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Shechter O, Sausen DG, Dahari H, Vaillant A, Cotler SJ, Borenstein R. Functional Cure for Hepatitis B Virus: Challenges and Achievements. Int J Mol Sci 2025; 26:3633. [PMID: 40332208 PMCID: PMC12026623 DOI: 10.3390/ijms26083633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Revised: 03/31/2025] [Accepted: 04/04/2025] [Indexed: 05/08/2025] Open
Abstract
The Hepatitis B Virus (HBV) presents a formidable global health challenge, impacting hundreds of millions worldwide and imposing a considerable burden on healthcare systems. The elusive nature of the virus, with its ability to establish chronic infection and evade immune detection, and the absence of curative agents have prompted efforts to develop novel therapeutic approaches beyond current antiviral treatments. This review addresses the challenging concept of a functional cure for HBV, a state characterized by the suppression of HBV and HBsAg, mitigating disease progression and transmission without a complete cure. We provide an overview of HBV epidemiology and its clinical impact, followed by an exploration of the current treatment landscape and its limitations. The immunological basis of a functional cure is then discussed, exploring the intricate interplay between the virus and the host immune response. Emerging therapeutic approaches, such as RNA interference-based interventions, entry inhibitors, nucleic acid polymers, and therapeutic vaccines, are discussed with regard to their success in achieving a functional cure. Lastly, the review underscores the urgent need for innovative strategies to achieve a functional cure for HBV.
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Affiliation(s)
- Oren Shechter
- Eastern Virginia Medical School, Norfolk, VA 23501, USA;
| | | | - Harel Dahari
- The Program for Experimental and Theoretical Modeling, Division of Hepatology, Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA; (H.D.); (S.J.C.)
| | - Andrew Vaillant
- Replicor Inc., 6100 Royalmount Ave., Montreal, QC H4P 2R2, Canada;
| | - Scott J. Cotler
- The Program for Experimental and Theoretical Modeling, Division of Hepatology, Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA; (H.D.); (S.J.C.)
| | - Ronen Borenstein
- The Program for Experimental and Theoretical Modeling, Division of Hepatology, Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA; (H.D.); (S.J.C.)
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Shi S, Zhang L, Zheng A, Xie F, Kesse S, Yang Y, Peng J, Xu Y. Enhanced anti-tumor efficacy of electroporation (EP)-mediated DNA vaccine boosted by allogeneic lymphocytes in pre-established tumor models. Cancer Immunol Immunother 2024; 73:248. [PMID: 39358555 PMCID: PMC11447239 DOI: 10.1007/s00262-024-03838-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 09/17/2024] [Indexed: 10/04/2024]
Abstract
BACKGROUND Tumor-reactive T cells play a crucial role in anti-tumor responses, but T cells induced by DNA vaccination are time-consuming processes and exhibit limited anti-tumor efficacy. Therefore, we evaluated the anti-tumor effectiveness of reactive T cells elicited by electroporation (EP)-mediated DNA vaccine targeting epidermal growth factor receptor variant III (pEGFRvIII plasmid), in conjunction with adoptive cell therapy (ACT), involving the transfer of lymphocytes from a pEGFRvIII EP-vaccinated healthy donor. METHODS The validation of the established pEGFRvIII plasmid and EGFRvIII-positive cell model was confirmed through immunofluorescence and western blot analysis. Flow cytometry and cytotoxicity assays were performed to evaluate the functionality of antigen-specific reactive T cells induced by EP-mediated pEGFRvIII vaccines, ACT, or their combination. The anti-tumor effectiveness of EP-mediated pEGFRvIII vaccines alone or combined with ACT was evaluated in the B16F10-EGFRvIII tumor model. RESULTS EP-mediated pEGFRvIII vaccines elicited serum antibodies and a robust cellular immune response in both healthy and tumor-bearing mice. However, this response only marginally inhibited early-stage tumor growth in established tumor models. EP-mediated pEGFRvIII vaccination followed by adoptive transfer of lymphocytes from vaccinated healthy donors led to notable anti-tumor efficacy, attributed to the synergistic action of antigen-specific CD4+ Th1 cells supplemented by ACT and antigen-specific CD8+ T cells elicited by the EP-mediated DNA vaccination. CONCLUSIONS Our preclinical studies results demonstrate an enhanced anti-tumor efficacy of EP-mediated DNA vaccination boosted with adoptively transferred, vaccinated healthy donor-derived allogeneic lymphocytes.
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Affiliation(s)
- Sanyuan Shi
- School of Pharmacy, Shanghai Jiao Tong University, No.800, Dongchuan Rd, Shanghai, 200240, People's Republic of China
| | - Luchen Zhang
- School of Pharmacy, Shanghai Jiao Tong University, No.800, Dongchuan Rd, Shanghai, 200240, People's Republic of China
| | - Anjie Zheng
- School of Pharmacy, Shanghai Jiao Tong University, No.800, Dongchuan Rd, Shanghai, 200240, People's Republic of China
| | - Fang Xie
- School of Pharmacy, Shanghai Jiao Tong University, No.800, Dongchuan Rd, Shanghai, 200240, People's Republic of China
| | - Samuel Kesse
- School of Pharmacy, Shanghai Jiao Tong University, No.800, Dongchuan Rd, Shanghai, 200240, People's Republic of China
| | - Yang Yang
- School of Pharmacy, Shanghai Jiao Tong University, No.800, Dongchuan Rd, Shanghai, 200240, People's Republic of China
| | - Jinliang Peng
- School of Pharmacy, Shanghai Jiao Tong University, No.800, Dongchuan Rd, Shanghai, 200240, People's Republic of China.
| | - Yuhong Xu
- School of Pharmacy, Shanghai Jiao Tong University, No.800, Dongchuan Rd, Shanghai, 200240, People's Republic of China.
- School of Pharmacy, Dali University, No. 22, Snowman Rd, Dali City, 671000, People's Republic of China.
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Geta M, Mengistu G, Yizengaw E, Manyzewal T, Hailu A, Woldeamanuel Y. Efficacy and safety of therapeutic vaccines for the treatment of chronic hepatitis B: A systematic review and meta-analysis of randomized controlled trials update. Medicine (Baltimore) 2024; 103:e39344. [PMID: 39213251 PMCID: PMC11365667 DOI: 10.1097/md.0000000000039344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 06/08/2024] [Accepted: 07/26/2024] [Indexed: 09/04/2024] Open
Abstract
BACKGROUND Most people diagnosed with chronic hepatitis B (CHB) need treatment to help reduce the risk of liver disease and limit disease transmission. Therapeutic vaccine (TV) candidates have been under study for their clinical effects on inducing HBV-specific host immune responses. This review aimed to systematically synthesize updated evidence on the efficacy and safety of TVs in patients with CHB. METHODS This systematic review was performed by searching different databases from January to February 2021. Completed randomized controlled trials that reported TVs' efficacy and/or safety for treating CHB compared with the standard of care (SOC) or placebo were included. Efficacy and safety estimates were reported as the logarithm of the odds ratio and risk differences, respectively. I2 > 50% was considered significant heterogeneity. Significant publication bias was considered when Egger's test P value < .10. The risk of bias was assessed using the Cochrane Risk of Bias tool. The GRADE methodology was used to assess the certainty of the evidence for each outcome. RESULTS Twenty-four articles with 2889 pooled samples were included. TVs made a significant difference in hepatitis B envelope antigen (HBeAg) SC (log OR = 0.76, P = .01) and (log OR = 0.40, P = .03) compared to placebo and combination therapy, respectively. HBeAg SC was significantly affected by TVs at the end of follow up (log OR = 0.49, P = .01), with significant HBsAg mean difference (MD = -0.62, P = .00). At the end of treatment, the TVs had no significant effect on HBV DNA negativity over the SOC (log OR = 0.62, P = .09) or placebo (log OR = -0.07, P = .91). TVs do not significantly affect the risk of serious adverse events (RD 0.02, 95% CI 0.00-0.04). CONCLUSION In patients with CHB, TVs had significant effects on HBeAg SC compared to the SOC or placebo. There was no significant difference between serious adverse events. TVs are promising treatment strategy to overcome CHB.
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Affiliation(s)
- Mekuanint Geta
- Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa), College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
- Department of Medical Microbiology, School of Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Getachew Mengistu
- Department of Medical Microbiology, School of Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
- Department of Laboratory Science, Debre Markos University, Debre Markos, Ethiopia
| | - Endalew Yizengaw
- Department of Medical Laboratory Science, College of Medicine and Health Sciences, Bahir Dar University, Bahir Dar, Ethiopia
- Institute of Biotechnology, Bahir Dar University, Bahir Dar, Ethiopia
| | - Tsegahun Manyzewal
- Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa), College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
| | - Asrat Hailu
- Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa), College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
| | - Yimtubeznash Woldeamanuel
- Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa), College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
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Liu F, Su R, Jiang X, Wang S, Mu W, Chang L. Advanced micro/nano-electroporation for gene therapy: recent advances and future outlook. NANOSCALE 2024; 16:10500-10521. [PMID: 38757536 DOI: 10.1039/d4nr01408a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/18/2024]
Abstract
Gene therapy is a promising disease treatment approach by editing target genes, and thus plays a fundamental role in precision medicine. To ensure gene therapy efficacy, the effective delivery of therapeutic genes into specific cells is a key challenge. Electroporation utilizes short electric pulses to physically break the cell membrane barrier, allowing gene transfer into the cells. It dodges the off-target risks associated with viral vectors, and also stands out from other physical-based gene delivery methods with its high-throughput and cargo-accelerating features. In recent years, with the help of advanced micro/nanotechnology, micro/nanostructure-integrated electroporation (micro/nano-electroporation) techniques and devices have significantly improved cell viability, transfection efficiency and dose controllability of the electroporation strategy, enhancing its application practicality especially in vivo. This technical advancement makes micro/nano-electroporation an effective and versatile tool for gene therapy. In this review, we first introduce the evolution of electroporation technique with a brief explanation of the perforation mechanism, and then provide an overview of the recent advancements and prospects of micro/nano-electroporation technology in the field of gene therapy. To comprehensively showcase the latest developments of micro/nano-electroporation technology in gene therapy, we focus on discussing micro/nano-electroporation devices and current applications at both in vitro and in vivo levels. Additionally, we outline the ongoing clinical studies of gene electrotransfer (GET), revealing the tremendous potential of electroporation-based gene delivery in disease treatment and healthcare. Lastly, the challenges and future directions in this field are discussed.
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Affiliation(s)
- Feng Liu
- Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100191, China
| | - Rongtai Su
- Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100191, China
| | - Xinran Jiang
- Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100191, China
| | - Siqi Wang
- Department of General Surgery and Obesity and Metabolic Disease Center, China-Japan Friendship Hospital, Beijing, 100029, China
| | - Wei Mu
- Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100191, China
- School of Engineering Medicine, Beihang University, Beijing, 100191, China
- Key Laboratory of Big Data-Based Precision Medicine (Beihang University), Ministry of Industry and Information Technology of the People's Republic of China, Beijing, 100191, China
| | - Lingqian Chang
- Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100191, China
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5
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Hudu SA, Jimoh AO, Ibrahim KG, Alshrari AS. Hepatitis B Therapeutic Vaccine: A Patent Review. Pharmaceuticals (Basel) 2022; 15:1542. [PMID: 36558991 PMCID: PMC9783911 DOI: 10.3390/ph15121542] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 12/04/2022] [Accepted: 12/05/2022] [Indexed: 12/15/2022] Open
Abstract
Viral hepatitis has long been underrated as a danger to global health. The UN only recently called for worldwide action to tackle viral hepatitis and lessen the disease burden in its "2030 Agenda for Sustainable Development". Hepatitis B virus (HBV), which causes liver cirrhosis and malignancy, is a main cause of death globally. This review analyses innovative HBV therapeutic vaccine candidates for which a patent was filed between January 2010 and March 2022 and presents future improvement techniques for vaccine efficacy. Although there is a preventative vaccine for HBV infection, over 3% of people worldwide have the disease on a long-term basis and can no longer benefit from it. Most people will have chronic HBV infection for the rest of their lives once it has been diagnosed. Moreover, only a small percentage of treated patients experience a functional cure with persistent hepatitis B surface antigen reduction. A significant proportion of deaths are caused by liver cirrhosis and hepatocellular cancer, which are both caused by chronic hepatitis B infection. Hence, there is an urgent need for novel medications due to the inadequacies of the current therapies.
