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Importance: The World Health Assembly has called for the elimination of hepatitis B and C by 2030. As hepatitis B has no cure, the US strategy to eliminate hepatitis B has focused on prevention through vaccination. However, there are limited data on the trend in vaccine-associated immunity since the US implementation of universal infant hepatitis B vaccination., Objective: To compare self-reported hepatitis B vaccination coverage among children and adolescents with serologic evidence of immunity and infection in the US from 1999 to 2016., Design, Setting, and Participants: This population-based cross-sectional study used data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2016. US-born persons aged 2 to 18 years without missing hepatitis B serologic test results and with reported vaccination history were included. Data were analyzed from September 2017 to June 2018., Main Outcomes and Measures: The proportion of participants who reported complete vaccination for hepatitis B and who had positive serologic test results indicating immunity., Results: Of 21 873 children and adolescents, 51.2%% were male, and the mean (SD) age was 10.6 (4.6) years. The survey reported that hepatitis B vaccination coverage increased significantly from 1999 to 2016 (from 62.6% [95% CI, 58.6%-66.4%] to 86.3% [95% CI, 82.9%-89.2%]; P < .001). Vaccine-associated immunity also increased from 1999 to 2016 among children aged 2 to 5 years (from 60.7% [95% CI, 48.8%-71.4%] to 65.2% [95% CI, 57.4%-72.3%]; P = .001) but decreased among children aged 6 to 10 years (from 64.6% [95% CI, 57.7%-70.9%] to 46.5% [95% CI, 39.1%-54.0%]; P < .001), adolescents aged 11 to 13 years (from 68.8% [95% CI, 58.1%-77.8%] to 26.2% [95% CI, 18.6%-35.5%]; P < .001), and adolescents aged 14 to 18 years (from 68.5% [95% CI, 62.9%-73.6%] to 15.6% [95% CI, 12.2%-19.8%]; P < .001). By birth year, serologic evidence of vaccine-associated immunity significantly decreased in the 1994-2003 NHANES birth cohort but not among those born between 1988 and 1993. Non-US-born children and adolescents did not show the same decreasing trend in immunity., Conclusions and Relevance: In this cross-sectional study, decreasing hepatitis B immunity was observed among US-born children and adolescents in the 1994-2003 NHANES birth cohort despite increasing rates of hepatitis B vaccination coverage. These findings suggest a possible need for surveillance and a booster vaccine dose for hepatitis B as those without serologic evidence of immunity become young adults and may engage in behaviors associated with an increased risk for infection.

Importance: Receipt of hepatitis B virus vaccine is important to prevent infection. However, adherence to the hepatitis B vaccine series among adults at risk of infection has been low., Objective: To assess whether recipients of a 2-dose hepatitis B vaccine with cytosine phosphoguanine adjuvant (HepB-CpG vaccine; Heplisav-B) are more likely to complete their series compared with recipients of a 3-dose vaccine with alum adjuvant (comparator vaccine; Engerix-B [HepB-alum])., Design, Setting, and Participants: This nested cohort study was conducted from August 7 to December 31, 2018, at Kaiser Permanente Southern California, an integrated health care system with a diverse population of approximately 4.6 million members. Adults not receiving dialysis who received a first dose of a hepatitis B vaccine series in family practice or internal medicine departments of 15 Kaiser Permanente Southern California medical centers were followed up through electronic health records for up to 1 year after receipt of the first dose. Data were analyzed from March 16 to September 23, 2020., Exposures: Receipt of a first dose of the HepB-CpG vaccine (2-dose vaccine) vs receipt of a first dose of the HepB-alum vaccine (3-dose vaccine)., Main Outcomes and Measures: Series completion within the recommended vaccine schedule plus 3 months (primary outcome) and series completion within 1 year after receipt of the first dose (secondary outcome)., Results: Of 4727 individuals who initiated the HepB-CpG vaccine series and 6161 individuals who initiated the HepB-alum vaccine series included in the study, 2876 (60.8%) and 3789 (61.5%), respectively, were ages 40 to 59 years, 2415 (51.1%) and 3113 (50.5%) were male, and 2364 (50.0%) and 2881 (46.8%) were Hispanic. The vaccine series was completed within the recommended schedule plus 3 months for 2111 (44.7%) individuals who initiated the HepB-CpG vaccine series and 1607 (26.1%) individuals who initiated the HepB-alum vaccine series, and within 1 year for 2858 (60.5%) and 1989 (32.3%) individuals, respectively. The individuals who initiated the HepB-CpG vaccine series were significantly more likely to complete the series (adjusted relative risk, 1.77; 95% CI, 1.68-1.87). Results were consistent across clinical and demographic strata., Conclusions and Relevance: In this study, use of the HepB-CpG vaccine was associated with hepatitis B vaccine series completion, but tailored strategies to increase completion of hepatitis B vaccine series are warranted.

