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Background & Aims: Mechanisms behind the impaired response of antigen-specific B cells to therapeutic vaccination in chronic hepatitis B virus (HBV) infection remain unclear. The development of vaccines or strategies to overcome this obstacle is vital for advancing the management of chronic hepatitis B., Methods: A mouse model, denominated as E6F6-B, was engineered to feature a knock-in of a B-cell receptor (BCR) that specifically recognizes HBsAg. This model served as a valuable tool for investigating the temporal and spatial dynamics of humoral responses following therapeutic vaccination under continuous antigen exposure. Using a suite of immunological techniques, we elucidated the differentiation trajectory of HBsAg-specific B cells post-therapeutic vaccination in HBV carrier mice., Results: Utilizing the E6F6-B transfer model, we observed a marked decline in antibody-secreting cells 2 weeks after vaccination. A dysfunctional and atypical pre-plasma cell population (BLIMP-1 + IRF4 + CD40 - CD138 - BCMA - ) emerged, manifested by sustained BCR signaling. By deploying an antibody to purge persistent HBsAg, we effectively prompted the therapeutic vaccine to provoke conventional plasma cell differentiation. This resulted in an enhanced anti-HBs antibody response and facilitated HBsAg clearance., Conclusions: Sustained high levels of HBsAg limit the ability of therapeutic hepatitis B vaccines to induce the canonical plasma cell differentiation necessary for anti-HBs antibody production. Employing a strategy combining antibodies with vaccines can surmount this altered humoral response associated with atypical pre-plasma cells, leading to improved therapeutic efficacy in HBV carrier mice., Impact and Implications: Therapeutic vaccines aimed at combatting HBV encounter suboptimal humoral responses in clinical settings, and the mechanisms impeding their effectiveness have remained obscure. Our research, utilizing the innovative E6F6-B mouse transfer model, reveals that the persistence of HBsAg can lead to the emergence of an atypical pre-plasma cell population, which proves to be relevant to the potency of therapeutic HBV vaccines. Targeting the aberrant differentiation process of these atypical pre-plasma cells stands out as a critical strategy to amplify the humoral response elicited by HBV therapeutic vaccines in carrier mouse models. This discovery suggests a compelling avenue for further study in the context of human chronic hepatitis B. Encouragingly, our findings indicate that synergistic therapy combining HBV-specific antibodies with vaccines offers a promising approach that could significantly advance the pursuit of a functional cure for HBV., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Immunotherapy for chronic hepatitis B virus (HBV) infection has not yet demonstrated sufficient efficacy. We developed a non-integrative lentiviral-vectored therapeutic vaccine for chronic hepatitis B and tested its antiviral effects in HBV-persistent mice and two inactive HBsAg carriers., Methods: Lentiviral vectors (LVs) encoding the core, preS1, or large HBsAg (LHBs) proteins of HBV were evaluated for immunogenicity in HBV-naïve mice and therapeutic efficacy in a murine model of chronic HBV infection. In addition, two inactive HBsAg carriers each received two doses of 5×10 7 transduction units (TU) or 1×10 8 TU of lentiviral-vectored LHBs (LV-LHBs), respectively. The endpoints were safety, LHBs-specific T-cell responses, and serum HBsAg levels during a 24-week follow-up., Results: In the mouse models, LV-LHBs was the most promising in eliciting robust antigen-specific T cells and in reducing the levels of serum HBsAg and viral load. By the end of the 34-week observation period, six out of ten (60%) HBV-persistent mice vaccinated with LV-LHBs achieved serum HBsAg loss and significant depletion of HBV-positive hepatocytes in the liver. In the two inactive HBsAg carriers, vaccination with LV-LHBs induced a considerable increase in the number of peripheral LHBs-specific T cells in one patient, and a weak but detectable response in the other, accompanied by a sustained reduction of HBsAg (-0.31 log 10 IU/ml and -0.46 log 10 IU/ml, respectively) from baseline to nadir., Conclusions: A lentiviral-vectored therapeutic vaccine for chronic HBV infection demonstrated the potential to improve HBV-specific T-cell responses and deplete HBV-positive hepatocytes, leading to a sustained loss or reduction of serum HBsAg., Impact and Implications: Chronic HBV infection is characterized by an extremely low number and profound hypo-responsiveness of HBV-specific T cells. Therapeutic vaccines are designed to improve HBV-specific T-cell responses. We show that