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Affiliation(s)
- Shuaibu Abdullahi Hudu
- Department of Basic Medical and Dental Sciences, Faculty of Dentistry, Zarqa University, Zarqa 13110, Jordan
| | - Abdulgafar Olayiwola Jimoh
- Department of Pharmacology and Therapeutics, Faculty of Basic Clinical Sciences, College of Health Sciences, Usmanu Danfodiyo University, Sokoto 840001, Nigeria
| | - Kasimu Ghandi Ibrahim
- Department of Basic Medical and Dental Sciences, Faculty of Dentistry, Zarqa University, Zarqa 13110, Jordan
| | - Ahmed Subeh Alshrari
- Department of Basic Health Sciences, Faculty of Pharmacy, Northern Border University, Rafha 91911, Saudi Arabia
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6
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Tsounis EP, Mouzaki A, Triantos C. Nucleic acid vaccines: A taboo broken and prospect for a hepatitis B virus cure. World J Gastroenterol 2021; 27:7005-7013. [PMID: 34887624 PMCID: PMC8613654 DOI: 10.3748/wjg.v27.i41.7005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 07/07/2021] [Accepted: 10/14/2021] [Indexed: 02/06/2023] Open
Abstract
Although a prophylactic vaccine is available, hepatitis B virus (HBV) remains a major cause of liver-related morbidity and mortality. Current treatment options are improving clinical outcomes in chronic hepatitis B; however, true functional cure is currently the exception rather than the rule. Nucleic acid vaccines are among the emerging immunotherapies that aim to restore weakened immune function in chronically infected hosts. DNA vaccines in particular have shown promising results in vivo by reducing viral replication, breaking immune tolerance in a sustained manner, or even decimating the intranuclear covalently closed circular DNA reservoir, the hallmark of HBV treatment. Although DNA vaccines encoding surface antigens administered by conventional injection elicit HBV-specific T cell responses in humans, initial clinical trials failed to demonstrate additional therapeutic benefit when administered with nucleos(t)ide analogs. In an attempt to improve vaccine immunogenicity, several techniques have been used, including codon/promoter optimization, coadministration of cytokine adjuvants, plasmids engineered to express multiple HBV epitopes, or combinations with other immunomodulators. DNA vaccine delivery by electroporation is among the most efficient strategies to enhance the production of plasmid-derived antigens to stimulate a potent cellular and humoral anti-HBV response. Preliminary results suggest that DNA vaccination via electroporation efficiently invigorates both arms of adaptive immunity and suppresses serum HBV DNA. In contrast, the study of mRNA-based vaccines is limited to a few in vitro experiments in this area. Further studies are needed to clarify the prospects of nucleic acid vaccines for HBV cure.
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Affiliation(s)
- Efthymios P Tsounis
- Division of Gastroenterology, Department of Internal Medicine, University of Patras, Patras 26504, Greece
| | - Athanasia Mouzaki
- Division of Hematology, Department of Internal Medicine, University of Patras, Patras 26504, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, University of Patras, Patras 26504, Greece
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7
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Akbar SMF, Al Mahtab M, Cesar Aguilar J, Uddin MH, Khan MSI, Yoshida O, Penton E, Gerardo GN, Hiasa Y. Exploring evidence-based innovative therapy for the treatment of chronic HBV infection: experimental and clinical. EXPLORATION OF MEDICINE 2021. [DOI: 10.37349/emed.2021.00058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 08/03/2021] [Indexed: 01/02/2025] Open
Abstract
With the advent of various vaccines and antimicrobial agents during the 20th century, the control and containment of infectious diseases appeared to be a matter of time. However, studies unveiled the diverse natures of microbes, their lifestyle, and pathogenetic potentials. Since the ground-breaking discovery of the hepatitis B virus (HBV) by Baruch Blumberg and the subsequent development of a vaccine in the early 1980s, the main task of the scientific community has been to develop a proper management strategy for HBV-induced chronic liver diseases. In the early 1980’s, standard interferon (IFN) induced a reduction of HBV DNA levels, followed by the normalization of serum transaminases (alanine aminotransferase, ALT), in some chronic hepatitis B (CHB) patients. However, in the course of time, the limitations of standard IFN became evident, and the search for an alternative began. In the late 1980’s, nucleoside analogs entered the arena of CHB treatment as oral drugs with potent antiviral capacities. At the beginning of the 21st century, insights were developed into the scope and limitations of standard IFN, pegylated-IFN as well as nucleoside analogs for treating CHB. Considering the non-cytopathic nature of the HBV, the presence of covalently closed circular DNA (cccDNA) in the nucleus of the infected hepatocytes and HBV-induced immune-mediated liver damages, a new field of CHB management was initiated by modulating the hosts’ immune system through immune therapy. This review will discuss the nature and design of innovative immune therapy for CHB.
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Affiliation(s)
- Sheikh Mohammad Fazle Akbar
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime 7910295, Japan
| | - Mamun Al Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka 1000, Bangladesh
| | - Julio Cesar Aguilar
- Center for Genetic Engineering and Biotechnology, Havana, Havana 10600, Cuba
| | | | - Md. Sakirul Islam Khan
- Department of Anatomy and Embryology, Ehime University Graduate School of Medicine, Ehime 7910295, Japan
| | - Osamu Yoshida
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime 7910295, Japan
| | - Eduardo Penton
- Center for Genetic Engineering and Biotechnology, Havana, Havana 10600, Cuba
| | | | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime 7910295, Japan
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8
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Edelblute C, Mangiamele C, Heller R. Moderate Heat-Assisted Gene Electrotransfer for Cutaneous Delivery of a DNA Vaccine Against Hepatitis B Virus. Hum Gene Ther 2021; 32:1360-1369. [PMID: 33926214 DOI: 10.1089/hum.2021.037] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
An estimated 350 million people are living with chronic Hepatitis B virus (HBV) worldwide. Preventative HBV vaccination in infants has reduced the disease burden; however, insufficient immunization programs and access obstacles leave vulnerable populations at risk for infection in endemic regions. Gene electrotransfer (GET) using a noninvasive multielectrode array (MEA) provides an alternative platform for DNA vaccination in the skin. DNA vaccines are nonlive and nonreplicating and temperature stable unlike their counterparts. In addition, their simple engineering allows them to be manufactured quickly at a low cost. In the current work, we present the combination of GET and moderate heating for delivery of a DNA vaccine against HBV. Our laboratory has previously shown the synergy between moderate tissue preheating at 43°C and GET with the MEA as a means to reduce both the applied voltage and pulse number to achieve similar if not higher gene expression than GET alone. In this study, we expand upon this work, by optimizing the plasmid dose to achieve the highest level of expression. Using the reporter gene luciferase, we found that an intradermal injection of 100 μL at 1 mg/mL induced the highest expression levels across all tested GET conditions. We then evaluated our moderate heat-assisted GET platform for the intradermal delivery of a plasmid encoding Hepatitis B surface antigen (pHBsAg) via a prime and prime plus boost vaccination protocol. At 18 weeks, following the prime plus boost protocol, we observed that a high-voltage low-pulse GET condition with moderate heating (45 V 36 p+heat) generated antibodies against Hepatitis B surface antigen (HBsAb) at peak measuring 230-fold over injection of plasmid DNA alone with moderate heating. HBsAbs remained robust over the 30-week observation period. These data suggest that moderate heat-assisted GET has the potential to induce strong immune responses, an attractive feature for development of an alternative vaccine delivery platform.
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Affiliation(s)
- Chelsea Edelblute
- Frank Reidy Research Center for Bioelectrics, and.,Department of Biomedical Sciences, Graduate School, Old Dominion University, Norfolk, Virginia, USA
| | | | - Richard Heller
- Frank Reidy Research Center for Bioelectrics, and.,Department of Medical Engineering, Colleges of Medicine and Engineering, University of South Florida, Tampa, Florida, USA
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9
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Cargill T, Barnes E. Therapeutic vaccination for treatment of chronic hepatitis B. Clin Exp Immunol 2021; 205:106-118. [PMID: 33969474 PMCID: PMC8274149 DOI: 10.1111/cei.13614] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 04/28/2021] [Accepted: 04/29/2021] [Indexed: 12/12/2022] Open
Abstract
Chronic hepatitis B infection remains a serious global health threat, contributing to a large number of deaths through liver cirrhosis and hepatocellular carcinoma. Current treatment does not eradicate disease, and therefore new treatments are urgently needed. In acute hepatitis B virus (HBV) a strong immune response is necessary to clear the virus, but in chronic infection the immune response is weakened and dysfunctional. Therapeutic vaccination describes the process of inoculating individuals with a non‐infective form of viral antigen with the aim of inducing or boosting existing HBV‐specific immune responses, resulting in sustained control of HBV infection. In this review we outline the rationale for therapeutic vaccination in chronic HBV infection, discuss previous and ongoing trials of novel HBV therapeutic vaccine candidates and outline strategies to improve vaccine efficacy going forward.
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Affiliation(s)
- Tamsin Cargill
- Peter Medawar Building for Pathogen Research, Oxford University, Oxford, United Kingdom.,Translational Gastroenterology Unit, Oxford University, Oxford, United Kingdom
| | - Eleanor Barnes
- Peter Medawar Building for Pathogen Research, Oxford University, Oxford, United Kingdom.,Translational Gastroenterology Unit, Oxford University, Oxford, United Kingdom.,Oxford NIHR Biomedical Research Centre and Nuffield Department of Medicine, Oxford University, Oxford, United Kingdom
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10
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Jansen DT, Dou Y, de Wilde JW, Woltman AM, Buschow SI. Designing the next-generation therapeutic vaccines to cure chronic hepatitis B: focus on antigen presentation, vaccine properties and effect measures. Clin Transl Immunology 2021; 10:e1232. [PMID: 33489122 PMCID: PMC7809700 DOI: 10.1002/cti2.1232] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 12/09/2020] [Accepted: 12/09/2020] [Indexed: 12/14/2022] Open
Abstract
In the mid‐90s, hepatitis B virus (HBV)‐directed immune responses were for the first time investigated in detail and revealed suboptimal T‐cell responses in chronic HBV patients. Based on these studies, therapeutic vaccination exploiting the antigen presentation capacity of dendritic cells to prime and/or boost HBV‐specific T‐cell responses was considered highly promising. Now, 25 years later, it has not yet delivered this promise. In this review, we summarise what has been clinically tested in terms of antigen targets and vaccine forms, how the immunological and therapeutic effects of these vaccines were assessed and what major clinical and immunological findings were reported. We combine the lessons learned from these trials with the most recent insights on HBV antigen presentation, T‐cell responses, vaccine composition, antiviral and immune‐modulatory drugs and disease biomarkers to derive novel opportunities for the next generation of therapeutic vaccines designed to cure chronic HBV either alone or in combination therapy.