Introduction: India introduced a hepatitis-B (HB) vaccine in the Universal Immunization Program in 2002-2003 on a pilot basis, expanded to ten states in 2007-2008 (phase-1), and the entire country in 2011-2012 (phase-2). We tested sera from a nationally representative serosurvey conducted duing 2017, to estimate the seroprevalence of different markers of HB infection among children aged 5-17 years in India and to assess the impact of vaccination., Methods: We tested sera from 8273 children for different markers of HB infection and estimated weighted age-group specific seroprevalence of children who were chronically infected (HBsAg and anti-HBc positive), and immune due to past infection (anti-HBc positive and HBsAg negative), and having serological evidence of HB vaccination (only anti-HBs positive). We compared the prevalence of serological markers among children born before (aged 11-17 years) and after (aged 5-10 years) introduction of HB-vaccine from phase-1 states., Results: Among children aged 5-8 years, 1.1% were chronic carriers, 5.3% immune due to past infection, and 23.2% vaccinated. The corresponding proportions among children aged 9-17 years were 1.1%, 8.0%, and 12.0%, respectively. In phase-1 states, children aged 5-10 years had a significantly lower prevalence of anti-HBc (4.9% vs. 7.6%, p<0.001) and higher prevalence of anti-HBs (37.7% vs. 14.7%, p<0.001) compared to children aged 11-17 years. HBsAg positivity, however, was not different in the two age groups., Conclusions: Children born after the introduction of HB vaccination had a lower prevalence of past HBV infection and a higher prevalence of anti-HBs. The findings of our study could be considered as an interim assessment of the impact of the hepatitis B vaccine introduction in India., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Single nucleotide polymorphisms (SNPs) in the interleukin 28B (IL28B) gene can influence the course of treated and untreated HBV infection. However, the correlation between different IL28B-SNPs and HBVDNA and quantitative HBsAg (qHBsAg) in chronic HBV infection remains to be fully elucidated. Patients with chronic HBV infection were analysed for qHBsAg, HBVDNA, HBV genotype and six IL28B-SNPs (rs12980275, rs8105790, rs8099917, rs7248668, rs12979860, rs10853728). Seventy patients were recruited: 80% Caucasian, 56% genotype D, 44% treated with nucleos(t)ide analogues, 11% cirrhotic, 37% inactive carriers (IC). Median (IQR) qHBsAg and HBVDNA were 3.2 log10 IU/ml (2.2-3.9) and 2.2 log10 IU/ml (0.3-3.3), respectively. Lower levels of qHBsAg were associated in the whole study population with rs12979860 CC vs. CT (p=0.05), rs12980275 AA vs. AG (p=0.04), rs8105790 TT vs. CT (p=0.05) and genotype D vs. A+E (p=0.01). rs8105790 TT was present in 81% of IC vs. 46% non-IC (p=0.005). These data were also confirmed in the untreated patients' subgroup. In multivariate analysis, IL28B-SNP haplogroups were associated with lower qHBsAg: CC/AA at rs12979860/rs12980275 (-0.70 log IU/mL, 95% CI -1.26;-0.14; p=0.01), CC/TT at rs12979860/rs8105790 (-0.78 log IU/mL, 95% CI -1.33;-0.23; p=0.006) and AA/TT at rs12980275/rs8105790 (-0.71 log IU/mL, 95% CI -1.27;-0.17; p=0.01) both in the whole population and in the untreated subgroup. Specific IL28-SNP haplogroups might be associated with lower qHBsAg.

The isolation of human antibodies with naturally paired heavy and light chains is crucial for understanding the human antibody immune response. Here, we present a protocol for antibody cloning from the sorted single human memory B cells recognizing hepatitis B virus (HBV) S antigen (HBsAg). A two-fluorescent-dye labeling strategy against HBsAg allows for an improved sorting specificity, while non-relevant protein staining allows for the exclusion of non-specific B cells. This protocol could also be widely adapted for other antigens. For complete details on the use and execution of this protocol, please refer to Wang et al. (2020)., Competing Interests: The authors declare no competing interests., (© 2020 The Author(s).)

Objective: To estimate the prevalence of immunity against Hepatitis B virus among all healthcare workers linked to the Departments of Public Health in Torrevieja and Elx-Crevillent,two municipalities in the Valencian Community, Spain., Methods: Cross-sectional descriptive study of healthcare workers in two different public health departments. Once the sample was obtained, the anti-hepatitis B surface antibody (anti-HBsAb) levels were abstracted based on serological test results recorded in the workers' medical records. Titers of anti-HBsAB ≥10mlU / ml were considered as evience of immunity. The variables analyzed were classified by department, gender, age (18-34; 35-49;≥50 years); professional category (physicians / nursing / other health personnel / nonhealth personnel); service at risk of contagion (Yes / No); immunity (≥10mlU/ml, 〈10mlU/ml,missing) and systematic anti-HBs vaccination by date of birth (Yes / No)., Results: The study population consisted of 2674 workers. The highest proportions of workers were female(68.8%), between 35 and 49 years of age (52.8%), and employed in nursing,(32.2%). Overall, 74.9% of employees had evidence of hepatitis B immunity, 11.3% had no inmunity, and 13.8% was missing information on serology. Among those employees with serological information (n=2306), lack of immunity was highest among males (17.8%).Protective titers were inversely proportional to age, with the lowest titers being found in the oldest age groups. Non-healthcare personnel and physicians also had lower levels of protection (36.9% and 11.1%, respectively)., Conclusions: Despite identifying high levels of immunity among healthcare workers, the percentages of non-immunized employees and those lacking immunological information underscores the need to implement new communication strategies aimed at these at-risk groups., (Copyright belongs to the Associació Catalana de Salut Laboral.)