immunization with a lentiviral-vectored therapeutic HBV vaccine was able to expand HBV-specific T cells in vivo, leading to reductions of HBV-positive hepatocytes and serum HBsAg., (Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: More than 292 million people are living with hepatitis B worldwide and are at risk of death from cirrhosis and liver cancer. The World Health Organization (WHO) has set global targets for the elimination of viral hepatitis as a public health threat by 2030. However, current levels of global investment in viral hepatitis elimination programmes are insufficient to achieve these goals., Methods: To catalyse political commitment and to encourage domestic and international financing, we used published modelling data and key stakeholder interviews to develop an investment framework to demonstrate the return on investment for viral hepatitis elimination., Results: The framework utilises a public health approach to identify evidence-based national activities that reduce viral hepatitis-related morbidity and mortality, as well as international activities and critical enablers that allow countries to achieve maximum impact on health outcomes from their investments - in the context of the WHO's 2030 viral elimination targets., Conclusion: Focusing on hepatitis B, this health policy paper employs the investment framework to estimate the substantial economic benefits of investing in the elimination of hepatitis B and demonstrates how such investments could be cost saving by 2030., Lay Summary: Hepatitis B infection is a major cause of death from liver disease and liver cancer globally. To reduce deaths from hepatitis B infection, we need more people to be tested and treated for hepatitis B. In this paper, we outline a framework of activities to reduce hepatitis B-related deaths and discuss ways in which governments could pay for them., Competing Interests: Conflict of interest JH has received investigator-initiated funding and speaker fees from Gilead Sciences. AHS reports grants to her institution from ViiV Healthcare. ETH is the former director of the Medicines Patent Pool. NS has received investigator-initiated research funding from Gilead Sciences. AP has received investigator-initiated research funding from Gilead Sciences, MSD and AbbVie, and honoraria from Gilead Sciences. JVL reports grants and personal fees from AbbVie, Gilead Sciences and MSD, personal fees from CEPHEID and Janssen, all outside the submitted work. MS is principal investigator in an investigator-initiated trial sponsored by Gilead Sciences (received no PI fees, trial closed April 17th 2019) and reports an educational grant to travel to EASL 2019 (Gilead Sciences). SJH received honoraria from Gilead, unrelated to submitted work. AJT is advisory board member for Gilead Sciences, Arbutus Biopharma, AbbVie, BMS, Bayer, Roche, Ipsen, Eisai, Immunocore Ltd, Clear B Therapeutics, ViR therapeutics and has received speaker fees and investigator-initiated funding from Gilead Sciences, AbbVie and BMS. MH's Institute receives investigator initiated research funding from Gilead Sciences, Abbvie and BMS. JH received the Gilead Sciences Australia fellowship (2017). DW, CK, RA, RBL, MB, LA, AG, SH, RH, WL, RBM, SO, RP, MS, CWS, MT, ESS have nothing to declare. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

The majority of persons currently treated for chronic hepatitis B require long-term or lifelong therapy. New inhibitors of hepatitis B virus entry, replication, assembly, or secretion and immune modulatory therapies are in development. The introduction of these novel compounds for chronic hepatitis B necessitates a standardised appraisal of the efficacy and safety of these treatments and definitions of new or additional endpoints to inform clinical trials. To move the field forward and to expedite the pathway from discovery to regulatory approval, a workshop with key stakeholders was held in September 2016 to develop a consensus on treatment endpoints to guide the design of clinical trials aimed at hepatitis B cure. The consensus reached was that a complete sterilising cure, i.e., viral eradication from the host, is unlikely to be feasible. Instead, a functional cure characterised by sustained loss of hepatitis B surface antigen with or without hepatitis B surface antibody seroconversion, which is associated with improved clinical outcomes, in a higher proportion of patients than is currently achieved with existing treatments is a feasible goal. Development of standardised assays for novel biomarkers toward better defining hepatitis B virus cure should occur in parallel with development of novel antiviral and immune modulatory therapies such that approval of new treatments can be linked to the approval of new