Overcoming immune tolerance in chronic hepatitis B by therapeutic vaccination

Dembek, Claudia J.; Protzer, Ulrike; Roggendorf, Michael

doi:10.1016/j.coviro.2018.04.003

Cited by 57 publications

(45 citation statements)

References 52 publications

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“…This control seems to be immune‐mediated as a result of reduction in HBsAg. It has been shown that large amounts of HBsAg have immunosuppressive effects in HBV infection and its clearance in the circulation establishes a more permissive immunological environment where functional control can be restored. Recent results indicate that REP 2139 exposure has no direct immunostimulatory properties .…”

Section: Discussionmentioning

confidence: 99%

Variants of hepatitis B virus surface antigen observed during therapy with nucleic acid polymer REP 2139‐Ca have no influence on treatment outcome and its detection by diagnostic assays

Mijočević

Karimzadeh

Seebach

et al. 2018

Journal of Viral Hepatitis

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Summary The treatment of patients suffering from HBeAg‐positive chronic hepatitis B with REP 2139‐Ca resulted in potent reductions in HBsAg and HBV DNA, seroconversion to anti‐HBs and the establishment of functional control of infection. In this cohort of 12 patients, we investigated whether differences between HBsAg sequences might explain the lack of response to REP 2139‐Ca observed in 3 of 12 patients. We also assessed if the reduction or complete loss of HBsAg in serum observed during therapy were caused by mutations in the “a” determinant preventing the detection of HBsAg by standard diagnostic assays. The complete pre‐S/S open reading frame (ORF) was sequenced and pre‐S1, pre‐S2 and S amino acid sequences were analysed. We found no major differences between pre‐S1, pre‐S2 and S sequences in responders and nonresponders correlated with low reduction in HBsAg. In addition, we found no mutations in the “a” determinant that would significantly affect the reactivity of HBsAg in diagnostic assays. These results demonstrate that the amino acid sequence of complete pre‐S/S ORF has no direct influence on response to REP 2139‐Ca therapy.

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Section: Discussionmentioning

confidence: 99%

Variants of hepatitis B virus surface antigen observed during therapy with nucleic acid polymer REP 2139‐Ca have no influence on treatment outcome and its detection by diagnostic assays

Mijočević

Karimzadeh

Seebach

et al. 2018

Journal of Viral Hepatitis

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“…In general, high HBV DNA, HBsAg, and HBeAg levels contribute to maintain HBV-specific immune tolerance in chronically HBV-infected individuals. Reduction of both circulating and intrahepatic HBV virions and proteins is a prerequisite for (re-)establishing efficient HBV-specific T-cell responses (45)(46)(47)(48). The first evidence that HBV clearance can be achieved by adoptive transfer of bone marrow from anti-HBs-positive donors (49) provides a certain way to cure HBV infection through immune modulation.…”

Section: Immune Pathogenesis Of Persistent Hbv Infectionmentioning

confidence: 99%

Advances in Targeting the Innate and Adaptive Immune Systems to Cure Chronic Hepatitis B Virus Infection

Zhao

Chen

2020

Front. Immunol.

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Functional cure" is being pursued as the ultimate endpoint of antiviral treatment in chronic hepatitis B (CHB), which is characterized by loss of HBsAg whether or not anti-HBs antibodies are present. "Functional cure" can be achieved in <10% of CHB patients with currently available therapeutic agents. The dysfunction of specific immune responses to hepatitis B virus (HBV) is considered the major cause of persistent HBV infection. Thus, modulating the host immune system to strengthen specific cellular immune reactions might help eliminate HBV. Strategies are needed to restore/enhance innate immunity and induce HBV-specific adaptive immune responses in a coordinated way. Immune and resident cells express pattern recognition receptors like TLRs and RIG I/MDA5, which play important roles in the induction of innate immunity through sensing of pathogen-associated molecular patterns (PAMPs) and bridging to adaptive immunity for pathogen-specific immune control. TLR/RIG I agonists activate innate immune responses and suppress HBV replication in vitro and in vivo, and are being investigated in clinical trials. On the other hand, HBV-specific immune responses could be induced by therapeutic vaccines, including protein (HBsAg/preS and HBcAg), DNA, and viral vector-based vaccines. More than 50 clinical trials have been performed to assess therapeutic vaccines in CHB treatment, some of which display potential effects. Most recently, using genetic editing technology to generate CAR-T or TCR-T, HBV-specific T cells have been produced to efficiently clear HBV. This review summarizes the progress in basic and clinical research investigating immunomodulatory strategies for curing chronic HBV infection, and critically discusses the rather disappointing results of current clinical trials and future strategies.