Rare individuals can naturally clear chronic hepatitis B virus (HBV) infection and acquire protection from reinfection as conferred by vaccination. To examine the protective humoral response against HBV, we cloned and characterized human antibodies specific to the viral surface glycoproteins (HBsAg) from memory B cells of HBV vaccinees and controllers. We found that human HBV antibodies are encoded by a diverse set of immunoglobulin genes and recognize various conformational HBsAg epitopes. Strikingly, HBsAg-specific memory B cells from natural controllers mainly produced neutralizing antibodies able to cross-react with several viral genotypes. Furthermore, monotherapy with the potent broadly neutralizing antibody Bc1.187 suppressed viremia in vivo in HBV mouse models and led to post-therapy control of the infection in a fraction of animals. Thus, human neutralizing HBsAg antibodies appear to play a key role in the spontaneous control of HBV and represent promising immunotherapeutic tools for achieving HBV functional cure in chronically infected humans., Competing Interests: Disclosures: V. Hehle reported a patent to anti-HBV antibodies and methods of use, pending. M. Beretta reported a patent to anti-HBV antibodies and methods of use, pending. M. Bourgine reported a patent to anti-HBV antibodies and methods of use, pending. M. Ait-Goughoulte reported a patent planned on the antibodies pending, "Roche." S. Pol reported personal fees from Gilead, Abbvie, BMS, Janssen, and Roche outside the submitted work. H. Strick-Marchand reported a patent to human neutralizing HBV antibodies and their use thereof, pending. N. Pelletier reported personal fees from Hoffmann-La Roche outside the submitted work; in addition, N. Pelletier had a patent planned to be submitted, pending "Roche Innovation Center Basel." H. Mouquet reported grants from Institut Roche during the conduct of the study; in addition, H. Mouquet had a patent to anti-HBV antibodies and methods of use, pending. No other disclosures were reported., (© 2020 Hehle et al.)

Chimeric antigen receptor (CAR)-T-cell is a safe and effective therapy of B-cell cancers but it is unknown if this is so in persons with prior hepatitis B virus (HBV) infection. We studied 70 subjects with advanced B-cell cancers receiving CAR-T-cell therapy, 12 of whom had chronic HBV-infection (HBsAg positive) and 29 with resolved HBV-infection (HBsAg negative and anti-HBc positive). Safety and efficacy were compared with 29 subjects without HBV-infection. HBV was reactivated in 2 subjects with chronic HBV-infection and 1 with resolved HBV-infection. There was no HBV-related hepatitis flare. Responses to CAR-T-cell therapy in the three cohorts were not significantly different. There was no significant difference in the incidence or severity of cytokine release syndrome (CRS) and neurologic toxicity between the cohorts. Our data suggest that chronic and resolved HBV-infection do not affect the safety and efficacy of CAR-T-cell therapy.

Our recent study showed a high rate of HBsAg seroconversion in inactive HBsAg carriers (IHCs) treated with pegylated IFN (PEG-IFN). To understand the immune-mediated component of the HBsAg seroconversion better, this study investigated the role of NK cells. A total of 44 IHCs were given 48 wk of PEG-IFN. Fifteen cases achieved HBsAg seroconversion (R group), whereas 29 failed (NR group). The proportion and activity (CD107α and IFN-γ production) of NK cells were measured before and during treatment. We found that the proportion of NK cells in the R group was higher than in the NR group at baseline and during PEG-IFN treatment, even when patients were matched for age, sex and treatment period. IFN- γ secretion and CD107α expression from NK cells in cases who achieved HBsAg seroconversion were significantly higher than patients matched for age, sex, HBsAg and treatment period in the NR group at baseline and during PEG-IFN treatment. We also found that in HBsAg seroconversion cases, NK cells activity increased after PEG-IFN treatment, especially before HBsAg seroconversion. These effects were not found in non-responders. In conclusion, we demonstrated that the increase of NK cells accompanied by enhanced activity during PEG-IFN treatment favoured HBsAg seroconversion for IHC, and that NK cells may play a role in HBV seroconversion.

In this study, we investigated the seroprevalence of anti-hepatitis D virus (HDV) antibodies in hepatitis B surface antigen (HBsAg)-positive children after 25 years of obligatory vaccination of infants against hepatitis B virus. This cross-sectional study included 120 treatment-naïve HBsAg-positive children, with a male-to-female ratio of 1.8:1 and a mean age of 7.8 ± 3.8 years (range, 1-17 years). Mothers were positive for HBsAg in 96.6% of the cases. HBeAg-positive chronic infection was observed in 60% of the cases, HBeAg-positive chronic hepatitis in 12.5%, and HBeAg-negative chronic infection in 26.7%. Anti-HDV antibodies were not detected in any of the cases. Thus, there is a lack of anti-HDV antibodies in HBsAg-positive children, despite the current burden in adults.