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Affiliation(s)
- Diahann Tsl Jansen
- Department of Gastroenterology and Hepatology Erasmus MC University Medical Center Rotterdam Rotterdam The Netherlands
| | - Yingying Dou
- Department of Gastroenterology and Hepatology Erasmus MC University Medical Center Rotterdam Rotterdam The Netherlands
| | - Janet W de Wilde
- Department of Gastroenterology and Hepatology Erasmus MC University Medical Center Rotterdam Rotterdam The Netherlands.,Present address: Department of Viroscience Erasmus MC University Medical Center Rotterdam Rotterdam The Netherlands
| | - Andrea M Woltman
- Department of Gastroenterology and Hepatology Erasmus MC University Medical Center Rotterdam Rotterdam The Netherlands.,Present address: Institute of Medical Research Education Rotterdam Erasmus MC University Medical Center Rotterdam Rotterdam The Netherlands
| | - Sonja I Buschow
- Department of Gastroenterology and Hepatology Erasmus MC University Medical Center Rotterdam Rotterdam The Netherlands
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11
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Ghozy S, Nam NH, Radwan I, Karimzadeh S, Tieu TM, Hashan MR, Abbas AS, Eid PS, Vuong NL, Khang NV, Elgabalawy E, Sayed AK, Hoa PTL, Huy NT. Therapeutic efficacy of hepatitis B virus vaccine in treatment of chronic HBV infections: A systematic review and meta-analysis. Rev Med Virol 2019; 30:e2089. [PMID: 31811678 DOI: 10.1002/rmv.2089] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Revised: 09/18/2019] [Accepted: 09/19/2019] [Indexed: 12/13/2022]
Abstract
There is a need for improved treatment of patients with chronic hepatitis B (CHB). We reviewed the literature to explore the efficacy of HB vaccines alone or in combination therapy (CT) with antiviral drugs in CHB patients and to meta-analyze data from randomized controlled trials. We conducted a systematic search in ten databases. All studies investigating the efficacy of HBV vaccine in HBV infected patients were included with no restrictions. Among 1359 studies initially identified, 23 studies (n = 1956 patients) were included for the final analysis. CT showed a significant reduction of HBV DNA compared with analogue monotherapy (AM) at the 12-month follow-up period (odds ratio (OR) = 2.835, 95% confidence interval (CI) [1.275, 6.306], p = .011). Additionally, CT also remarkably induce HbsAg loss in comparison with AM (OR = 11.736, 95% CI [1.841, 74.794], p = .009). Our pooled data revealed no difference between treatment and control regarding alanine aminotransferase normalization, HBeAg seroconversion, and HBeAg disappearance. In addition, CT using vaccine and NAs resulted in a statistically significant higher incidence of adverse effects than AM. The therapeutic effects of combination therapy for patients with CHB were encouraging, but future studies need to investigate all possible treatment combinations and assess their cost-effectiveness.
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Affiliation(s)
- Sherief Ghozy
- Neurosurgery Department, El Sheikh Zayed Specialized Hospital, Giza, Egypt.,Online Research Club (http://www.onlineresearchclub.org), Nagasaki, Japan
| | - Nguyen Hai Nam
- Online Research Club (http://www.onlineresearchclub.org), Nagasaki, Japan.,Department of General Surgery, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam
| | - Ibrahim Radwan
- Online Research Club (http://www.onlineresearchclub.org), Nagasaki, Japan.,Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Sedighe Karimzadeh
- Online Research Club (http://www.onlineresearchclub.org), Nagasaki, Japan.,School of Medicine, Sabzevar University of Medical Sciences, Sabzevar, Iran
| | - Thuan Minh Tieu
- Online Research Club (http://www.onlineresearchclub.org), Nagasaki, Japan.,Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
| | - Mohammad Rashidul Hashan
- Online Research Club (http://www.onlineresearchclub.org), Nagasaki, Japan.,Respiratory and Enteric Infections Department, Infectious Disease Division, International Centre for Diarrheal Disease and Research, Dhaka, Bangladesh
| | - Alzhraa Salah Abbas
- Online Research Club (http://www.onlineresearchclub.org), Nagasaki, Japan.,Department of Anesthesia, Al-Ahrar Teaching Hospital, Zagazig, Egypt
| | - Peter Samuel Eid
- Online Research Club (http://www.onlineresearchclub.org), Nagasaki, Japan.,Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Nguyen Lam Vuong
- Online Research Club (http://www.onlineresearchclub.org), Nagasaki, Japan.,Department of Medical Statistics and Informatics, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam
| | - Nguyen Vinh Khang
- Online Research Club (http://www.onlineresearchclub.org), Nagasaki, Japan.,Department of Neurology, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam
| | - Eman Elgabalawy
- Online Research Club (http://www.onlineresearchclub.org), Nagasaki, Japan.,Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | | | - Pham Thi Le Hoa
- Department of Infectious Diseases, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam
| | - Nguyen Tien Huy
- Evidence Based Medicine Research Group, Ton Duc Thang University, Ho Chi Minh City, Vietnam.,Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, Vietnam.,Department of Clinical Product Development, Institute of Tropical Medicine (NEKKEN), School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan
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12
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Nucleic acid vaccines for hepatitis B and C virus. INFECTION GENETICS AND EVOLUTION 2019; 75:103968. [PMID: 31325609 DOI: 10.1016/j.meegid.2019.103968] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Revised: 05/25/2019] [Accepted: 07/15/2019] [Indexed: 02/07/2023]
Abstract
Hepatitis B virus (HBV) and Hepatitis C virus (HCV) infections accounts for an important global health problem affecting over 250 million people all around the world. They can cause acute, transient and chronic infections in the human liver. Chronic infection of liver can lead to its failure or cancer. To deal with this problem, alternative approaches or strategies to inhibit these infections have already been started. DNA and mRNA-based vaccination will increase the efficacy and reduce toxicity in patients with Hepatitis B virus (HBV) and Hepatitis C virus (HCV) infections. Gene vaccines represent a promising alternative to conventional vaccine approaches because of their high potency, capacity for rapid development, low-cost manufacture and safe administration. MRNA-based vaccination is a method to elicit potent antigen-specific humoral and cell-mediated immune responses with a superior safety profile compared with DNA vaccines. Exploring the intricacies of these pathways can potentially help the researchers to explore newer vaccines. In this study, DNA and mRNA-based vaccination are introduced as an approach to treat Hepatitis B virus (HBV) and Hepatitis C virus (HCV) infections. DNA and mRNA-based vaccines as one of the most successful therapeutics are introduced and the clinical outcomes of their exploitation are explained.
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13
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Lim SG, Agcaoili J, De Souza NNA, Chan E. Therapeutic vaccination for chronic hepatitis B: A systematic review and meta-analysis. J Viral Hepat 2019; 26:803-817. [PMID: 30801899 DOI: 10.1111/jvh.13085] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Accepted: 01/11/2019] [Indexed: 12/21/2022]
Abstract
Therapeutic vaccines may be promising treatments for chronic hepatitis B (CHB), but their clinical efficacy and safety are unclear. We conducted a systematic review of the evidence for the efficacy and safety of therapeutic vaccines in CHB patients. We searched PubMed, EMBASE and Google Scholar from 1990 until present and abstracts from EASL, APASL and AASLD from 2012 to 2017 and selected randomized controlled trials of CHB patients, comparing therapeutic vaccines with no treatment or standard of care. The Cochrane Risk of Bias tool v2.0 and GRADE method were used. Analyses were stratified by hepatitis B e antigen (HBeAg) status and the comparator (therapeutic vaccines vs no treatment, or therapeutic vaccines + standard of care vs standard of care). Efficacy outcomes were HBeAg seroconversion, hepatitis B virus DNA reduction and hepatitis B virus surface antigen (HBsAg) loss, measured at the end of treatment or end of follow-up. Effects were reported as risk differences with 95% confidence intervals using a random effects model. Fifteen studies were included. A wide variety of therapeutic vaccines were tested. For HBeAg clearance at the end of follow-up, when comparing therapeutic vaccines vs no therapy, RD = 0.01, 95% CI -0.05 to 0.07, and when comparing therapeutic vaccines + standard of care vs standard of care, RD = 0.03, 95% CI -0.03 to 0.09. For HBVDNA reduction at the end of follow-up, when comparing therapeutic vaccines vs no therapy, RD = -0.03, 95% CI -0.08 to 0.02, and when comparing therapeutic vaccines + standard of care, RD = 0.15, 95% CI 0.02-0.28. There were only a few studies on HBsAg loss, and hence, the findings were inconclusive. The only efficacy finding was HBVDNA reduction at the end of follow-up for therapeutic vaccines + standard of care vs standard of care; otherwise, therapeutic vaccines do not appear to be efficacious for the treatment of CHB, but were limited by few RCTs, suboptimal therapeutic vaccines and patient selection.
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Affiliation(s)
- Seng Gee Lim
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore.,Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | | | - Nurun Nisa Amatullah De Souza
- Singapore Clinical Research Institute, Singapore, Singapore.,Singapore Cochrane Group, Singapore, Singapore.,Duke-NUS Medical School, National University of Singapore, Singapore, Singapore
| | - Edwin Chan
- Singapore Clinical Research Institute, Singapore, Singapore.,Singapore Cochrane Group, Singapore, Singapore.,Duke-NUS Medical School, National University of Singapore, Singapore, Singapore
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14
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Treatment of chronic hepatitis B naïve patients with a therapeutic vaccine containing HBs and HBc antigens (a randomized, open and treatment controlled phase III clinical trial). PLoS One 2018; 13:e0201236. [PMID: 30133478 PMCID: PMC6104936 DOI: 10.1371/journal.pone.0201236] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Accepted: 07/11/2018] [Indexed: 12/11/2022] Open
Abstract
Context Current drugs for chronic hepatitis B therapy have a poor efficacy in terms of post-treatment sustained viral suppression and generate important side effects during and after therapy. Therapeutic vaccination with HBV antigens is an attractive alternative to test. Objective Evaluating the efficacy of a therapeutic vaccine candidate (designated NASVAC) containing both hepatitis B surface antigen (HBsAg) and core antigen (HBcAg) versus pegylated interferon (Peg-IFN) in naïve chronic hepatitis B patients. Design, setting, participants An open phase III, randomised and treatment controlled clinical trial was conducted in a total of 160 CHB patients, allocated into two groups of 80 patients each to receive NASVAC or Peg-IFN. The vaccine formulation comprised 100 μg of each HBsAg and HBcAg, and was administered in 2 cycles of 5 doses. The control group received 48 subcutaneous injections of Peg-IFN alfa 2b, 180 μg per dose, every week, for 48 consecutive weeks. Main outcome measure The primary outcome measure was in relation with the proportion of patients showing reduction of the viral load under the limit of detection (250 copies/mL) after 24 weeks of treatment completion. Results Sustained control of HBV DNA was significantly more common in NASVAC group (p<0.05) at 24 weeks of follow up. NASVAC-induced increases of alanine aminotransferases (ALT) were detected in 85% patients after 5 nasal vaccinations, although seen in only 30% of patients receiving Peg-IFN. At the end of treatment (EOT) antiviral effect was comparable in both NASVAC and Peg-IFN groups. Clearance of Hepatitis B e antigen (HBeAg) was also more frequent in NASVAC group compared to Peg-IFN recipients. A lower progression to cirrhosis was found in NASVAC group compared to Peg-IFN group. Conclusion Nasvac induced a superior reduction of the viral load under the limit of detection compared to Peg-IFN treatment. It is a safe and efficacious finite alternative of antiviral treatment for CHB patients. Trial registration ClinicalTrials.gov NCT 01374308.