diagnostic assays used to measure efficacy or to predict response. Combination of antiviral and immune modulatory therapies will likely be needed to achieve functional hepatitis B virus cure. Limited proof-of-concept monotherapy studies to evaluate safety and antiviral activity should be conducted prior to proceeding to combination therapies. The safety of any new curative therapies will be paramount given the excellent safety of currently approved nucleos(t)ide analogues., (Copyright © 2017 American Association for the Study of Liver Diseases, European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Hepatitis B virus (HBV) infection poses a global public health threat. HBV vaccination has proven highly effective in preventing the infection; however, its long-term impact on the general population has not been addressed. We conducted analysis to determine the total and changing burden of chronic HBV infection and evaluate the serological status between vaccinated and unvaccinated in Taiwan., Methods: Participants in "The Taiwanese Survey on Prevalence of Hyperglycemia, Hyperlipidemia and Hypertension" in 2002 (n=6602), and 4088 with follow-up survey in 2007 were included. HBsAg (including titers), anti-HBs, anti-HBc, HBeAg, anti-HBe, HBV genotypes and viral loads were assayed. Prevalence and evolving patterns of these seromarkers was compared between vaccinated and unvaccinated cohorts and predictors of persistent HBsAg positivity and negativity were examined., Results: The overall prevalence of chronic HBV infection was 13·7% (95% CI, 12.9% to 14.5%) and about two thirds had past exposure (anti-HBc: 68·46%) in 2002. The vaccinated cohort tended to have lower prevalence of HBsAg and anti-HBc, and a higher proportion of anti-HBs and HBeAg positivity, genotype C and high viral load. The majority (85·42%) were consistently HBsAg negative while 12·65% were consistently positive, and 8·98% achieved seroclearance in a five-year period. In the vaccinated cohort, no subjects had acquired new exposure and became HBsAg positive, and only one (0.54%) cleared HBsAg, demonstrating the durability of vaccination through teenage and young adulthood., Conclusions: This comprehensive, population-representative-survey shows that 20 years after universal vaccination, the backlog still composed a substantial burden of chronic HBV infections in Taiwan., (Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

The treatment of chronic hepatitis B virus (HBV) infection has greatly improved over the last 10 years, but alternative treatments are still needed. Therapeutic vaccination is a promising new strategy for controlling chronic infection. However, this approach has not been as successful as initially anticipated for chronic hepatitis B. General impairment of the immune responses generated during persistent HBV infection, with exhausted T cells not responding correctly to therapeutic vaccination, is probably responsible for the poor clinical responses observed to date. Intensive research efforts are now focusing on increasing the efficacy of therapeutic vaccination without causing liver disease. Here we describe new approaches to use with therapeutic vaccination, in order to overcome the inhibitory mechanisms impairing immune responses. We also describe innovative strategies for generating functional immune responses and inducing sustained control of this persistent infection., (Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Hepatitis B virus infection is a global health problem. Worldwide, about 360 million people are chronically infected with the virus. They continue to spread the virus to others and are themselves at risk of chronic liver diseases and hepatocellular carcinoma. The infection can now be treated by antivirals or interferons and the transmission route can be interrupted. Nevertheless, the most effective means is to immunize all susceptible individuals, especially young children, with safe and efficacious vaccines. The combined efforts of vaccination, effective treatment and interruption of transmission make elimination of the infection plausible and may eventually lead to eradication of the virus. Because hepatitis B vaccination has a key role in the control of hepatitis B, properties of this vaccine, its effectiveness in pre-exposure and post-exposure settings, duration of protection after vaccination and the need of booster doses are discussed. Mass hepatitis B vaccination in children decreases the carriage of the virus, and the diseases associated with acute and chronic infection, including hepatocellular carcinoma. Challenges that need to be solved to expand mass vaccination, and the strategies towards elimination and eventual eradication of hepatitis B in the world are also discussed.