Background: Previous studies have reported that platelet count is associated with the progression of liver disease caused by hepatitis B virus (HBV), but there have been no reports on whether platelet count is associated with immune recovery in HIV/HBV co-infected patients., Methods: A retrospective analysis was conducted on 167 HIV-infected patients whose continuously highly active antiretroviral therapy (HAART) strategy was lamivudine +tenofovir+ efavirenz, of which 75 were HIV/HBV co-infected patients and 92 were HIV mono-infected patients. The biochemical examination results and demographic characteristics of all patients before HAART were collected, and routine blood test results (including platelet count) and immune cell count (including CD4 cells count) after all time points of HAART were obtained. All patients were observed until 72 months. CD4 cells count of 350 or 500 cells/μl 72 months after HAART served as the boundary for judging the immune reconstruction effect., Results: The basic characteristics of HIV/HBV co-infected patients and HIV mono-infected patients were matched. All patients had a good viral response (HIV RNA <20 copies/ml, HBV DNA < 100 copies/mL) and immune response during HAART. The platelets with poor immune recovery in HIV/HBV co-infected patients were also maintained at an apparent lower level than that in patients with good immune recovery. However, this phenomenon was not found in HIV mono-infected patients. The platelet level at many time points after HAART therapy in HIV/HBV co-infected patients can predict the effect of immune recovery at 72 months after HAART., Conclusion: The platelet counts of HIV/HBV co-infected patients were correlated with CD4 counts during the follow-up of HAART. These results suggest that the mechanisms associated with thrombocytopenia may be involved in the regulation of immune recovery after treatment in HIV/HBV co-infected patients., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020. Published by Elsevier B.V.)

Pattern recognition receptors (PRRs) are a pivotal part of the immune system. They are distributed in almost every site of higher organisms, able to recognize foreign pathogens or unwanted remnants of metabolism and mount innate immune response. Moreover, PRRs create bridging signaling to initiate adaptive immunity. The liver being the largest organ of the body, exposed to myriads of foreign substances often being immunogenic, is well equipped with PRRs. They act as sentinels of the organ, both in health and disease. In viral hepatitis C at least two of them, RIG-1 and TLR3 sense HCV, induce protective interferon production and create proinflammatory status. The hepatitis B virus is apparently invisible to PRRs, which has recently been denied. Besides, they are active in the course of infection. In liver injury and hepatic fibrogenesis Toll-like receptors (TLRs), predominantly TLR4, TLR3 and TLR9 are associated with gut microflora-related products and DNA from dying hepatocytes, lead to the activation of hepatic stellate cells. The latter initiate production of fibrillar collagens, the main agents forming hepatic fibrosis. Tumor cells of primary liver cancer also express PRRs, mainly TLRs. In concert with non-resolving liver inflammation, they are considered pivotal factors leading to carcinogenesis.

N 6 -Methyladenosine (m 6 A), the methylation of the adenosine base at the nitrogen 6 position, is the most common epitranscriptomic modification of mRNA that affects a wide variety of biological functions. We have previously reported that hepatitis B viral RNAs are m 6 A-modified, displaying a dual functional role in the viral life cycle. Here, we show that cellular m 6 A machinery regulates host innate immunity against hepatitis B and C viral infections by inducing m 6 A modification of viral transcripts. The depletion of the m 6 A writer enzymes (METTL3 and METTL14) leads to an increase in viral RNA recognition by retinoic acid-inducible gene I (RIG-I), thereby stimulating type I interferon production. This is reversed in cells in which m 6 A METTL3 and METTL14 are overexpressed. The m 6 A modification of viral RNAs renders RIG-I signaling less effective, whereas single nucleotide mutation of m 6 A consensus motif of viral RNAs enhances RIG-I sensing activity. Importantly, m 6 A reader proteins (YTHDF2 and YTHDF3) inhibit RIG-I-transduced signaling activated by viral RNAs by occupying m 6 A-modified RNAs and inhibiting RIG-I recognition. Collectively, our results provide new insights into the mechanism of immune evasion via m 6 A modification of viral RNAs., Competing Interests: Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article., (© 2020 Kim et al.)

Despite the fact that both Hepatitis B virus (HBV) infection and excessive alcohol consumption represent health problems worldwide, the mechanism by which alcohol affected the progression of HBV-associated liver disease are not completely understood. Therefore, we studied how alcohol affects the development of HBV infection and the role of T cells and NK cells in the antiviral response. Mononuclear cells (MNCs) derived from HBV-carrier mice and wild type (WT) mice were characterized for phenotype by flow cytometry, HBV antigen and gene expression were detected by Radio Immunoassay (RIA), immunohistochemistry and quantitative real-time (qRT)-PCR. Metabolomics changes were detected in mice liver tissue based on ultra high performance liquid tandem chromatography quadrupole time of flight mass spectrometry (UHPLC-QTOFMS). The mice after ethanol consumption shows higher levels of HBV surface Ag (HBsAg), HBV core antigen (HBcAg) and HBV 3.5 kb RNA expression, and a lower level of CD8 + T cells during HBV persistence, with an increased lymphocyte activation gene-3 (LAG-3) expression on CD8 + T cell. In addition, the energy metabolism was downregulated and the oxidative stress was upregulated in the liver tissue. Furthermore, NK cells depletion results in a lower levels of HBV surface Ag (HBsAg) and HBV 3.5 kb RNA expression, and a higher level of CD8 + T cells with reduced expression of LAG-3. In conclusion, alcohol abuse induces CD8 + T cells failure after acute HBV infection, but depletion of NK cells could retore CD8 + T cell activity. Moreover, downregulation of energy metabolism and upregulation of oxidative stress may also contribute to CD8 + T cell failure., (Copyright © 2020. Published by Elsevier B.V.)