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15
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Mf Akbar S, Al-Mahtab M, I Khan S. Nature of Host Immunity during Hepatitis B Virus Infection and designing Immune Therapy. Euroasian J Hepatogastroenterol 2018; 8:42-46. [PMID: 29963460 PMCID: PMC6024052 DOI: 10.5005/jp-journals-10018-1256] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Accepted: 02/14/2018] [Indexed: 12/23/2022] Open
Abstract
Hepatitis B virus (HBV) infections represent one of the major public health problems in global context. More than 2 billion people in the world have been infected with this virus at some point of time in their life and millions are chronically infected, indicating that chronic HBV-infected subjects remain as a living source of HBV transmission. The public health impact of this is tremendous. Considerable numbers of chronic HBV-infected individuals would eventually develop progressive liver diseases and their complications like hepatic failure, liver cirrhosis (LC), and hepatocellular carcinoma (HCC). Epidemiological studies have suggested that about 0.6 to 1.2 million people die annually from HBV-related liver diseases. These figures about death due to HBV and sufferings from HBV-related diseases indicate a notion of medical emergencies about HBV. In addition to these, the impact of HBV on health care delivery system moves beyond these numbers of HBV-related patients and HB-related deaths. This is because significant insights have already been developed about epidemiology, virology, and pathogenesis of HBV. Also, an effective and widely used preventive vaccine is available against HBV. In addition to these, antiviral drugs against HBV have been developed from early 1980s and several such drugs are now available commercially in the open market around the worldwide. Unfortunately, the ongoing therapeutic regimens could not stand the test of time and new insights about HBV pathogenesis are required for the development of new, novel, and evidence-based therapies for chronic HBV infections. How to cite this article: Akbar SMF, Al-Mahtab M, Khan SI. Nature of Host Immunity during Hepatitis B Virus Infection and designing Immune Therapy. Euroasian J Hepato-Gastroenterol 2018;8(1):42-46.
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Affiliation(s)
- Sheikh Mf Akbar
- Department of Medical Sciences, Toshiba General Hospital, Tokyo, Japan and Miyakawa Memorial Research Foundation, Tokyo Japan
| | - Mamun Al-Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Sakirul I Khan
- Department of Anatomy and Embryology, Graduate School of Medicine, Ehime University, Ehime, Japan
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16
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Zhou C, Li C, Gong GZ, Wang S, Zhang JM, Xu DZ, Guo LM, Ren H, Xu M, Xie Q, Pan C, Xu J, Hu Z, Geng S, Zhou X, Wang X, Zhou X, Mi H, Zhao G, Yu W, Wen YM, Huang L, Wang XY, Wang B. Analysis of immunological mechanisms exerted by HBsAg-HBIG therapeutic vaccine combined with Adefovir in chronic hepatitis B patients. Hum Vaccin Immunother 2017; 13:1989-1996. [PMID: 28665747 DOI: 10.1080/21645515.2017.1335840] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
An HBsAg-HBIG therapeutic vaccine (Yeast-derived Immune Complexes, YIC) for chronic hepatitis B (CHB) patients has undergone a series of clinical trials. The HBeAg sero-conversion rate of YIC varied from 21.9% to 14% depending on the immunization protocols from 6 to 12 injections. To analyze the immunological mechanisms exerted by 6 injections of YIC, 44 CHB patients were separately immunized with YIC, alum as adjuvant control or normal saline as blank control, with add on of antiviral drug Adefovir in all groups. Kinetic increase in Th1 and Th2 cells CD4+ T cell sub-populations with association in decrease in Treg cells and increase of Tc1 and Tc17 cells in CD8+ T cells were observed in YIC immunized group. No such changes were found in the other groups. By multifunctional analysis of cytokine profiles, significant increase of IL-2 levels was observed, both in CD4+ and CD8+ T cells in the YIC immunized group, accompanied by increase in IFN-gamma and decrease of inhibitory factors (IL-10, TGF-β and Foxp3) in CD4+ T cells. In the alum immunized group, slight increase of IL-10, TGF-β and Foxp3 in CD4+ T cells was found after the second injection, but decreased after more injections, suggesting that alum induced early inflammatory responses to a certain extent. Similar patterns of responses of IL-17A and TNF-α in CD8+T cells were shown between YIC and the saline group. Results indicate that add on of Adefovir, did not affect host specific immune responses.
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Affiliation(s)
- Chenliang Zhou
- a Key Laboratory of Medical Molecular Virology , MoE/MoH, School of Basic Medical Sciences, Shanghai Medical College, Fudan University , Shanghai , People's Republic of China
| | - Chaofan Li
- a Key Laboratory of Medical Molecular Virology , MoE/MoH, School of Basic Medical Sciences, Shanghai Medical College, Fudan University , Shanghai , People's Republic of China
| | - Guo-Zhong Gong
- b The Second Xiangya Hospital , Central South University , Changsha , People's Republic of China
| | - Shuang Wang
- a Key Laboratory of Medical Molecular Virology , MoE/MoH, School of Basic Medical Sciences, Shanghai Medical College, Fudan University , Shanghai , People's Republic of China
| | - Ji-Ming Zhang
- c Huashan Hospital , Fudan University , Shanghai , People's Republic of China
| | - Dao-Zhen Xu
- d Beijing Ditan Hospital , Capital Medical University , Beijing , People's Republic of China
| | - Li-Min Guo
- d Beijing Ditan Hospital , Capital Medical University , Beijing , People's Republic of China
| | - Hong Ren
- e The Second Affiliated Hospital , Chongqing Medical University , Chongqing , People's Republic of China
| | - Min Xu
- f Guangzhou Eighth People's Hospital , Guangzhou , People's Republic of China
| | - Qing Xie
- g Ruijin Hospital , Jiaotong University , Shanghai , People's Republic of China
| | - Chen Pan
- h Fuzhou Infectious Disease Hospital , Fuzhou , People's Republic of China
| | - Jie Xu
- i The Third People's Hospital , Jiaotong University , Shanghai , People's Republic of China
| | - Zhongyu Hu
- j National Institutes for Food and Drug Control , Beijing , People's Republic of China
| | - Shuang Geng
- a Key Laboratory of Medical Molecular Virology , MoE/MoH, School of Basic Medical Sciences, Shanghai Medical College, Fudan University , Shanghai , People's Republic of China
| | - Xian Zhou
- a Key Laboratory of Medical Molecular Virology , MoE/MoH, School of Basic Medical Sciences, Shanghai Medical College, Fudan University , Shanghai , People's Republic of China
| | - Xianzheng Wang
- a Key Laboratory of Medical Molecular Virology , MoE/MoH, School of Basic Medical Sciences, Shanghai Medical College, Fudan University , Shanghai , People's Republic of China
| | - Xiaoyu Zhou
- a Key Laboratory of Medical Molecular Virology , MoE/MoH, School of Basic Medical Sciences, Shanghai Medical College, Fudan University , Shanghai , People's Republic of China
| | - Haili Mi
- a Key Laboratory of Medical Molecular Virology , MoE/MoH, School of Basic Medical Sciences, Shanghai Medical College, Fudan University , Shanghai , People's Republic of China
| | - Gan Zhao
- a Key Laboratory of Medical Molecular Virology , MoE/MoH, School of Basic Medical Sciences, Shanghai Medical College, Fudan University , Shanghai , People's Republic of China
| | - Wencong Yu
- a Key Laboratory of Medical Molecular Virology , MoE/MoH, School of Basic Medical Sciences, Shanghai Medical College, Fudan University , Shanghai , People's Republic of China
| | - Yu-Mei Wen
- a Key Laboratory of Medical Molecular Virology , MoE/MoH, School of Basic Medical Sciences, Shanghai Medical College, Fudan University , Shanghai , People's Republic of China
| | - Lihua Huang
- k Wuxi Fifth People's Hospital , Wuxi , People's Republic of China
| | - Xuan-Yi Wang
- a Key Laboratory of Medical Molecular Virology , MoE/MoH, School of Basic Medical Sciences, Shanghai Medical College, Fudan University , Shanghai , People's Republic of China
| | - Bin Wang
- a Key Laboratory of Medical Molecular Virology , MoE/MoH, School of Basic Medical Sciences, Shanghai Medical College, Fudan University , Shanghai , People's Republic of China
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17
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Gehring AJ. New treatments to reach functional cure: Rationale and challenges for emerging immune-based therapies. Best Pract Res Clin Gastroenterol 2017; 31:337-345. [PMID: 28774416 DOI: 10.1016/j.bpg.2017.05.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Revised: 05/03/2017] [Accepted: 05/13/2017] [Indexed: 01/31/2023]
Abstract
The landscape for chronic HBV therapy is rapidly evolving. The latest generation of antiviral drugs provide robust virus suppression with a high barrier to resistance that facilitates long-term treatment. However, low rates of HBsAg loss demonstrate that additional strategies are needed to consistency achieve a functional cure. The immune system can clear HBV and establish long-term control over the virus. Sufficiently boosting HBV immunity in chronic patients has been very difficult due to immune exhaustion, immune dysregulation, and inhibitory pathways suppressing the immune response. Therapeutic vaccines employing new technology, vectors and new immunomodulatory drugs that can elicit direct antiviral effects and cancel inhibitory mechanism may be able to overcome exhaustion. This review will discuss the justification for immunotherapy, lessons from previous trials and new vaccines/drugs in early stage clinical trials. The challenges of correlating immune responses induced by these drugs to clinical efficacy will also be addressed.
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Affiliation(s)
- Adam J Gehring
- Toronto Centre for Liver Disease and Toronto General Hospital Research Institute, University Health Network, Toronto, Canada; Department of Immunology, University of Toronto, Toronto, Canada.
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18
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Li J, Bao M, Ge J, Ren S, Zhou T, Qi F, Pu X, Dou J. Research progress of therapeutic vaccines for treating chronic hepatitis B. Hum Vaccin Immunother 2017; 13:986-997. [PMID: 28118084 DOI: 10.1080/21645515.2016.1276125] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Hepatitis B virus (HBV) is a member of Hepadnavirus family, which leads to chronic infection in around 5% of patients with a high risk of developing liver cirrhosis, liver failure, and hepatocellular carcinoma. 1 Despite the availability of prophylactic vaccines against hepatitis B for over 3 decades, there are still more than 2 billion people have been infected and 240 million of them were chronic. Antiviral therapies currently used in the treatment of CHB (chronic hepatitis B) infection include peg-interferon, standard α-interferon and nucleos/tide analogs (NAs), but none of them can provide sustained control of viral replication. As an alternative strategy, therapeutic vaccines for CHB patients have been widely studied and showed some promising efficacies in dozens of preclinical and clinical trials. In this article, we review current research progress in several types of therapeutic vaccines for CHB treatment, including protein-based vaccines, DNA-based vaccines, live vector-based vaccines, peptide-based vaccines and cell-based therapies. These researches may provide some clues for developing new treatments in CHB infection.
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Affiliation(s)
- Jianqiang Li
- a Jiangsu Theravac Bio-pharmaceutical Co., Ltd. , Nanjing , China
| | - Mengru Bao
- a Jiangsu Theravac Bio-pharmaceutical Co., Ltd. , Nanjing , China
| | - Jun Ge
- a Jiangsu Theravac Bio-pharmaceutical Co., Ltd. , Nanjing , China
| | - Sulin Ren
- a Jiangsu Theravac Bio-pharmaceutical Co., Ltd. , Nanjing , China
| | - Tong Zhou
- a Jiangsu Theravac Bio-pharmaceutical Co., Ltd. , Nanjing , China
| | - Fengchun Qi
- a Jiangsu Theravac Bio-pharmaceutical Co., Ltd. , Nanjing , China
| | - Xiuying Pu
- b School of Life Science and Engineering, Lanzhou University of Technology , Lanzhou , China
| | - Jia Dou
- c Dalian Institute for Drug Control , Dalian , China
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19
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Yang FQ, Rao GR, Wang GQ, Li YQ, Xie Y, Zhang ZQ, Deng CL, Mao Q, Li J, Zhao W, Wang MR, Han T, Chen SJ, Pan C, Tan DM, Shang J, Zhang MX, Zhang YX, Yang JM, Chen GM. Phase IIb trial of in vivo electroporation mediated dual-plasmid hepatitis B virus DNA vaccine in chronic hepatitis B patients under lamivudine therapy. World J Gastroenterol 2017; 23:306-317. [PMID: 28127204 PMCID: PMC5236510 DOI: 10.3748/wjg.v23.i2.306] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Revised: 09/30/2016] [Accepted: 10/27/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To assess the efficacy and safety of in vivo electroporation (EP)-mediated dual-plasmid hepatitis B virus (HBV) DNA vaccine vs placebo for sequential combination therapy with lamivudine (LAM) in patients with chronic hepatitis B.
