Protein-prime/modified vaccinia virus Ankara vector-boost vaccination overcomes tolerance in high-antigenemic HBV-transgenic mice

Backes, Simone; Jäger, Clemens; Dembek, Claudia J.; Kosinska, Anna D.; Bauer, Tanja; Stephan, A.; Dislers, Andris; Mutwiri, George; Busch, Dirk H.; Babiuk, Lorne A.; Gasteiger, Georg; Protzer, Ulrike

doi:10.1016/j.vaccine.2015.12.060

Cited by 51 publications

(71 citation statements)

References 39 publications

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“…In order to improve immunogenicity and efficacy of therapeutic vaccine candidates for chronic HBV infection, others have used a combination of approaches, such as adjuvants, addition of checkpoint inhibitors, and prime/boost regimens (7,9). Recent studies showed that an optimized, heterologous prime/boost strategy produced strong T and B responses to HBV in various preclinical models of CHB (32)(33)(34). A combination of an HBsAg/HBcAg protein prime with TLR9 agonists followed by a boost with non-replicating modified vaccinia Ankara viruses, optimized for higher level expression of the same antigens was able to overcome the high-level tolerance observed in HBV-transgenic mice (34).…”

Section: Discussionmentioning

confidence: 99%

Virus-like vesicles expressing multiple antigens for immunotherapy of chronic hepatitis B

Yarovinsky

Mason

Menon

et al. 2018

Preprint

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Infection with hepatitis B virus (HBV) can initiate chronic hepatitis and liver injury, eventually progressing to liver fibrosis or cancer and causing more than 600,000 deaths each year worldwide. Current treatments for chronic hepatitis B, relying on nucleoside antivirals and interferon, are inadequate and leave an unmet need for immunotherapeutic approaches. This report describes virus-like vesicles (VLV), a form of self-amplifying RNA replicons, which express multiple HBV antigens (polymerase, core, and middle surface) from a single vector (HBV-VLV). The HBV-VLV induces HBV-specific T cell responses to all three HBV antigens. Immunization of naive mice with the multiantigen HBV-VLV renders them resistant to acute challenge with HBV delivered by adeno-associated virus (AAV). Using a chronic model of HBV infection by AAV delivery of HBV, we demonstrate immunotherapeutic potential of the multiantigen HBV-VLV in combination with DNA booster immunization, as 40% of the HBV-VLV-treated mice showed a decline of the serum HBV surface antigen below the detection limit and marked reduction in liver HBV RNA accompanied by induction of HBsAg-specific CD8 T cells. These results warrant further evaluation of multiantigen HBV-VLV for immunotherapy of chronic hepatitis B.IMPORTANCEMore than 240 million people worldwide are chronically infected with hepatitis B virus. Current therapies are not sufficiently effective and are often beyond reach in the developing world. We describe a virus-like vesicle-based immunotherapeutic vaccine that expresses three major antigens of hepatitis B virus as a self-amplifying RNA replicon. By incorporating three HBV antigens in a single vaccine, we ensure broad T cell responses. We demonstrate that immunization with this vaccine protects mice from hepatitis B virus in a model of acute challenge. Importantly, treatment with this vaccine shows 40% efficacy in a mouse model of chronic hepatitis B. Thus, this study paves the way for evaluation of the multi-antigen virus-like vesicles as a tool for immunotherapy of chronic hepatitis B.

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Section: Discussionmentioning

confidence: 99%

Virus-like vesicles expressing multiple antigens for immunotherapy of chronic hepatitis B

Yarovinsky

Mason

Menon

et al. 2018

Preprint

View full text Add to dashboard Cite

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“…The HepG2.2.15 cell is an HBV-producing human hepatocellular carcinoma cell, which can be used to measure the effects of an immunotherapeutic approach for HBV infection [79]. The inhibition of HBV replication should also be proved in vivo: HBV transgenic mice are an animal model that can be used to assess the effects of HBV therapeutic vaccines [13]. However, the epitopes predicted in the present research are binding to human MHC molecules; thus, the HBV polymerase epitopes targeting MHC molecules of HBV transgenic mice must be predicted and a corresponding vaccine should be constructed.…”

