频率增加表明鼻途径在细胞归巢过程中的作用。多剂量时间表似乎是基于蛋白质的免疫的先决条件，以克服HBV携带小鼠的免疫耐受。这些发现为进一步的临床前和临床开发提供了新的途径。
关键词：

慢性乙型肝炎;乙型肝炎病毒;鼻路线;治疗性疫苗

结论：
    29510155
DOI：
    10.1016 / j.antiviral.2018.02.019

MP4

巴斯德研究所的Michel ML多年来一直做治疗疫苗的研究
P4级研究所

StephenW

使用的疫苗似乎是abx203 (古巴的NASVAC),  临床试验不成功, 尽管早先成功. 如果HBsAg水平低时多次应用似乎有效.

MP4

http://hbvhbv.info/forum/thread-1197951-1-1.html