METHODS Two hundred and twenty-five patients were randomized to receive either LAM + vaccine (vaccine group, n = 109) or LAM + placebo (control group, n = 116). LAM treatment lasted 72 wk. Patients received the DNA vaccine or placebo by intramuscular injection mediated by EP at weeks 12 (start of treatment with vaccine or placebo, SOT), 16, 24, and 36 (end of treatment with vaccine or placebo, EOT).
RESULTS In the modified intent-to-treat population, more patients had a decrease in HBV DNA > 2 log10 IU/mL in the vaccine group at week 12 after EOT compared with the control group. A trend toward a difference in the number of patients with undetectable HBV DNA at week 28 after EOT was obtained. Adverse events were similar. In the dynamic per-protocol set, which excluded adefovir (ADV) add-on cases at each time point instantly after ADV administration due to LAM antiviral failure, more patients had a decrease in HBV DNA > 2 log10 IU/mL in the vaccine group at week 12 and 28 after EOT compared with the control group. More patients with undetectable HBV DNA at week 28 after EOT in the vaccine group were also observed. Among patients with a viral load < 1000 copies/mL at week 12, more patients achieved HBeAg seroconversion in the vaccine group than among controls at week 36 after EOT, as well as less virological breakthrough and YMDD mutations.
CONCLUSION The primary endpoint was not achieved using the HBV DNA vaccine. The HBV DNA vaccine could only be beneficial in subjects that have achieved initial virological response under LAM chemotherapy.
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MESH Headings
- Adult
- DNA, Viral/administration & dosage
- DNA, Viral/adverse effects
- DNA, Viral/isolation & purification
- DNA, Viral/therapeutic use
- Double-Blind Method
- Drug Resistance, Viral/drug effects
- Electroporation/methods
- Female
- Hepatitis B Vaccines/administration & dosage
- Hepatitis B Vaccines/adverse effects
- Hepatitis B Vaccines/therapeutic use
- Hepatitis B virus/genetics
- Hepatitis B virus/isolation & purification
- Hepatitis B, Chronic/drug therapy
- Humans
- Injections, Intramuscular
- Lamivudine/administration & dosage
- Lamivudine/therapeutic use
- Male
- Plasmids
- Reverse Transcriptase Inhibitors/administration & dosage
- Reverse Transcriptase Inhibitors/therapeutic use
- Treatment Outcome
- Vaccines, DNA/administration & dosage
- Vaccines, DNA/adverse effects
- Vaccines, DNA/therapeutic use
- Viral Load
- Young Adult
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20
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Heller R, Teissie J, Rols MP, Gehl J, Sersa G, Mir LM, Neal RE, Bhonsle S, Davalos R, Beebe S, Hargrave B, Nuccitelli R, Jiang C, Cemazar M, Tamzali Y, Tozon N. Medical Applications. BIOELECTRICS 2017:275-388. [DOI: 10.1007/978-4-431-56095-1_5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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21
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Herrero MJ, Sendra L, Miguel A, Aliño SF. Physical Methods of Gene Delivery. SAFETY AND EFFICACY OF GENE-BASED THERAPEUTICS FOR INHERITED DISORDERS 2017:113-135. [DOI: 10.1007/978-3-319-53457-2_6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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22
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Affiliation(s)
- Lucyna Cova
- INSERM U1052, Centre de Recherche en Cancérologie de Lyon (CRCL), University Lyon 1, Lyon, France
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23
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Meng ZJ, Yang YD. Potential strategies for "cure" of hepatitis B. Shijie Huaren Xiaohua Zazhi 2016; 24:4438-4449. [DOI: 10.11569/wcjd.v24.i33.4438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B is a worldwide health problem and the main cause of liver cirrhosis, liver failure, and liver cancer. The steady state of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) in HBV infected hepatocytes and virus specific immune tolerance contribute to the chronic persistent infection and hard-to-cure of hepatitis B. The presently available therapeutics for hepatitis B can control viral replication, but rarely eliminate HBV surface antigen (HBsAg) or HBV cccDNA. The "cure" of hepatitis B, which is characterized by the HBsAg loss or HBsAg seroconversion, and cccDNA clearance, has been the goal of researchers for years. In recent years, with the robust progress in understanding the HBV pathogenesis and the rapid development of gene editing technology, the "cure" of hepatitis B becomes prospective. This paper aims to summarize the potential strategies for the "cure" of hepatitis B.
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24
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Akbar SMF, Al-Mahtab M, Jahan M, Yoshida O, Hiasa Y. Novel insights into immunotherapy for hepatitis B patients. Expert Rev Gastroenterol Hepatol 2016; 10:267-76. [PMID: 26626120 DOI: 10.1586/17474124.2016.1112266] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The possible use of immunotherapy for hepatitis B has emerged for two major reasons: (1) chronic hepatitis B (CHB) is an immune-mediated pathological condition, and (2) commercially available antiviral drugs are of limited efficacy. Although various immunomodulatory agents have been used to treat patients with CHB during the last three decades, there is currently no consensus among physicians and hepatologists regarding the suitability of immunotherapy for patients with CHB. However, new insights into immunotherapy for CHB have emerged; these may facilitate design of effective and tolerable immunotherapy regimens for these patients. This review provides a comprehensive overview of immunotherapy for CHB.
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Affiliation(s)
| | - Mamun Al-Mahtab
- b Department of Hepatology , Bangabandhu Sheikh Mujib Medical University , Dhaka , Bangladesh
| | - Munira Jahan
- c Department of Virology , Bangabandhu Sheikh Mujib Medical University , Dhaka , Bangladesh
| | - Osamu Yoshida
- d Department of Gastroenterology and Metabology , Ehime University Graduate School of Medicine , Toon , Japan
| | - Yoichi Hiasa
- d Department of Gastroenterology and Metabology , Ehime University Graduate School of Medicine , Toon , Japan
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25
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Akbar SMF, Al-Mahtab M, Khan MSI, Raihan R, Shrestha A. Immune therapy for hepatitis B. ANNALS OF TRANSLATIONAL MEDICINE 2016; 4:335. [PMID: 27761439 DOI: 10.21037/atm.2016.08.48] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Although several antiviral drugs are now available for treatment of patients with chronic hepatitis B (CHB), sustained off-treatment clinical responses and containment of CHB-related complications are not achieved in majority of CHB patients by antiviral therapy. In addition, use of these drugs is endowed with substantial long term risk of viral resistance and drug toxicity. The infinite treatment regimens of antiviral drugs for CHB patients are also costly and usually unbearable by most patients of developing and resource-constrained countries. Taken together, there is a pressing need to develop new and innovative therapeutic approaches for CHB patients. Immune therapy seems to be an alternate therapeutic approach for CHB patients because impaired or distorted or diminished immune responses have been detected in most of these patients. Also, investigators have shown that restoration or induction of proper types of immune responses may have therapeutic implications in CHB. Various immunomodulatory agents have been used to treat patients with CHB around the world and the outcomes of these clinical trials show that the properties of immune modulators and nature and designing of immune therapeutic regimens seem to be highly relevant in the context of treatment of CHB patients. In this review, the general properties and specific features of immune therapy for CHB have been discussed for developing the guidelines of effective regimens of immune therapy for CHB.
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Affiliation(s)
| | - Mamun Al-Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Md Sakilur Islam Khan
- Department of Anatomy and Embryology, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Ruksana Raihan
- Department of Virology, AIMST University, Semeling, Bedong, Kedah, Malaysia
| | - Ananta Shrestha
- Department of Hepatology, The Liver Clinic, Liver Foundation, Kathmandu, Nepal
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Ren Y, Min YQ, Liu M, Chi L, Zhao P, Zhang XL. N-glycosylation-mutated HCV envelope glycoprotein complex enhances antigen-presenting activity and cellular and neutralizing antibody responses. Biochim Biophys Acta Gen Subj 2016; 1860:1764-75. [DOI: 10.1016/j.bbagen.2015.08.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2015] [Revised: 08/07/2015] [Accepted: 08/08/2015] [Indexed: 02/08/2023]
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Backes S, Jäger C, Dembek CJ, Kosinska AD, Bauer T, Stephan AS, Dišlers A, Mutwiri G, Busch DH, Babiuk LA, Gasteiger G, Protzer U. Protein-prime/modified vaccinia virus Ankara vector-boost vaccination overcomes tolerance in high-antigenemic HBV-transgenic mice. Vaccine 2016; 34:923-32. [DOI: 10.1016/j.vaccine.2015.12.060] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Revised: 11/30/2015] [Accepted: 12/24/2015] [Indexed: 12/31/2022]
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Chen M, Jagya N, Bansal R, Frelin L, Sällberg M. Prospects and progress of DNA vaccines for treating hepatitis B. Expert Rev Vaccines 2016; 15:629-40. [PMID: 26652035 DOI: 10.1586/14760584.2016.1131615] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The hepatitis B virus (HBV) is a global cause of liver disease. The preventive HBV vaccine has effectively reduced the disease burden. However, an estimated 340 million chronic HBV cases are in need of treatment. Current standard therapy for chronic HBV blocks reverse transcription. As this therapy blocks viral maturation and not viral protein expression, any immune inhibition exerted by these proteins will remain throughout therapy. This may help to explain why these drugs rarely induce off-therapy responses. Albeit some restoration of immune function occurs during therapy, this is clearly insufficient to control replication. Central questions when considering therapeutic DNA vaccination as an addition to blocking virus production are as follows: what does one hope to achieve? What do we think is wrong and how can the vaccination correct this? We here discuss different scenarios with respect to the lack of success of tested DNA vaccines, and suggest strategies for improvement.
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Affiliation(s)
- Margaret Chen
- a Division of Clinical Microbiology, F 68, Department of Laboratory Medicine , Karolinska Institutet at Karolinska University Hospital , Stockholm , Sweden.,b Department of Dental Medicine , Karolinska Institutet , Stockholm , Sweden
| | - Neetu Jagya
- a Division of Clinical Microbiology, F 68, Department of Laboratory Medicine , Karolinska Institutet at Karolinska University Hospital , Stockholm , Sweden
| | - Ruchi Bansal
- c Targeted Therapeutics, Department of Biomaterials Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine , University of Twente , Enschede , The Netherlands
| | - Lars Frelin
- a Division of Clinical Microbiology, F 68, Department of Laboratory Medicine , Karolinska Institutet at Karolinska University Hospital , Stockholm , Sweden
| | - Matti Sällberg
- a Division of Clinical Microbiology, F 68, Department of Laboratory Medicine , Karolinska Institutet at Karolinska University Hospital , Stockholm , Sweden
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Wang W, Li J, Zhang X, Wen Y, Wang XY, Yuan Z. A Pilot Study of MicroRNAs Expression Profile in Serum and HBsAg Particles: Predictors of Therapeutic Vaccine Efficacy in Chronic Hepatitis B Patients. Medicine (Baltimore) 2016; 95:e2511. [PMID: 26765470 PMCID: PMC4718296 DOI: 10.1097/md.0000000000002511] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Chronic hepatitis B (CHB) remains a global health problem. Therapeutic vaccination has been successfully employed to treat a subpopulation of CHB patients. Personalized treatment can not only improve therapeutic efficacy, but also decrease the cost of medical care. Since microRNAs (miRNAs) are highly conserved and are involved in many cellular processes, exploring their expression profiles in CHB patients in association with responsiveness to therapeutic vaccination may be an approach for personalized treatment. In this study, we examined the kinetic expression profiles of 13 miRNAs in sera and serum-derived hepatitis surface antigen (HBsAg) particles in 10 CHB patients including 5 responders and 5 nonresponders selected from a large cohort of 136 patients enroled in a phase III clinical trial using antigen-antibody immunogenic complex based therapeutic vaccine (YIC). Eight miRNAs were detected in both sera and HBsAg particles. Among them, the levels of serum miRNAs and serum-derived HBsAg-carried miRNAs (let-7f, miR-22, miR-30a, and miR-122) were significantly lower in the responders group compared to those in the nonresponders group at baseline and throughout the course of treatment. The lower baseline levels of serum miRNAs and HBsAg-carried miRNAs were also associated with hepatitis e antigen clearance at week 76 and hepatitis e antigen seroconversion during the study period. In summary, our study suggests that lower baseline levels of serum miRNAs and HBsAg-carried miRNAs (let-7f, miR-22, miR-30a, and miR-122) associated with YIC treatment response and the variation trend of these 4 miRNAs could have a prognostic value for responsiveness to YIC treatment.