Background/aims: Antigen-pulsed dendritic cells (DCs) are now used for treatment of patients with cancers, however, the efficacy of these DCs has never been evaluated for prophylactic purposes. The aim of this study was (1) to prepare hepatitis B surface antigen (HBsAg)-pulsed human blood DCs, (2) to assess immunogenicity of HBsAg-pulsed DCs in vitro and (3) to evaluate the efficacy of HBsAg-pulsed DCs in hepatitis B (HB) vaccine nonresponders., Methods: Human peripheral blood DCs were cultured with HBsAg to prepare HBsAg-pulsed DCs. The expression of immunogenic epitopes of HBsAg on HBsAg-pulsed DCs was assessed in vitro. Finally, HBsAg-pulsed DCs were administered, intradermally to six HB vaccine nonresponders and the levels of antibody to HBsAg (anti-HBs) in the sera were assessed., Results: HB vaccine nonresponders did not exhibit features of immediate, early or delayed adverse reactions due to administration of HBsAg-pulsed DCs. Anti-HBs were detected in the sera of all HB vaccine nonresponders within 28 days after administration of HBsAg-pulsed DCs., Conclusions: This study opens a new field of application of antigen-pulsed DCs for prophylactic purposes when adequate levels of protective antibody cannot be induced by traditional vaccination approaches.

Background/aims: In this revaccination study, we explored the determinants of response to booster hepatitis B (HB) vaccination in anti-HBs-seronegative adolescents who had received primary HB vaccination 15-18 years before., Results: After controlling for prebooster anti-HBs levels, cigarette smoking, betel-quid chewing, alcohol drinking, and indigenous ethnicity were significantly associated with elevated risks of non-response to booster HB vaccination. The adjusted odds ratios (aORs) were 3.21 (CI: 1.33-7.84), 8.78 (CI: 2.03-37.94), 2.64 (CI: 1.15-6.02), and 2.46 (CI: 1.28-4.72), respectively. Among adolescents with undetectable prebooster anti-HBs titers, only indigenous ethnicity significantly associated with elevated risk, with an adjusted OR of 2.57 (CI: 1.20-5.54), of non-response to booster HB vaccination. On the contrary, the influences of cigarette smoking, betel-quid chewing, and alcohol drinking were restricted to adolescents with prebooster anti-HBs titers of 0.1-9.9mIU/mL. The corresponding multivariate-adjusted ORs were 5.70, 17.41, and 3.72, respectively. Adolescents who smoked cigarettes and chewed betel-quid were at highest risk of non-response (aOR, 25.3; CI: 2.97-215.7)., Conclusions: A booster dose of HB vaccine may be insufficient to induce immunological response in healthy adolescents who had undetectable prebooster anti-HBs titers or who were of Malay-Polynesian ethnicity. Responses to booster vaccination are probably modified by recent cigarette smoking and/or betel-quid chewing.

Background/aims: Lamivudine prophylaxis against hepatitis B virus (HBV) reinfection after liver transplantation is associated with recurrence due to escape mutants., Methods: Fifty-two patients on lamivudine prophylaxis at a median of 412 days (median, 370-2040 days) after transplantation for chronic HBV-related liver disease received two courses of an accelerated schedule of double-dose recombinant HBV vaccine. Before vaccination, all patients were seronegative for HBsAg, anti-HBs and HBV DNA (by qPCR). Three intramuscular doses of vaccine (40 microg each) were administered monthly and another identical course was repeated after 3 months. Lamivudine (100mg/day) was continued throughout the study., Results: After the first course, two patients developed a weak response (anti-HBs titre of 12 mIU/mL) that disappeared rapidly. One early responder developed anti-HBs (27 mIU/mL) again after the second course but the other did not. Two other patients developed response (anti-HBs titre of 17 and 103 mIU/mL, respectively) giving an overall response rate of 7.7%. The antibody level declined rapidly. At the end of the study, one patient who did not respond had developed viral breakthrough which was treated with adefovir dipivoxil therapy., Conclusions: Active immunization with two courses of double-dose recombinant HBV vaccine has limited efficacy in patients receiving lamividine prophylaxis after liver transplantation.

