Efficacy and limitations of a specific immunotherapy in chronic hepatitis B

Pol, Stanislas; Nalpas, Bertrand; Driss, Françoise; Michel, Marie‐Louise; Tiollais, Pierre; Denis, Jacques; Bréchot, Christian

doi:10.1016/s0168-8278(01)00028-9

Cited by 169 publications

(119 citation statements)

References 19 publications

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“…Previous animal studies revealed that immunization with a hepatitis B surface Ag (HBsAg) vaccine resulted in decreased HBV titers and the generation of anti-HBs in HBV-transgenic (tg) mice (8,9). However, clinical studies using these strategies revealed poor therapeutic effects in CHB patients in an immunotolerant phase (10,11). The divergence in therapeutic outcome may be due, in part, to differences in the type of tolerance induced between HBV-tg mice and CHB patients (12,13).…”

mentioning

confidence: 99%

IL-12–Based Vaccination Therapy Reverses Liver-Induced Systemic Tolerance in a Mouse Model of Hepatitis B Virus Carrier

Zeng

Kong

et al. 2013

The Journal of Immunology

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Liver-induced systemic immune tolerance that occurs during chronic hepadnavirus infection is the biggest obstacle for effective viral clearance. Immunotherapeutic reversal of this tolerance is a promising strategy in the clinic but remains to be explored. In this study, using a hepatitis B virus (HBV)-carrier mouse model, we report that IL-12–based vaccination therapy can efficiently reverse systemic tolerance toward HBV. HBV-carrier mice lost responsiveness to hepatitis B surface Ag (HBsAg) vaccination, and IL-12 alone could not reverse this liver-induced immune tolerance. However, after IL-12–based vaccination therapy, the majority of treated mice became HBsAg− in serum; hepatitis B core Ag was also undetectable in hepatocytes. HBV clearance was dependent on HBsAg vaccine-induced anti-HBV immunity. Further results showed that IL-12–based vaccination therapy strongly enhanced hepatic HBV-specific CD8+ T cell responses, including proliferation and IFN-γ secretion. Systemic HBV-specific CD4+ T cell responses were also restored in HBV-carrier mice, leading to the arousal of HBsAg-specific follicular Th–germinal center B cell responses and anti–hepatitis B surface Ag Ab production. Recovery of HBsAg-specific responses also correlated with both reduced CD4+Foxp3+ regulatory T cell frequency and an enhanced capacity of effector T cells to overcome inhibition by regulatory T cells. In conclusion, IL-12–based vaccination therapy may reverse liver-induced immune tolerance toward HBV by restoring systemic HBV-specific CD4+ T cell responses, eliciting robust hepatic HBV-specific CD8+ T cell responses, and facilitating the generation of HBsAg-specific humoral immunity; thus, this therapy may become a viable approach to treating patients with chronic hepatitis B.

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confidence: 99%

IL-12–Based Vaccination Therapy Reverses Liver-Induced Systemic Tolerance in a Mouse Model of Hepatitis B Virus Carrier

Zeng

Kong

et al. 2013

The Journal of Immunology

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“…Although many experimental, therapeutic HBV vaccines have been developed (17)(18)(19)(20)(21), these have failed so far to reproducibly clear chronic HBV infection. The major problem for therapeutic HBV vaccines is the delivery of Ags into the tolerogen milieu of chronically infected patients.…”

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confidence: 99%

Elimination of Immunodominant Epitopes from Multispecific DNA-Based Vaccines Allows Induction of CD8 T Cells That Have a Striking Antiviral Potential