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Affiliation(s)
- Weixia Wang
- From the Key Laboratory of Medical Molecular Virology (WW, JL, YW, X-YW, ZY), School of Basic Medical Sciences, Shanghai Medical College, Fudan University; and Shanghai Public Health Clinical Center (WW, JL, XZ), Shanghai Medical College, Fudan University, Shanghai, China
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Lambricht L, Lopes A, Kos S, Sersa G, Préat V, Vandermeulen G. Clinical potential of electroporation for gene therapy and DNA vaccine delivery. Expert Opin Drug Deliv 2015; 13:295-310. [PMID: 26578324 DOI: 10.1517/17425247.2016.1121990] [Citation(s) in RCA: 163] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Electroporation allows efficient delivery of DNA into cells and tissues, thereby improving the expression of therapeutic or immunogenic proteins that are encoded by plasmid DNA. This simple and versatile method holds a great potential and could address unmet medical needs such as the prevention or treatment of many cancers or infectious diseases. AREAS COVERED This review explores the electroporation mechanism and the parameters affecting its efficacy. An analysis of past and current clinical trials focused on DNA electroporation is presented. The pathologies addressed, the protocol used, the treatment outcome and the tolerability are highlighted. In addition, several of the possible optimization strategies for improving patient compliance and therapeutic efficacy are discussed such as plasmid design, use of genetic adjuvants for DNA vaccines, choice of appropriate delivery site and electrodes as well as pulse parameters. EXPERT OPINION The growing number of clinical trials and the results already available underline the strong potential of DNA electroporation which combines both safety and efficiency. Nevertheless, it remains critical to further increase fundamental knowledge to refine future strategies, to develop concerted and common DNA electroporation protocols and to continue exploring new electroporation-based therapeutic options.
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Affiliation(s)
- Laure Lambricht
- a Université catholique de Louvain, Louvain Drug Research Institute , Advanced Drug Delivery and Biomaterials , Brussels , Belgium
| | - Alessandra Lopes
- a Université catholique de Louvain, Louvain Drug Research Institute , Advanced Drug Delivery and Biomaterials , Brussels , Belgium
| | - Spela Kos
- b Institute of Oncology Ljubljana , Department of Experimental Oncology , Ljubljana , Slovenia
| | - Gregor Sersa
- b Institute of Oncology Ljubljana , Department of Experimental Oncology , Ljubljana , Slovenia
| | - Véronique Préat
- a Université catholique de Louvain, Louvain Drug Research Institute , Advanced Drug Delivery and Biomaterials , Brussels , Belgium
| | - Gaëlle Vandermeulen
- a Université catholique de Louvain, Louvain Drug Research Institute , Advanced Drug Delivery and Biomaterials , Brussels , Belgium
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Meng Z, Zhang X, Pei R, Zhang E, Kemper T, Vollmer J, Davis HL, Glebe D, Gerlich W, Roggendorf M, Lu M. Combination therapy including CpG oligodeoxynucleotides and entecavir induces early viral response and enhanced inhibition of viral replication in a woodchuck model of chronic hepadnaviral infection. Antiviral Res 2015; 125:14-24. [PMID: 26585244 DOI: 10.1016/j.antiviral.2015.11.001] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Revised: 10/17/2015] [Accepted: 11/09/2015] [Indexed: 02/07/2023]
Abstract
CpG oligodeoxynucleotides (ODNs) stimulate immune cells via TLR9 and are potentially useful immunomodulators for the treatment of chronic viral infections. In the present study, different classes of CpGs were tested for their capacities for innate immune activation and antiviral activities in the woodchuck model. A class P CpG ODN was found to stimulate interferon (IFN) production in woodchuck peripheral blood mononuclear cells (PBMCs) in vitro, and following subcutaneous administration in vivo, it was observed to induce IFN and MxA expression in woodchuck PBMCs. Combination treatment with CpG ODN and entecavir (ETV) led to effective suppression of the woodchuck hepatitis virus (WHV) load in the woodchucks, with early viral responses and inhibition of replication. The woodchuck hepatitis surface antigen (WHsAg) serum concentrations were strongly decreased by CpG and ETV together but not by either agent alone, indicating synergistic effects. However, viral control post-treatment was still transient, similar to that observed with ETV alone. Significantly elevated levels of serum aspartate aminotransferase (AST) but not of alanine aminotransferase (ALT) in some of the woodchucks receiving CpG ODN were noted, but these increases were resolved before the completion of treatment and were not associated with an elevated serum bilirubin level or coagulation disorders, suggesting the absence of a significant safety concern.
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Affiliation(s)
- Zhongji Meng
- Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany; Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Xiaoyong Zhang
- Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
| | - Rongjuan Pei
- Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
| | - Ejuan Zhang
- Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
| | - Thekla Kemper
- Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
| | - Jörg Vollmer
- Pfizer Oligonucleotides Therapeutics Unit, Düsseldorf, Germany
| | | | - Dieter Glebe
- Institute of Medical Virology, Justus-Liebig University Giessen, Giessen, Germany
| | - Wolfram Gerlich
- Institute of Medical Virology, Justus-Liebig University Giessen, Giessen, Germany
| | - Michael Roggendorf
- Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
| | - Mengji Lu
- Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
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Isorce N, Lucifora J, Zoulim F, Durantel D. Immune-modulators to combat hepatitis B virus infection: From IFN-α to novel investigational immunotherapeutic strategies. Antiviral Res 2015; 122:69-81. [PMID: 26275801 DOI: 10.1016/j.antiviral.2015.08.008] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2015] [Accepted: 08/11/2015] [Indexed: 02/07/2023]
Abstract
Chronic hepatitis B virus (HBV) infection remains a major challenge for clinicians, as there are only two types of approved therapies: interferon-alpha (IFN-α) or its pegylated form, Peg-IFN-α and nucleoside analogs (e.g. tenofovir, entecavir...). The first are used as finite-duration treatments of around 48-52 weeks, while the second must be taken life-long to prevent rebound. Other immune-modulators, including other types of recombinant IFNs and cytokines/chemokines, could be developed for treating chronic hepatitis B. Alternatively, strategies aimed either at restoring or favoring the endogenous production of IFNs, cytokines and/or chemokines, or at alleviating HBV-mediated inhibitory processes could also be envisaged. In this article, we review current investigational, preclinical and clinical efforts to implement immune-modulatory components in the therapy of chronic hepatitis B. This review forms part of a symposium in Antiviral Research on "An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis B".
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Affiliation(s)
- Nathalie Isorce
- INSERM, U1052, CNRS UMR_5286, Cancer Research Centre of Lyon (CRCL), Lyon, France; University of Lyon, Université Claude Bernard (UCBL), Lyon, France
| | - Julie Lucifora
- INSERM, U1052, CNRS UMR_5286, Cancer Research Centre of Lyon (CRCL), Lyon, France; University of Lyon, Université Claude Bernard (UCBL), Lyon, France
| | - Fabien Zoulim
- INSERM, U1052, CNRS UMR_5286, Cancer Research Centre of Lyon (CRCL), Lyon, France; University of Lyon, Université Claude Bernard (UCBL), Lyon, France; Labex DEVweCAN, Lyon, France; Hospices Civils de Lyon (HCL), Croix-Rousse Hospital, Lyon, France
| | - David Durantel
- INSERM, U1052, CNRS UMR_5286, Cancer Research Centre of Lyon (CRCL), Lyon, France; University of Lyon, Université Claude Bernard (UCBL), Lyon, France; Labex DEVweCAN, Lyon, France.
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Song KM, Choi MJ, Kwon MH, Ghatak K, Park SH, Ryu DS, Ryu JK, Suh JK. Optimizing in vivo gene transfer into mouse corpus cavernosum by use of surface electroporation. Korean J Urol 2015; 56:197-204. [PMID: 25763123 PMCID: PMC4355430 DOI: 10.4111/kju.2015.56.3.197] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Accepted: 01/08/2015] [Indexed: 11/22/2022] Open
Abstract
Purpose Electroporation is known to enhance the efficiency of gene transfer through a transient increase in cell membrane permeability. The aim of this study was to determine the optimal conditions for in vivo electroporation-mediated gene delivery into mouse corpus cavernosum. Materials and Methods Diabetes was induced in C57BL/6 mice by intraperitoneal injections of streptozotocin. After intracavernous injection of pCMV-Luc (100 µg/40 µL), different electroporation settings (5-50 V, 8-16 pulses with a duration of 40-100 ms) were applied to the penis to establish the optimal conditions for electroporation. Gene expression was evaluated by luciferase assay. We also assessed the undesired consequences of electroporation by visual inspection and hematoxylin-eosin staining of penile tissue. Results Electroporation profoundly induced gene expression in the corpus cavernosum tissue of normal mice in a voltage-dependent manner. We observed electrical burn scars in the penis of normal mice who received electroporation with eight 40-ms pulses at a voltage of 50 V and sixteen 40-ms pulses, eight 100-ms pulses, and sixteen 100-ms pulses at a voltage of 30 V. No detectable burn scars were noted in normal mice stimulated with eight 40-ms pulses at a voltage of 30 V. Electroporation also significantly induced gene expression in diabetic mice stimulated with 40-ms pulse at a voltage of 30 V without injury to the penis. Conclusions We have established the optimal electroporation conditions for maximizing gene transfer into the corpus cavernosum of mice while avoiding damage to the erectile tissue. The electroporation-mediated gene delivery technique will be a valuable tool for gene therapy in the field of erectile dysfunction.