Acute liver failure (ALF) caused by hepatitis B virus (HBV) is common type of liver failure in the world, with high morbidity and mortality rates. However, the prevalence, genetic background and factors determining the development of HBV-related ALF are rarely studied. In this study, we examined three Gene Expression Omnibus (GEO) data sets by bioinformatics analysis to identify differentially expressed genes (DEGs), key biological processes and pathways. Immune infiltration analysis showed high immune cells infiltration in HBV-related ALF tissue. We then confirmed natural killer cells and macrophages infiltration in clinical samples by immunohistochemistry assay, implying these cells play a significant role in HBV-ALF. We found 1277 genes were co-up-regulated and that 1082 genes were co-down-regulated in the 3 data sets. Inflammation-related pathways were enriched in the co-up-regulated genes and synthetic metabolic pathways were enriched in the co-down-regulated genes. WGCNA also revealed a key module enriching in immune inflammation response and identified 10 hub genes, differentially expressed in an independent data set. In conclusion, we identified fierce immune inflammatory response to elucidate the immune-driven mechanism of HBV-ALF and 10 hub genes based on gene expression profiles., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background and Aims: To date, conflicting data exist as to whether hepatitis B virus (HBV) has the ability to induce innate immune responses. Here, we investigated cellular changes after the first contact between HBV and primary human hepatocytes (PHH) in vitro and in vivo., Approach and Results: The exposure of PHH to HBV particles resulted in nuclear translocation of NFκB, followed by the expression and secretion of inflammatory cytokines (IL [interleukin] 1B, IL6, and TNF [tumor necrosis factor]). Ultraviolet irradiation of viral particles suppressed HBV infectivity but not the induction of cytokines in PHH, suggesting that the inoculum contains the immune-inducing agent. Purified HBV particles on the whole, which were prepared from HBV DNA-positive and protein-rich fractions after heparin column separation, still had immune-inducing capacity in PHH. The HBV-induced gene expression profile was similar to that induced by toll-like receptor 2 (TLR2) ligand Pam3Cys, but different from those induced by the viral sensors TLR3 or TLR7-9. Treatment of PHH with both HBV particles and Pam3Cys led to phosphorylation of ERK (extracellular signal-regulated kinase), JNK, and p38 mitogen-activated protein kinases as well as NFκB (nuclear factor kappa B). Finally, HBV-induced gene expression could be neutralized by TLR2-specific antibodies. Of note, pretreatment with an HBV entry inhibitor attenuated the TLR2-mediated response to HBV, suggesting a receptor binding-related mechanism. In liver-humanized uPA/severe combined immunodeficient (SCID)/beige mice challenged with HBV in vivo, immune induction could only marginally be seen., Conclusions: PHHs are able to sense HBV particles through TLR2, leading to an activation of anti-HBV immune responses in vitro. These findings challenge the previously described stealth properties of HBV., (© 2020 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of American Association for the Study of Liver Diseases.)

Hepatitis B virus (HBV) is a global virus responsible for a universal disease burden for millions of people. Various vaccination strategies have been developed using viral vector, nucleic acid, protein, peptide, and virus-like particles (VLPs) to stimulate favorable immune responses against HBV. Given the pivotal role of specific immune responses of hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) in infection control, we designed a VLP-based vaccine by placing the antibody-binding fragments of HBsAg in the major immunodominant region (MIR) epitope of HBcAg to stimulate multilateral immunity. A computational approach was employed to predict and evaluate the conservation, antigenicity, allergenicity, and immunogenicity of the construct. Modeling and molecular dynamics (MD) demonstrated the folding stability of HBcAg as a carrier in inserting Myrcludex and "a" determinant of HBsAg. Regions 1-50 and 118-150 of HBsAg were considered to have the highest stability to be involved in the designed vaccine. Molecular docking revealed appropriate interactions between the B cell epitope of the designed vaccine and the antibodies. Totally, the final construct was promising for inducing humoral and cellular responses against HBV., (Copyright © 2020 Mobini, Chizari, Mafakher, Rismani and Rismani.)