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“…The pathogenesis of CHB is a consequence of persistent HBV replication, expression of various viral antigens and complex defects in acquired and innate host immune responses [ 21 , 22 ]. HB-sAg, which can be present with as high as 10 14 particles/mL in HBV carriers or patients, has been shown to inhibit host immune responses by multiple mechanisms including mediating T cell clonal depletion, exhaustion of HBV-specific T [23][24][25] . Thus, clearance of HBsAg is considered a crucial step for restoration of host immunity and achieving functional cure of CHB.…”

Section: Discussionmentioning

confidence: 99%

“…The "sandwich" treatment regime was administered three times as indicated and mice were sacrificed three weeks after the third treatment ( n = 5/group) (a). The mice serum was collected at day 0, 2, 5,9,12,15,19,23,28,34,41,55 tably, after the three treatments, a significant reduction of HBeAg levels was only observed in the sandwich group compared to the control TDF group ( p = 0.01; Fig. 4 c).…”

Section: Combination Therapy With G12 Antibody Tdf and Hbsag-hbsab Imentioning

confidence: 95%

Evaluation of antiviral - passive - active immunization (“sandwich”) therapeutic strategy for functional cure of chronic hepatitis B in mice

Shi

Wang

et al. 2019

eBioMedicine

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a b s t r a c tBackground: Chronic Hepatitis B (CHB) remains a major problem for global public health. Viral persistence and immune defects are the two major reasons for CHB, and it was hypothesized that based on a transient clearance of serum viral DNA and HBsAg "window stage", active immunization against hepatitis B virus (HBV) might initiate effective host immune responses versus HBV to achieve functional cure of CHB. Methods: Two experimental mouse models that mice hydrodynamic injected HBV DNA or infected with recombinant AAV/HBV were used. The "sandwich" therapeutic effect by using a potent human anti-HBsAg neutralizing monoclonal antibody (G12) in combination with antiviral drug tenofovir disoproxil fumarate (TDF), followed by active immunization with HBsAg-HBsAb (mYIC) was evaluated. Findings: A single G12 injection rapidly cleared serum HBsAg in HDI-HBV carrier mice, with a synergistic effect in decreasing viral DNA load when TDF was given orally. When both serum viral DNA and HBsAg load became low or undetectable, mYIC was administered. A more effective clearance of viral DNA and HBsAg was observed and serum HBsAb was developed only in these "sandwich"-treated mice. Efficient intrahepatic anti-HBV immune responses were also observed in these mice, including the formation of aggregates of myeloid cells with CD8 + T cells and increased TNF-α, granzyme B production. Interpretation:The "sandwich" combination therapy not only efficiently decreased HBsAg and HBV DNA levels but also induced effective cellular and humoral immunity, which may result in functional cure of CHB. Research in context section Evidence before this studyPersistence of HBV cccDNA and various host immune defects were shown as the two main obstacles for HBV clearance. Blocking a single target will not be sufficient to achieve functional cure of CHB. A very small percentage of CHB patients could attain "functional cure" by antiviral treatment fol- * Corresponding authors. .cn (Z. Yuan). lowed by interferon therapy. Therapeutic vaccination for CHB showed substantial efficacy. A humanized HBsAb G12 could efficiently block HBV infection and decrease HBsAg level in mice model. Added value of this studyThis research showed that when both serum viral DNA and HB-sAg load became low or undetectable by antiviral and HBsAb treatment, therapeutic vaccine (mYIC) add on induced effective, host humoral and intrahepatic cellular anti-HBV immune responses, with more rapid and efficient clearance of HBV and HBsAg.

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Overcoming immune tolerance in chronic hepatitis B by therapeutic vaccination

Cited by 57 publications

References 52 publications

Variants of hepatitis B virus surface antigen observed during therapy with nucleic acid polymer REP 2139‐Ca have no influence on treatment outcome and its detection by diagnostic assays

Variants of hepatitis B virus surface antigen observed during therapy with nucleic acid polymer REP 2139‐Ca have no influence on treatment outcome and its detection by diagnostic assays

Advances in Targeting the Innate and Adaptive Immune Systems to Cure Chronic Hepatitis B Virus Infection

Evaluation of antiviral - passive - active immunization (“sandwich”) therapeutic strategy for functional cure of chronic hepatitis B in mice

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