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Affiliation(s)
- Kang-Moon Song
- National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Korea
| | - Min Ji Choi
- National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Korea
| | - Mi-Hye Kwon
- National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Korea
| | - Kalyan Ghatak
- National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Korea
| | - Soo-Hwan Park
- National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Korea
| | - Dong-Soo Ryu
- Department of Urology, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea
| | - Ji-Kan Ryu
- National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Korea
| | - Jun-Kyu Suh
- National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Korea
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Gebbing M, Bergmann T, Schulz E, Ehrhardt A. Gene therapeutic approaches to inhibit hepatitis B virus replication. World J Hepatol 2015; 7:150-164. [PMID: 25729471 PMCID: PMC4342598 DOI: 10.4254/wjh.v7.i2.150] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2014] [Revised: 10/23/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023] Open
Abstract
Acute and chronic hepatitis B virus (HBV) infections remain to present a major global health problem. The infection can be associated with acute symptomatic or asymptomatic hepatitis which can cause chronic inflammation of the liver and over years this can lead to cirrhosis and the development of hepatocellular carcinomas. Currently available therapeutics for chronically infected individuals aim at reducing viral replication and to slow down or stop the progression of the disease. Therefore, novel treatment options are needed to efficiently combat and eradicate this disease. Here we provide a state of the art overview of gene therapeutic approaches to inhibit HBV replication. We discuss non-viral and viral approaches which were explored to deliver therapeutic nucleic acids aiming at reducing HBV replication. Types of delivered therapeutic nucleic acids which were studied since many years include antisense oligodeoxynucleotides and antisense RNA, ribozymes and DNAzymes, RNA interference, and external guide sequences. More recently designer nucleases gained increased attention and were exploited to destroy the HBV genome. In addition we mention other strategies to reduce HBV replication based on delivery of DNA encoding dominant negative mutants and DNA vaccination. In combination with available cell culture and animal models for HBV infection, in vitro and in vivo studies can be performed to test efficacy of gene therapeutic approaches. Recent progress but also challenges will be specified and future perspectives will be discussed. This is an exciting time to explore such approaches because recent successes of gene therapeutic strategies in the clinic to treat genetic diseases raise hope to find alternative treatment options for patients chronically infected with HBV.
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Therapeutic vaccines in HBV: lessons from HCV. Med Microbiol Immunol 2015; 204:79-86. [PMID: 25573348 PMCID: PMC4305103 DOI: 10.1007/s00430-014-0376-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2014] [Accepted: 10/07/2014] [Indexed: 12/15/2022]
Abstract
Currently, millions of people infected with hepatitis B virus (HBV) are committed to decades of treatment with anti-viral therapy to control viral replication. However, new tools for immunotherapy that include both viral vectors and molecular checkpoint inhibitors are now available. This has led to a resurgence of interest in new strategies to develop immunotherapeutic strategies with the aim of inducing HBeAg seroconversion—an end-point that has been associated with a decrease in the rates of disease progression. Ultimately, a true cure will involve the elimination of covalently closed circular DNA which presents a greater challenge for immunotherapy. In this manuscript, I describe the development of immunotherapeutic strategies for HBV that are approaching or currently in clinical studies, and draw on observations of T cell function in natural infection supported by recent animal studies that may lead to additional rational vaccine strategies using checkpoint inhibitors. I also draw on our recent experience in developing potent vaccines for HCV prophylaxis based on simian adenoviral and MVA vectors used in prime–boost strategies in both healthy volunteers and HCV infected patients. I have shown that the induction of T cell immune responses is markedly attenuated when administered to people with persistent HCV viremia. These studies and recently published animal studies using the woodchuck model suggest that potent vaccines based on DNA or adenoviral vectored vaccination represent a rational way forward. However, combining these with drugs to suppress viral replication, alongside checkpoint inhibitors may be required to induce long-term immune control.
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Fontaine H, Kahi S, Chazallon C, Bourgine M, Varaut A, Buffet C, Godon O, Meritet JF, Saïdi Y, Michel ML, Scott-Algara D, Aboulker JP, Pol S. Anti-HBV DNA vaccination does not prevent relapse after discontinuation of analogues in the treatment of chronic hepatitis B: a randomised trial--ANRS HB02 VAC-ADN. Gut 2015; 64:139-47. [PMID: 24555998 DOI: 10.1136/gutjnl-2013-305707] [Citation(s) in RCA: 85] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
OBJECTIVE The antiviral efficacy of nucleos(t)ide analogues whose main limitation is relapse after discontinuation requires long-term therapy. To overcome the risk of relapse and virological breakthrough during long-term therapy, we performed a phase I/II, open, prospective, multicentre trial using a HBV envelope-expressing DNA vaccine. DESIGN 70 patients treated effectively with nucleos(t)ide analogues for a median of 3 years (HBV DNA <12 IU/mL for at least 12 months) were randomised into two groups: one received five intramuscular injections of vaccine (weeks 0, 8, 16, 40 and 44) and one did not receive the vaccine. Analogues were stopped after an additional 48 weeks of treatment in patients who maintained HBV DNA <12 IU/mL with no clinical progression and monthly HBV DNA for 6 months. The primary endpoint was defined as viral reactivation at week 72 (HBV DNA >120 IU/mL) or impossibility of stopping treatment at week 48. RESULTS Reactivation occurred in 97% of each group after a median 28 days without liver failure but with an HBV DNA <2000 IU/mL in 33%; 99% of adverse reactions were mild to moderate. Immune responses were evaluated by enzyme-linked immunosorbent spot and proliferation assays: there was no difference in the percentage of patients with interferon-γ secreting cells and a specific T-cell proliferation to HBcAg but not to HBsAg after reactivation in each group. CONCLUSIONS Although it is fairly well tolerated, the HBV DNA vaccine does not decrease the risk of relapse in HBV-treated patients or the rate of virological breakthrough, and does not restore the anti-HBV immune response despite effective viral suppression by analogues. TRIAL REGISTRATION NUMBER NCT00536627.
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Affiliation(s)
- H Fontaine
- Institut Cochin, CNRS (UMR 8104) and INSERM U-1016, Université Paris Descartes, et Assistance Publique-Hôpitaux de Paris, Service d'Hépatologie, Cochin Hospital, Paris, France
| | - S Kahi
- INSERM SC10, Villejuif, France
| | | | - M Bourgine
- Laboratoire de pathogénèse des virus de l'hépatite B and INSERM U845, Institut Pasteur, Paris, France
| | - A Varaut
- Gastroenterology and Hepatology Unit, Pitié-Salpétrière Hospital, Paris, France
| | - C Buffet
- Gastroenterology and Hepatology Unit, Kremlin-Bicêtre Hospital, le Kremlin-Bicêtre, France
| | - O Godon
- Laboratoire de pathogénèse des virus de l'hépatite B and INSERM U845, Institut Pasteur, Paris, France
| | - J F Meritet
- Virology Unit, Cochin Hospital, Paris, France
| | - Y Saïdi
- INSERM SC10, Villejuif, France
| | - M L Michel
- Laboratoire de pathogénèse des virus de l'hépatite B and INSERM U845, Institut Pasteur, Paris, France
| | - D Scott-Algara
- Unité de Régulation des Infections Rétrovirales, Institut Pasteur
| | | | - S Pol
- Institut Cochin, CNRS (UMR 8104) and INSERM U-1016, Université Paris Descartes, et Assistance Publique-Hôpitaux de Paris, Service d'Hépatologie, Cochin Hospital, Paris, France
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Therapeutic vaccines in treating chronic hepatitis B: the end of the beginning or the beginning of the end? Med Microbiol Immunol 2014; 204:121-9. [DOI: 10.1007/s00430-014-0381-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Accepted: 09/15/2014] [Indexed: 12/13/2022]
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Abstract
Plasmid or non-viral gene therapy offers an alternative to classic viral gene delivery that negates the need for a biological vector. In this case, delivery is enhanced by a variety of approaches including lipid or polymer conjugation, particle-mediated delivery, hydrodynamic delivery, ultrasound or electroporation. Electroporation was originally used as a laboratory tool to deliver DNA to bacterial and mammalian cells in culture. Electrode development allowed this technique to be modified for in vivo use. After preclinical therapeutic studies, clinical delivery of cell impermeant chemotherapeutic agents progressed to clinical delivery of plasmid DNA. One huge benefit of this delivery technique is its malleability. The pulse protocol used for plasmid delivery can be fine-tuned to control the levels and duration of subsequent transgene expression. This fine-tuning allows transgene expression to be tailored to each therapeutic application. Effective and appropriate expression induces the desired clinical response that is a critical component for any gene therapy. This chapter focuses on clinical trials using in vivo electroporation or electrotransfer as a plasmid delivery method. The first clinical trial was initiated in 2004, and now more than fifty trials use electric fields for gene delivery. Safety and tolerability has been demonstrated by several groups, and early clinical efficacy results are promising in both cancer therapeutic and infectious disease vaccine applications.
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Affiliation(s)
- Richard Heller
- Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA, USA; School of Medical Diagnostics and Translational Sciences, College of Health Sciences, Old Dominion University, Norfolk, VA, USA
| | - Loree C Heller
- Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA, USA; School of Medical Diagnostics and Translational Sciences, College of Health Sciences, Old Dominion University, Norfolk, VA, USA
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Baltayiannis G, Karayiannis P. Treatment options beyond IFNα and NUCs for chronic HBV infection: expectations for tomorrow. J Viral Hepat 2014; 21:753-61. [PMID: 25271858 DOI: 10.1111/jvh.12307] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2014] [Accepted: 07/01/2014] [Indexed: 12/21/2022]
Abstract
Chronic hepatitis B virus (HBV) infection may progress to cirrhosis, hepatocellular carcinoma (HCC) and end-stage liver failure with time. Interruption of this process can only be achieved through effective antiviral treatment. This approach has so far involved the use of immunomodulators such as pegylated interferon alpha (Peg-IFNα) for a finite period of up to a year and nucleos-(t)ide analogues (NUCs) for treatment over much longer periods of time. The latter act by suppressing HBV replication at the level of DNA synthesis by inhibiting the viral reverse transcriptase/DNA polymerase and causing premature termination of DNA synthesis. The ideal treatment end point is loss of HBsAg in both HBeAg+ve and HBeAg-ve patients following monotherapy. This, however, is only achievable in a minority of patients. Secondary outcomes are durable HBeAg loss and seroconversion to anti-HBe, which occur in about 18-30% of HBeAg+ve patients depending on the antiviral used, and sustained suppression of HBV-DNA accompanied by biochemical normalization and histological improvement in non-HBeAg+ve seroconverting and HBeAg-ve patients. There is therefore a need for additional direct-acting antivirals (DAAs) targeting different stages of the life cycle of the virus, as well as immunotherapeutic approaches. Such developments may pave the way for their use either alone or more likely in combination in the fight against chronic HBV infection. Such drugs or approaches, which are currently undergoing preclinical or clinical testing, are the subject of this review.
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Affiliation(s)
- G Baltayiannis
- Medical School, University of Ioannina, Ioannina, Greece
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Abstract
Presently-available antiviral drugs may not be a satisfactory option for treatment of patients with chronic hepatitis B (CHB). In spite of presence of several antiviral drugs, sustained off-treatment clinical responses are not common in CHB patients treated with antiviral drugs. In addition, antiviral drug treatment may have limited effects on blocking the progression of HBV-related complications. However, substantial long-term risk of viral resistance and drug toxicity are related with maintenance antiviral therapy in CHB patients with presently-available antiviral agents. The infinite treatments with antiviral drugs for CHB patients are also costly and may be unbearable by most patients of developing and resource-constrained countries. In this situation, there is pressing need to develop new and innovative therapeutic approaches for patients with chronic hepatitis B virus (HBV) infection. Immune therapy has emerged as an alternate therapeutic approach for CHB patients because studies have shown that host immunity is either impaired or derailed or distorted or diminished in CHB patients compared to patients with acute resolved hepatitis B who contain the HBV replication and control liver damages. Both non antigen-specific immune modulators and HBV antigen-specific agents have been used in CHB patients during last three decades. However, similar to antiviral therapy, the ongoing regimens of immune therapeutic approaches have also been unable to show real promises for treating CHB patients. The concept of immune therapy for treating CHB patients seems to be rationale and scientific, however, concerns remain about suitable designs of immune therapy for CHB patients.
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Wen Y, Wang X, Wang B, Yuan Z. Vaccine therapies for chronic hepatitis B: can we go further? Front Med 2014; 8:17-23. [PMID: 24464422 DOI: 10.1007/s11684-014-0313-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2013] [Accepted: 11/06/2013] [Indexed: 12/16/2022]
Abstract
Chronic hepatitis B is a major health burden worldwide. In addition to the recent progress in antiviral treatment, therapeutic vaccination is a promising new strategy for the control of chronic hepatitis B. On the basis of the major specific and non-specific immune dysregulations and defects in chronic hepatitis B patients, this paper presents the peptide and protein-based, DNA-based, cell-based, and antigen-antibody-based therapeutic vaccines, which have undergone clinical trials. The advantages, disadvantages, and future perspectives for these therapeutic vaccines are discussed.