Background: Botswana introduced the HBV vaccine at birth for all newborns in 2000. To the best of our knowledge, since the introduction of HBV vaccination, there have been limited data for vaccine response to HBV and its impact on early childhood HBV infections among children HIV exposed but uninfected in Botswana., Aims: To determine the prevalence of hepatitis B surface antigen (HBsAg) and HBV vaccine response in 18 months old children HIV exposed but uninfected in Botswana., Methods: Stored plasma samples from 304 children at 18 months of age and 287 mothers from delivery were tested for HBsAg. Mothers with positive HBsAg had HBV DNA level tested, and their HBV genotypes were determined by amplifying a 415-base pair (bp) region of the surface gene. Plasma samples from children exposed to HIV were tested for hepatitis B surface antibody (anti-HBs) titers., Results: No children (0 of 304) were positive for HBsAg at 18 months while 5 (1.74%) of 287 HIV-positive mothers were HBsAg positive. Four of the HBsAg positive mothers were infected with genotype A1, while 1 was infected with genotype E. The median anti-HBs titer in children was 174 mIU/mL [QR: 70, 457]. Three (1.1%) of 269 children had an inadequate vaccine response (<10 mIU/mL), while 266 (98.9%) of 269 had protective immunity. However, when using the ≥100mIU/mL threshold, only 170 (63.2%) of 269 children had complete protection., Conclusion: No HBsAg positivity was identified in a cohort of children HIV exposed but uninfected. The absence of HBsAg positives was associated with good HBV vaccine responses and low maternal HBsAg prevalence in Botswana., Competing Interests: The authors have declared that no competing interest exists.

In 1991, Peru launched the first vaccination program against hepatitis B in children aged under 5 years in the hyperendemic [hepatitis B virus (HBV) and hepatitis D virus (HDV)] province of Abancay. We conducted a cross-sectional study to determine the prevalence of HBV and HDV infections, 23 years after the launch of the vaccination program, as well as the post-vaccine response against hepatitis B in terms of prevalence of hepatitis B surface antibody (anti-HBs ≥10 mUI/ml). Among 3165 participants aged from 0 to 94 years, the prevalence rates of hepatitis B surface antigen (HBsAg), and hepatitis B core antibody (total anti-HBc) were 1.2% [95% confidence interval (CI) 0.85-1.64%], and 41.67% (95% CI 39.95-43.41%), respectively. The prevalence rate of anti-HBs at protective levels (≥10 mUI/ml) in individuals who HBsAg and anti-HBc negative was 66.36% (95% CI 64.15-68.51%). The prevalence rate of HBsAg in children aged <15 years was nil, and among adult HBsAg carriers, the prevalence of hepatitis D antibody (anti-HDV) was 5.26% (2/38; 95% CI 0.64-17.74). These findings showed that HBV prevalence has changed from high to low endemicity, 23 years following implementation of the vaccination program against hepatitis B, and HDV infection was not detected in those aged <30 years., Competing Interests: The authors have declared that no competing interests exist.

Hepatitis B virus (HBV) is characterized with high mutations, which is attributed to the lack of proof-reading of the viral reverse transcriptase and host immune pressure. In this study, 31 HBV chronic carriers from 14 families were enrolled to investigate the evolution of the same original HBV sources in different hosts. Sequences of pre-C and C (pre-C/C) genes were analyzed in eight pairs of HBV-infected mothers with longitudinal sera (at an interval of 6.0-7.2 years) and their children (5.5-6.7 years old), and in 15 adults (21-78 years old) from six families with known intrafamilial HBV infection. The pre-C/C sequences had almost no change in eight mothers during 6.0-7.2 years and their children who were in immune tolerant phase. The pre-C/C sequences from the 15 adults of six families, mostly in the immune-clearance phase or the low replicative phase, showed various diversified mutations between individuals from each family. Compared to a reference stain (GQ205441) isolated nearby, the pre-C/C in individuals in immune tolerant phase showed 98.56%-99.52% homology at nucleotide level and 99.5%-100% homology at amino acid level. In contrast, multiple mutations were developed in the immune-clearance phase or the low replicative phase, affecting immune epitopes in core gene and G1896 in pre-C gene. The results indicate that the evolution of new HBV variants is not mainly resulted from the spontaneous error rate of viral reverse transcription, but from the host immune pressure.

Immature immune system and immune tolerance induced by exposure to HBeAg in utero and/or shortly after infection in newborns were reportedly the causes of chronic HBV infection. To investigate the effect of maternal-derived HBeAg on neonatal T cell immunity, we analysed and compared T cell phenotypes and functions among neonates born to HBsAg + /HBeAg + mothers (HBeAg + neonates), HBsAg + /HBeAg - mothers (HBeAg - neonates) and healthy control mothers (HC neonates), using flow cytometry. The results showed that neonatal T cell phenotypes were similar regardless of HBeAg exposure. Upon anti-CD3 and anti-CD28 stimulation in HBeAg + neonates, CD4 + T cell production of IFN-γ (P < .05) was significantly enhanced, while CD8 + T cells secreted significantly more IL-2 compared with those in HBeAg - and HC groups (P < .05). Moreover, similar levels of IFN-γ and IL-10 were observed in the culture supernatant after stimulation with rHBsAg, rHBcAg or rHBeAg among HBeAg + , HBeAg - and HC neonates, whereas HBeAg + neonates produced more TNF-α than HBeAg - neonates upon stimulation with rHBcAg. In conclusion, the results indicated that the HBsAg + /HBeAg + maternal environment did not influence the phenotypes of cord blood T cells but boosted neonatal non-specific Th1-type cytokine production., (© 2020 The Scandinavian Foundation for Immunology.)