Background/aims: This controlled study aimed to evaluate the efficacy and potential side effects of hepatitis B virus (HBV) vaccination as active immunotherapy in HBV-related chronic hepatitis., Methods: The 118 included patients were 'naive' subjects who had never received any previous anti-HBV therapy, showed detectable serum HBV DNA and had biopsy-proven chronic hepatitis. In a 12-month follow-up they were given either five intramuscular injections of 20 microg of a preS2/S (GenHevac B, Pasteur-Mérieux) (n = 46) or an S vaccine (Recombivax Merck & Co.) (n = 34) or no treatment as a control (n = 37). The efficacy of vaccination was evaluated by testing for serum HBV DNA negativation using a standard liquid hybridization assay., Results: Three months after the first three vaccine injections, the percentage of serum HBV DNA negativation was higher in the vaccine groups (16.3%) than in the control group (2.7%) (P = 0.033, by the chi2 Pearson test) and was more frequently observed in patients who had pretreatment viremia >200 pg/ml (none in the control group vs. 16.7% in the vaccinated groups) (P = 0.025). After 12 months follow-up and five vaccine injections, there was no difference in the rate of serum HBV DNA negativation between vaccinated and unvaccinated subjects but HBV vaccines significantly decreased the HBV viral load between the sixth and twelfth months (P = 0.04) in contrast with the control group. The rate of HBe/anti-HBe seroconversion after 6 months of follow-up occurred only in eight (13.3%) vaccinated patients and in one (3.6%) of the controls. Disappearance of serum HBsAg was not observed in any of the patients., Conclusions: This controlled study offers direct evidence that the HBV vaccine may decrease HBV replication in chronic hepatitis B patients. It also emphasizes the need for reinforced immunization strategies as well as combination therapies.

Although hepatitis B is an ancient disease, most of the advances in our knowledge of its epidemiology, prevention, pathogenesis, natural history and treatment were made in the last 30 years. The prospect of global eradication of HBV infection within the next 50 years is technologically possible but implementation of worldwide vaccination against hepatitis B will require significantly more time to overcome the social and economic hurdles. While there is reasonable optimism that HBV infection will be eradicated, there are currently 300 million HBV carriers worldwide who are at risk of dying from liver failure or hepatocellular carcinoma, and there will continue to be new cases of HBV infection for many more years. Thus, HBV infection cannot be considered to be a health problem of the past. The focus of hepatitis B research at the turn of the millenium will be the development of more effective therapies that can be applied to all patients with chronic HBV infection. These treatments need to be effective in inhibiting HBV DNA synthesis and in eliminating ccc DNA. They may involve monotherapy with more potent antiviral agents that do not induce resistance, but are more likely to require a combination of antiviral agents or antiviral and immunomodulatory agents. These treatments must be safe, convenient to administer, and affordable. It is likely that new therapies with increasing efficacy will be available in the next one to two decades and combination therapy will be used widely by 2010. These treatments will induce sustained remission in the majority of patients who can afford them but provision of treatment to all those who need them will be more difficult. Other areas of hepatitis B that need to be addressed are the prevalence of occult HBV infection, the changing epidemiology and clinical significance of HBV variants, in particular the A1896 mutant, and the mechanisms of immune clearance and pathogenesis.

In a hepatitis B vaccination program (1982-1992), 705 infants born to HBsAg-positive mothers received HBIg within 2 h of birth and were vaccinated according to a three- or four-dose vaccination schedule, starting either at 3 months or directly after birth. Eight children HBsAg-positive during the first year of life (group 1: infected nonresponders). To determine whether failure of the hepatitis B vaccination was due to perinatal high-level maternal viraemia or genetically determined infant nonresponsiveness to the vaccine, we measured HBsAg and anti-HBs levels in infants and HBeAg and hepatitis B virus-DNA levels in maternal serum, and determined the HLA type of the infants. Controls included 14 infants with a normal anti-HBs response 1 year after vaccination (group 2: noninfected responders) and all eight infants without HBsAg and anti-HBs 1 year after vaccination (group 3: noninfected low responders). HBsAg, HBeAg and anti-HBs were measured by radioimmunoassay (Abbott Laboratories), hepatitis B virus-DNA was measured quantitatively by solution hybridization for groups 1, 2, and 3 (Abbott hepatitis B virus-DNA assay, Abbott Laboratories), and HLA was characterized by microcytotoxicity test for groups 1 and 3. All infants in groups 1 and 2 were born to HBeAg carrier mothers, and those in group 3 to HBeAg-negative mothers. Hepatitis B virus-DNA levels in maternal serum in group 1 were significantly higher than in group 2 (Wilcoxon rank-sum test: p < 0.01). Hepatitis B virus-DNA was not observed in group 3 maternal serum samples.(ABSTRACT TRUNCATED AT 250 WORDS)