Riedl

Wieland

Lamberth

et al. 2009

The Journal of Immunology

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Immunodominance limits the TCR diversity of specific antiviral CD8 T cell responses elicited by vaccination or infection. To prime multispecific T cell responses, we constructed DNA vaccines that coexpress chimeric, multidomain Ags (with CD8 T cell-defined epitopes of the hepatitis B virus (HBV) surface (S), core (C), and polymerase (Pol) proteins and/or the OVA Ag as stress protein-capturing fusion proteins. Priming of mono- or multispecific, HLA-A*0201- or Kb-restricted CD8 T cell responses by these DNA vaccines differed. Kb/OVA257–264- and Kb/S190–197-specific CD8 T cell responses did not allow priming of a Kb/C93–100-specific CD8 T cell response in mice immunized with multidomain vaccines. Tolerance to the S- Ag in transgenic Alb/HBs mice (that express large amounts of transgene-encoded S- Ag in the liver) facilitated priming of subdominant, Kb/C93–100-specific CD8 T cell immunity by multidomain Ags. The “weak” (i.e., easily suppressed) Kb/C93–100-specific CD8 T cell response was efficiently elicited by a HBV core Ag-encoding vector in 1.4HBV-Smut tg mice (that harbor a replicating HBV genome that produces HBV surface, core, and precore Ag in the liver). Kb/C93–100-specific CD8 T cells accumulated in the liver of vaccinated 1.4HBV-Smut transgenic mice where they suppressed HBV replication. Subdominant epitopes in vaccines can hence prime specific CD8 T cell immunity in a tolerogenic milieu that delivers specific antiviral effects to HBV-expressing hepatocytes.

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“…Currently, the vaccines that are being evaluated in CHB patients and experimental animals include recombinant proteins, specific peptides, DNA vaccine or DNA delivered by viral vectors. Clinical trials using vaccines containing HBcAg and HBsAg peptides showed a reduction of HBV replication that that were not accompanied by HBsAg clearance [95,96] . However, a recent vaccine formulation that comprised HBsAg and HBcAg particles and was delivered together with a saponin based ISCOMATRIX adjuvant in transgenic mice induced the activation HBsAg-and HBcAg-specific CTLs and the high production of their antibody [97] .…”

Section: Therapeutic Vaccinationmentioning

confidence: 99%

Current and future antiviral drug therapies of hepatitis B chronic infection

Koumbi¹

2015

WJH

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Despite significant improvement in the management of chronic hepatitis B virus (HBV) it remains a public health problem, affecting more than 350 million people worldwide. The natural course of the infection is dynamic and involves a complex interplay between the virus and the host's immune system. Currently the approved therapeutic regimens include pegylated-interferon (IFN)-α and monotherapy with five nucleos(t)ide analogues (NAs). Both antiviral treatments are not capable to eliminate the virus and do not establish longterm control of infection after treatment withdrawal. IFN therapy is of finite duration and associates with low response rates, liver decompensating and numerous side effects. NAs are well-tolerated therapies but have a high risk of drug resistance development that limits their prolonged use. The imperative for the development of new approaches for the treatment of chronic HBV infection is a challenging issue that cannot be over-sided. Research efforts are focusing on the identification and evaluation of various viral replication inhibitors that target viral replication and a number of immunomodulators that aim to restore the HBV specific immune hyporesponsiveness without inducing liver damage. This review brings together our current knowledge on the available treatment and discusses potential therapeutic approaches in the battle against chronic HBV infection. Core tip: Despite significant improvement in the management of chronic hepatitis B virus (HBV) it remains a public health problem. Current therapeutic regimens include pegylated-interferon (IFN)-α and nucleos(t)ide analogues (NAs). Both treatments do not eradicate the virus and have numerous limitations. IFN therapy is of finite duration and has low response rates while longterm NA therapies have a high risk of drug resistance. The development of new therapeutic approaches is imperative. This review brings together current treatments and the ongoing research efforts on evaluating potential therapeutic strategies that target the suppression of HBV replication the restoration of the weak immune responses against HBV.

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Efficacy and limitations of a specific immunotherapy in chronic hepatitis B

Cited by 169 publications

References 19 publications

IL-12–Based Vaccination Therapy Reverses Liver-Induced Systemic Tolerance in a Mouse Model of Hepatitis B Virus Carrier

IL-12–Based Vaccination Therapy Reverses Liver-Induced Systemic Tolerance in a Mouse Model of Hepatitis B Virus Carrier

Elimination of Immunodominant Epitopes from Multispecific DNA-Based Vaccines Allows Induction of CD8 T Cells That Have a Striking Antiviral Potential

Current and future antiviral drug therapies of hepatitis B chronic infection

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