The covalently closed circular DNA (cccDNA) of hepatitis B virus (HBV) is critical for viral persistence in vivo. The lack of reliable, characterized and convenient small animal models for studying cccDNA persistence has long been a bottleneck for basic and translational research on HBV cure. A mouse model that can maintain intrahepatic cccDNA is urgently needed. Through combining the Cre/loxP-mediated recombination and adeno-associated virus (AAV) vector delivery strategy, we establish a novel recombinant cccDNA (rcccDNA) mouse model. AAV-rcccDNA mice supported long-term maintenance of intrahepatic rcccDNA which could be easily detected by Southern blotting within 30 weeks after transduction. Quantitative PCR could detect the rcccDNA signal throughout the experiment duration (>51 weeks). Furthermore, rcccDNA supported persistent serum antigenemia (>72 weeks) and intrahepatic HBsAg and HBcAg expression (>51 weeks). Flow cytometry analysis and single-cell RNA sequencing showed that AAV-rcccDNA mice displayed a compromised CD8 + T cell response. Meanwhile, minimal intrahepatic inflammation and fibrosis were observed. Furthermore, three anti-HBV compounds, AKEX0007, a post-transcriptional inhibitor, Bay 41-4109, a capsid allosteric modulator, and Entecavir were assessed in this AAV-rcccDNA mouse model. The changes of viral markers by these drugs were consistent with their mode of action although neither of them diminished the level of rcccDNA. This mouse model recapitulated the immune tolerant state of HBV infection with long term maintenance of cccDNA and antigenemia, which will provide a suitable platform for studying cccDNA persistence and developing intervention strategies that would eventually break the tolerance and clear the virus., (Copyright © 2020. Published by Elsevier B.V.)

Hepatitis B virus (HBV) is a major cause of acute liver failure (ALF) worldwide. While liver damage in classic acute hepatitis B is believed to be T-cell mediated, the pathogenesis of HBV-associated ALF remains largely unknown. Access to liver specimens from well-characterized patients with HBV-associated ALF provided us with the opportunity to perform next-generation sequencing (NGS) of the entire VH repertoires of IgM and IgG from the livers of four ALF patients, a control liver donor and a patient with chronic HBV infection. We found that ALF is not associated with expansion of specific B-cell lineages. However, NGS showed that the intrahepatic VH repertoires from ALF patients were characterized by the abundant presence of antibodies in germline configuration in contrast to their marginal prevalence in controls. Moreover, NGS identified a large number of VH genes in germline configuration with identical VDJ sequences in the IgM and IgG repertoires in all four ALF patients, indicating that isotype switch from IgM to IgG had occurred without somatic hypermutation. The results of this study indicate that the presence of intrahepatic antibodies in unmutated germline configuration is a broad phenomenon in the global antibody repertoire generated from total RNA derived from whole-liver tissue that is strongly associated with ALF, suggesting a major role of T cell-independent humoral immunity in the pathogenesis of ALF., (© 2020 John Wiley & Sons Ltd.)

Aluminium hydroxide is a well-known adjuvant used in vaccines. Although it can enhance an adaptive immune response to a co-administered antigen, it causes adverse effects, including macrophagic myofasciitis (MMF), subcutaneous pseudolymphoma, and drug hypersensitivity. The object of this study is to demonstrate pediatric cases of aluminium hydroxide-induced diseases focusing on its rarity, under-recognition, and distinctive pathology. Seven child patients with biopsy-proven MMF were retrieved from the Seoul National University Hospital (SNUH) pathology archives from 2015 to 2019. The medical records and immunisation history were reviewed, and a full pathological muscle examination was carried out. The mean age was 1.7 years (8.9-40 months), who had records of vaccination against hepatitis B, hepatitis A, and tetanus toxoid on the quadriceps muscle. The chief complaints were muscle weakness (n = 6), delayed motor milestones (n = 6), instability, dysarthria, and involuntary movement (n = 1), swallowing difficulty (n = 1), high myopia (n = 1), and palpable subcutaneous nodules with skin papules (n = 1). Muscle biopsy showed MMF (n = 6) and pseudolymphoma (n = 1) with pathognomic basophilic large macrophage infiltration, which had distinctive spiculated inclusions on electron microscopy. The intracytoplasmic aluminium was positive for PAS and Morin stains. Distinctive pathology and ultrastructure suggested an association with aluminium hydroxide-containing vaccines. To avoid misdiagnosis and mistreatment, we must further investigate this uncommon condition, and pharmaceutical companies should attempt to formulate better adjuvants that do not cause such adverse effects.

Currently, the treatment of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) [HBV-HCC] relies on blunt tools that are unable to offer effective therapy for later stage pathogenesis. The potential of miRNA to treat HBV-HCC offer a more targeted approach to managing this lethal carcinoma; however, the complexity of miRNA as an ancillary regulator of the immune system remains poorly understood. This review examines the overlapping roles of HBx-dysregulated miRNA in HBV-HCC and immune pathways and seeks to demonstrate that specific miRNA response in immune cells is not independent of their expression in hepatocytes. This interplay between the two pathways may provide us with the possibility of using candidate miRNA to manipulate this interaction as a potential therapeutic option.