Section: Discussionmentioning

confidence: 99%

“…High HBV antigen levels, especially HBsAg, contribute to specific T cell exhaustion and limit the immunological response to therapeutic vaccination [13]. Persistent exposure of antigens to the immune system is responsible for immune tolerance, which is the reason for the poor clinical responses of therapeutic vaccines constituted by HBsAg and HBcAg.…”

Section: Introductionmentioning

confidence: 99%

In Silico Analysis of Epitope-Based Vaccine Candidates against Hepatitis B Virus Polymerase Protein

Zheng

Lin

Wang

et al. 2017

Viruses

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Hepatitis B virus (HBV) infection has persisted as a major public health problem due to the lack of an effective treatment for those chronically infected. Therapeutic vaccination holds promise, and targeting HBV polymerase is pivotal for viral eradication. In this research, a computational approach was employed to predict suitable HBV polymerase targeting multi-peptides for vaccine candidate selection. We then performed in-depth computational analysis to evaluate the predicted epitopes’ immunogenicity, conservation, population coverage, and toxicity. Lastly, molecular docking and MHC-peptide complex stabilization assay were utilized to determine the binding energy and affinity of epitopes to the HLA-A0201 molecule. Criteria-based analysis provided four predicted epitopes, RVTGGVFLV, VSIPWTHKV, YMDDVVLGA and HLYSHPIIL. Assay results indicated the lowest binding energy and high affinity to the HLA-A0201 molecule for epitopes VSIPWTHKV and YMDDVVLGA and epitopes RVTGGVFLV and VSIPWTHKV, respectively. Regions 307 to 320 and 377 to 387 were considered to have the highest probability to be involved in B cell epitopes. The T cell and B cell epitopes identified in this study are promising targets for an epitope-focused, peptide-based HBV vaccine, and provide insight into HBV-induced immune response.

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“…Therapeutic vaccination using HBsAg was shown to induce the production of anti‐HBV antibodies in animal models, reducing the antigen levels and thus priming the T‐cell response. However, it was only effective in mice with low viral titres …”

Section: Immune Regulation and Hbsagmentioning

confidence: 99%

“…However, it was only effective in mice with low viral titres. 57 Much has been accomplish in understanding HBV-specific adaptive immunity and its connection with HBsAg. However, innate immune responses in acute or chronic HBV infection remain obscure.…”

Section: Covalently Closed Circular Dna Epigeneticsmentioning

confidence: 99%

Biological basis for functional cure of chronic hepatitis B

Martínez

Testoni

Zoulim

2019

Journal of Viral Hepatitis

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Summary Chronic hepatitis B (CHB) infection affects over 250 millon people worldwide and 800000 are expected to die yearly due to the development of hepatocellular carcinoma (HCC). Current antiviral therapies include nucleoside analogs (NAs) that target the viral retrotranscriptase inhibiting de novo viral production. Pegylated interferon (Peg‐IFN) is also effective in reducing the viral DNA load in serum. However, both treatments remain limited to control the infection, aiming for viral suppression and improving the quality of life of the infected patients. Complete cure is not possible due to the presence of the stable DNA intermediate covalently closed circular DNA (cccDNA). Attempts to achieve a functional cure are thus ongoing and novel targets and molecules, together with different combination therapies are currently in the pipeline for early clinical trials. In this review we discuss novel treatments both targeting directly and indirectly cccDNA. As we gain knowledge in the Hepatitis B virus (HBV) transcriptional control, and newer technologies emerge that could potentially allow the destruction of cccDNA, exciting new possibilities for curative therapies are discussed.

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Protein-prime/modified vaccinia virus Ankara vector-boost vaccination overcomes tolerance in high-antigenemic HBV-transgenic mice

Cited by 51 publications

References 39 publications

Virus-like vesicles expressing multiple antigens for immunotherapy of chronic hepatitis B

Virus-like vesicles expressing multiple antigens for immunotherapy of chronic hepatitis B

In Silico Analysis of Epitope-Based Vaccine Candidates against Hepatitis B Virus Polymerase Protein

Biological basis for functional cure of chronic hepatitis B

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