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Affiliation(s)
- Yumei Wen
- Key Laboratory Medical Molecular Virology of Ministry of Education/Ministry of Health, Shanghai Medical College, Fudan University, Shanghai, 200032, China,
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Abstract
Vaccines to prevent HIV remain desperately needed, but a number of challenges, including retroviral integration, establishment of anatomic reservoir sites, high sequence diversity, and heavy envelope glycosylation. have precluded development of a highly effective vaccine. DNA vaccines have been utilized as candidate HIV vaccines because of their ability to generate cellular and humoral immune responses, the lack of anti-vector response allowing for repeat administration, and their ability to prime the response to viral-vectored vaccines. Because the HIV epidemic has disproportionately affected the developing world, the favorable thermostability profile and relative ease and low cost of manufacture of DNA vaccines offer additional advantages. In vivo electroporation (EP) has been utilized to improve immune responses to DNA vaccines as candidate HIV-1 vaccines in standalone or prime-boost regimens with both proteins and viral-vectored vaccines in several animal models and, more recently, in human clinical trials. This chapter describes the preclinical and clinical development of candidate DNA vaccines for HIV-1 delivered by EP, including challenges to bringing this technology to the developing world.
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Affiliation(s)
- Sandhya Vasan
- Department of Retrovirology, US Army Medical Component, Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand
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Villarreal DO, Talbott KT, Choo DK, Shedlock DJ, Weiner DB. Synthetic DNA vaccine strategies against persistent viral infections. Expert Rev Vaccines 2013; 12:537-54. [PMID: 23659301 DOI: 10.1586/erv.13.33] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The human body has developed an elaborate defense system against microbial pathogens and foreign antigens. However, particular microbes have evolved sophisticated mechanisms to evade immune surveillance, allowing persistence within the human host. In an effort to combat such infections, intensive research has focused on the development of effective prophylactic and therapeutic countermeasures to suppress or clear persistent viral infections. To date, popular therapeutic strategies have included the use of live-attenuated microbes, viral vectors and dendritic-cell vaccines aiming to help suppress or clear infection. In recent years, improved DNA vaccines have now re-emerged as a promising candidate for therapeutic intervention due to the development of advanced optimization and delivery technologies. For instance, genetic optimization of synthetic plasmid constructs and their encoded antigens, in vivo electroporation-mediated vaccine delivery, as well as codelivery with molecular adjuvants have collectively enhanced both transgene expression and the elicitation of vaccine-induced immunity. In addition, the development of potent heterologous prime-boost regimens has also provided significant contributions to DNA vaccine immunogenicity. Herein, the authors will focus on these recent improvements to this synthetic platform in relation to their application in combating persistent virus infection.
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Affiliation(s)
- Daniel O Villarreal
- University of Pennsylvania, Perelman School of Medicine, Department of Pathology & Laboratory Medicine, Philadelphia, PA 19104, USA
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Wu B, Zou Q, Hu Y, Wang B. Interleukin-22 as a molecular adjuvant facilitates IL-17-producing CD8+ T cell responses against a HBV DNA vaccine in mice. Hum Vaccin Immunother 2013; 9:2133-41. [PMID: 23941891 PMCID: PMC3906397 DOI: 10.4161/hv.26047] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2013] [Revised: 07/19/2013] [Accepted: 08/05/2013] [Indexed: 01/06/2023] Open
Abstract
Interleukin-22 (IL-22) is mainly produced by activated Th1 cells, Th17 cells and NK cells and promotes anti-microbial defense, pro-inflammatory and tissue remodeling responses. However, its potential use as a vaccine adjuvant has not been tested. In this study, we tested if a DNA construct expressing IL-22 (pVAX-IL-22) could be used as a molecular adjuvant to enhance host immune responses induced by HBV DNA vaccination (pcD-S2). After immunizing mice with pcD-S2 combined with pVAX-IL-22, we didn't find enhancement of HBsAg-specific antibody responses in comparison to mice immunized with pcD-S2 alone. However, there was an enhancement of the level of IL-17 expression in antigen specific CD8(+) cytotoxic T lymphocytes (Tc17). By using CD8 T-cell knockout (KO) and IL-17 KO mice, Tc17 cells were found to be a dominant population driving cytotoxicity. Importantly, there was a correlation between pVAX-IL-22 enhancement of T lymphocytes and a reduction of HBsAg-positive hepatocytes in HBsAg transgenic mice. These results demonstrate that IL-22 might be used as an effective adjuvant to enhance cellular immune responses during HBsAg DNA vaccination since it can induce Tc17 cells to break tolerance in HBsAg transgenic mice.
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Affiliation(s)
- Bing Wu
- State Key Laboratory for Agro-Biotechnology; College of Biological Science; China Agricultural University; Beijing, P.R. China
| | - Qiang Zou
- State Key Laboratory for Agro-Biotechnology; College of Biological Science; China Agricultural University; Beijing, P.R. China
| | - Yanxin Hu
- College of Veterinary Medicine; China Agricultural University; Beijing, P.R. China
| | - Bin Wang
- State Key Laboratory for Agro-Biotechnology; College of Biological Science; China Agricultural University; Beijing, P.R. China
- Key Laboratory of Medical Molecular Virology of MOH and MOE; Fudan University Shanghai Medical College; Shanghai, P.R. China
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HBsAg, HBcAg, and combined HBsAg/HBcAg-based therapeutic vaccines in treating chronic hepatitis B virus infection. Hepatobiliary Pancreat Dis Int 2013; 12:363-9. [PMID: 23924493 DOI: 10.1016/s1499-3872(13)60057-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND As the host immunity is diminished in patients with chronic hepatitis B (CHB), different approaches have been used to up-regulate their immune responses to produce therapeutic effects. But, cytokines, growth factors and polyclonal immune modulators could not exhibit sufficient therapeutic effects in these patients. Immune therapy with HBV-related antigens (vaccine therapy) has been used in CHB patients. But there is a paucity of information about the design of HBV antigen-based immune therapy in these patients. DATA SOURCE Preclinical and clinical studies on immune therapy with HBsAg-based vaccine, HBcAg and combination of HBsAg/HBcAg-based vaccines have been discussed. RESULTS HBsAg-based prophylactic vaccine was used as an immune therapeutic agent in CHB patients; however, monotherapy with HBsAg-based immune therapy could not lead to sustained control of HBV replication and/or liver damages. HBsAg-based vaccine was used as a combination therapy with cytokines, growth factors, and antiviral drugs. HBsAg-based vaccine was also used for cell-based therapy. However, satisfactory therapeutic effects of HBsAg-based vaccine could not be documented in CHB patients. In the mean time, evidences have supported that HBcAg-specific immunity is endowed with antiviral and liver protecting capacities in CHB patients. Recent data concentrate on the clinical use of combined HBsAg- and HBcAg-based vaccines in CHB patients. CONCLUSION Antigen-based immune therapy with HBV-related antigens may be an alternative method for the treatment of CHB patients but proper designs of antigens, types of adjuvants, dose of vaccinations, and routes of administration need further analyses for the development of an effective regimen of immune therapy against HBV.
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Akbar SMF, Al-Mahtab M, Khan MSI. Non-antigen-specific and antigen-specific immune therapies for chronic hepatitis B: evidences from laboratory benches and patient's bedsides. Expert Opin Biol Ther 2013; 13:1063-74. [PMID: 23581572 DOI: 10.1517/14712598.2013.789016] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Due to unsatisfactory therapeutic efficacy and considerable side effects of antiviral drugs in patients with chronic hepatitis B (CHB), immunotherapy has emerged as an alternative approach. CHB immunotherapy may be categorized into two main types: i) non-antigen-specific immune therapy and ii) hepatitis B virus (HBV) antigen-specific immune therapy. Although different immune modulators have been used in CHB patients for the last two to three decades, the nature and design of ongoing regimens of immunotherapeutic approaches need considerable modifications. AREAS COVERED In this review, the authors have outlined the relevant immunotherapies for CHB patients that have been used for the last two to three decades. The mechanisms underlying the limited therapeutic efficacy of available therapeutic agents for CHB patients have been discussed to aid in the development of an effective therapeutic approach for these patients. EXPERT OPINION Circumstantial evidence indicates that a better regimen of immunotherapy may be developed using different HBV-related antigens or combinations of two or more HBV-related antigens, or combinations of HBV-related antigens and antiviral drugs. However, the capacity of 'inducible immunity' by immune modulators to cure or block progression of liver diseases in CHB patients needs to be addressed.
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Affiliation(s)
- Sheikh Mohammad Fazle Akbar
- Toshiba General Hospital, Department of Medical Sciences, Higashi Oi 6-3-22, Shinagawa, Tokyo 140-8522, Japan.
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Khawaja G, Buronfosse T, Jamard C, Abdul F, Guerret S, Zoulim F, Luxembourg A, Hannaman D, Evans CF, Hartmann D, Cova L. In vivo electroporation improves therapeutic potency of a DNA vaccine targeting hepadnaviral proteins. Virology 2012; 433:192-202. [PMID: 22921316 DOI: 10.1016/j.virol.2012.07.014] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2012] [Revised: 06/01/2012] [Accepted: 07/16/2012] [Indexed: 12/15/2022]
Abstract
This preclinical study investigated the therapeutic efficacy of electroporation (EP)-based delivery of plasmid DNA (pDNA) encoding viral proteins (envelope, core) and IFN-γ in the duck model of chronic hepatitis B virus (DHBV) infection. Importantly, only DNA EP-therapy resulted in a significant decrease in mean viremia titers and in intrahepatic covalently closed circular DNA (cccDNA) levels in chronic DHBV-carrier animals, compared with standard needle pDNA injection (SI). In addition, DNA EP-therapy stimulated in all virus-carriers a humoral response to DHBV preS protein, recognizing a broader range of major antigenic regions, including neutralizing epitopes, compared with SI. DNA EP-therapy led also to significant higher intrahepatic IFN-γ RNA levels in DHBV-carriers compared to other groups, in the absence of adverse effects. We provide the first evidence on DNA EP-therapy benefit in terms of hepadnaviral infection clearance and break of immune tolerance in virus-carriers, supporting its clinical application for chronic hepatitis B.
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MESH Headings
- Animals
- Antibodies, Viral/biosynthesis
- Antibodies, Viral/immunology
- Chronic Disease
- DNA, Circular/genetics
- DNA, Circular/immunology
- Disease Models, Animal
- Ducks
- Electroporation
- Epitopes
- Hepadnaviridae Infections/immunology
- Hepadnaviridae Infections/prevention & control
- Hepadnaviridae Infections/veterinary
- Hepadnaviridae Infections/virology
- Hepatitis B Vaccines/administration & dosage
- Hepatitis B Vaccines/immunology
- Hepatitis B Virus, Duck/immunology
- Hepatitis, Viral, Animal/immunology
- Hepatitis, Viral, Animal/prevention & control
- Hepatitis, Viral, Animal/virology
- Immune Tolerance
- Immunity, Humoral
- Interferon-gamma/biosynthesis
- Interferon-gamma/immunology
- Plasmids
- Vaccines, DNA/administration & dosage
- Vaccines, DNA/immunology
- Viral Core Proteins/genetics
- Viral Core Proteins/immunology
- Viral Envelope Proteins/genetics
- Viral Envelope Proteins/immunology
- Viremia/immunology
- Viremia/prevention & control
- Viremia/veterinary
- Viremia/virology
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