Therapeutic vaccination with lentiviral vector in HBV-persistent mice and two inactive HBsAg carriers.

Chronic hepatitis B Immunotherapy Immunotolerance Lentiviral-vectored vaccine

Journal

Journal of hepatology
ISSN: 1600-0641
Titre abrégé: J Hepatol
Pays: Netherlands
ID NLM: 8503886

Informations de publication

Date de publication:
11 Oct 2023
Historique:
received: 07 12 2022
revised: 09 08 2023
accepted: 06 09 2023
pubmed: 13 10 2023
medline: 13 10 2023
entrez: 12 10 2023
Statut: aheadofprint

Résumé

Immunotherapy for chronic hepatitis B virus (HBV) infection has not yet demonstrated sufficient efficacy. We developed a non-integrative lentiviral-vectored therapeutic vaccine for chronic hepatitis B and tested its antiviral effects in HBV-persistent mice and two inactive HBsAg carriers. Lentiviral vectors (LVs) encoding the core, preS1, or large HBsAg (LHBs) proteins of HBV were evaluated for immunogenicity in HBV-naïve mice and therapeutic efficacy in a murine model of chronic HBV infection. In addition, two inactive HBsAg carriers each received two doses of 5×10 In the mouse models, LV-LHBs was the most promising in eliciting robust antigen-specific T cells and in reducing the levels of serum HBsAg and viral load. By the end of the 34-week observation period, six out of ten (60%) HBV-persistent mice vaccinated with LV-LHBs achieved serum HBsAg loss and significant depletion of HBV-positive hepatocytes in the liver. In the two inactive HBsAg carriers, vaccination with LV-LHBs induced a considerable increase in the number of peripheral LHBs-specific T cells in one patient, and a weak but detectable response in the other, accompanied by a sustained reduction of HBsAg (-0.31 log A lentiviral-vectored therapeutic vaccine for chronic HBV infection demonstrated the potential to improve HBV-specific T-cell responses and deplete HBV-positive hepatocytes, leading to a sustained loss or reduction of serum HBsAg. Chronic HBV infection is characterized by an extremely low number and profound hypo-responsiveness of HBV-specific T cells. Therapeutic vaccines are designed to improve HBV-specific T-cell responses. We show that immunization with a lentiviral-vectored therapeutic HBV vaccine was able to expand HBV-specific T cells in vivo, leading to reductions of HBV-positive hepatocytes and serum HBsAg.

Sections du résumé

BACKGROUND & AIMS OBJECTIVE
Immunotherapy for chronic hepatitis B virus (HBV) infection has not yet demonstrated sufficient efficacy. We developed a non-integrative lentiviral-vectored therapeutic vaccine for chronic hepatitis B and tested its antiviral effects in HBV-persistent mice and two inactive HBsAg carriers.
METHODS METHODS
Lentiviral vectors (LVs) encoding the core, preS1, or large HBsAg (LHBs) proteins of HBV were evaluated for immunogenicity in HBV-naïve mice and therapeutic efficacy in a murine model of chronic HBV infection. In addition, two inactive HBsAg carriers each received two doses of 5×10
RESULTS RESULTS
In the mouse models, LV-LHBs was the most promising in eliciting robust antigen-specific T cells and in reducing the levels of serum HBsAg and viral load. By the end of the 34-week observation period, six out of ten (60%) HBV-persistent mice vaccinated with LV-LHBs achieved serum HBsAg loss and significant depletion of HBV-positive hepatocytes in the liver. In the two inactive HBsAg carriers, vaccination with LV-LHBs induced a considerable increase in the number of peripheral LHBs-specific T cells in one patient, and a weak but detectable response in the other, accompanied by a sustained reduction of HBsAg (-0.31 log
CONCLUSIONS CONCLUSIONS
A lentiviral-vectored therapeutic vaccine for chronic HBV infection demonstrated the potential to improve HBV-specific T-cell responses and deplete HBV-positive hepatocytes, leading to a sustained loss or reduction of serum HBsAg.
IMPACT AND IMPLICATIONS UNASSIGNED
Chronic HBV infection is characterized by an extremely low number and profound hypo-responsiveness of HBV-specific T cells. Therapeutic vaccines are designed to improve HBV-specific T-cell responses. We show that immunization with a lentiviral-vectored therapeutic HBV vaccine was able to expand HBV-specific T cells in vivo, leading to reductions of HBV-positive hepatocytes and serum HBsAg.

Identifiants

DOI: 10.1016/j.jhep.2023.09.019 PMID: 37827470
pubmed: 37827470
pii: S0168-8278(23)05146-2
doi: 10.1016/j.jhep.2023.09.019
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Auteurs

Yumeng Zhang (Y)

Department of Infectious Disease, National Medical Center for Infectious Diseases and Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Huashan Hospital, Fudan University, Shanghai, China; Shanghai Sci-Tech Inno Center for Infection & Immunity, Shanghai, 200052, China.

Maryline Bourgine (M)

Institut Pasteur-TheraVectys Joint Lab, Institut Pasteur, Université Paris Cité, F-75015 Paris, France.

Yanmin Wan (Y)

Department of Infectious Disease, National Medical Center for Infectious Diseases and Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Huashan Hospital, Fudan University, Shanghai, China; Shanghai Sci-Tech Inno Center for Infection & Immunity, Shanghai, 200052, China.

Jieyu Song (J)

Department of Infectious Disease, National Medical Center for Infectious Diseases and Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Huashan Hospital, Fudan University, Shanghai, China.

Zongying Li (Z)

Changzhi People's Hospital, Changzhi, China.

Yiqi Yu (Y)

Department of Infectious Disease, National Medical Center for Infectious Diseases and Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Huashan Hospital, Fudan University, Shanghai, China.

Wangfang Jiang (W)

Changzhi People's Hospital, Changzhi, China.

Mingzhe Zhou (M)

Department of Infectious Disease, National Medical Center for Infectious Diseases and Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Huashan Hospital, Fudan University, Shanghai, China.

Cuiyuan Guo (C)

Department of Laboratory Medicine, Shanghai Public Health Clinical Center, Shanghai, China; Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Key Laboratory of Laboratory Medicine of Henan Province, Zhengzhou, China.

Didier Santucci (D)

Jinwei Biotechnology, Shanghai, China.

Xiao Liang (X)

Henzhun Biotechnology, Shanghai, China.

Christian Brechot (C)

TheraVectys S.A., Paris, France; University of South Florida, Tampa, USA. Electronic address: cbrechot@usf.edu.

Wenhong Zhang (W)

Department of Infectious Disease, National Medical Center for Infectious Diseases and Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Huashan Hospital, Fudan University, Shanghai, China; Shanghai Sci-Tech Inno Center for Infection & Immunity, Shanghai, 200052, China. Electronic address: zhangwenhong@fudan.edu.cn.

Pierre Charneau (P)

Institut Pasteur-TheraVectys Joint Lab, Institut Pasteur, Université Paris Cité, F-75015 Paris, France. Electronic address: pierre.charneau@pasteur.fr.

Hong Wu (H)

Changzhi People's Hospital, Changzhi, China. Electronic address: x2611249@163.com.

Chao Qiu (C)

Department of Infectious Disease, National Medical Center for Infectious Diseases and Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Huashan Hospital, Fudan University, Shanghai, China; Shanghai Sci-Tech Inno Center for Infection & Immunity, Shanghai, 200052, China; Institutes of Biomedical Sciences, Fudan University, Shanghai, China.. Electronic address: qiuchao@fudan.edu.cn.

Classifications MeSH