Background: Screening and vaccination against Hepatitis B virus (HBV) infection remains the most effective intervention in curbing the disease. However, there is limited evidence on the factors associated with the uptake of these services in Uganda. This study determined the uptake of HBV screening and vaccination status, and associated factors among Healthcare Providers (HCPs) in Wakiso district, Uganda., Materials and Methods: This cross-sectional study was conducted among 306 HCPs, randomly selected from 55 healthcare facilities. Prevalence ratios (PR) were used to determine the factors associated with HBV screening and vaccination status of HCPs., Results: Of the 306 HCPs, 230 (75.2%) had ever screened for HBV infection while 177 (57.8%) were fully vaccinated. Being male was positively associated with 'ever been screened' for HBV infection (Adjusted PR = 1.27, 95%CI 1.13-1.41). Working in a public healthcare facility (Adjusted PR = 0.78, 95%CI 0.68-0.90) was negatively associated with ever been screened. Male sex (Adjusted PR = 1.21, 95%CI 1.01-1.46), the belief that the HBV vaccine was safe (Adjusted PR = 1.72, 95%CI 1.03-2.89) and ever been screened (Adjusted PR = 2.28, 95%CI 1.56-3.34) were positively associated with being fully vaccinated. However, working in a public healthcare facility (Adjusted PR = 0.79, 95%CI 0.64-0.98), self-perceived risk of HBV infection (Adjusted PR = 0.72, 95% CI:0.62-0.84), and working in a healthcare facility with infection control guidelines (Adjusted PR = 0.79, 95%CI 0.66-0.95) were negatively associated with being fully vaccinated., Conclusion: Three quarters of HCPs had ever been screened for HBV while slightly more than half were fully vaccinated. HBV screening and vaccination interventions need to consider the HCP sex, risk perception, attitude towards safety and efficacy of the hepatitis B vaccine, and healthcare facility characteristics such as ownership and availability of infection control guidelines, in order to be successful., Competing Interests: The authors have declared that no competing interests exist.

Hepatitis B virus (HBV) is the primary cause of liver-related malignancies worldwide, and there is no effective cure for chronic HBV infection (CHB) currently. Strong immunological responses induced by T cells are associated with HBV clearance during acute infection; however, the repertoire of epitopes ( epi ) presented by major histocompatibility complexes (MHCs) to elicit these responses in various African populations is not well understood. In silico approaches were used to map and investigate 15-mers HBV peptides restricted to 9 HLA class II alleles with high population coverage in Botswana. Sequences from 44 HBV genotype A and 48 genotype D surface genes ( PreS/S ) from Botswana were used. Of the 1819 epi bindings predicted, 20.2% were strong binders (SB), and none of the putative epi bind to all the 9 alleles suggesting that multi-epitope, genotype-based, population-based vaccines will be more effective against HBV infections as opposed to previously proposed broad potency epitope-vaccines which were assumed to work for all alleles. In total, there were 297 unique epi predicted from the 3 proteins and amongst, S regions had the highest number of epi (n = 186). Epitope-densities (D epi ) between genotypes A and D were similar. A number of mutations that hindered HLA-peptide binding were observed. We also identified antigenic and genotype-specific peptides with characteristics that are well suited for the development of sensitive diagnostic kits. This study identified candidate peptides that can be used for developing multi-epitope vaccines and highly sensitive diagnostic kits against HBV infection in an African population. Our results suggest that viral variability may hinder HBV peptide-MHC binding, required to initiate a cascade of immunological responses against infection.

Objectives: The study sought to determine the prevalence and risk factors associated with Hepatitis B surface antigenemia (HBsAg) positivity among pregnant women in Jos, Nigeria., Methodology: This was a cross-sectional study carried out among the pregnant population in five healthcare facilities in Jos, between November 1, 2017 and April 30, 2018. Informed consent was obtained, and data on sociodemographic and risk factors for hepatitis B virus (HBV) infection were collected. Hepatitis B viral infection was assessed using the in vitro HBsAg diagnostic rapid kit (Acon Laboratories, USA). Descriptive statistics, Chi-square test, and logistic regression were performed to identify predictors of HBV infection in the study population. All statistical analyses were carried out on STATA version 15., Results: Of the 3,238 women enrolled, 7.4% (241/3238) (95% confidence interval [CI] = 6.6% to 8.4%) were HBsAg positive. The absence of HBV vaccination (adjusted odds ratio [AOR] = 2.49; 95% CI = 1.49-4.09; P < 0.001), co-infection with HIV (AOR = 1.90; 95% CI = 1.18-3.08; P = 0.009), and higher parity (AOR = 1.37; 95% CI = 1.04-1.79; P = 0.024) were independently associated with HBV infection in pregnancy., Conclusions: The prevalence of HBV infection among pregnant women was high, especially among those without prior vaccination for HBV, those with HIV co-infection and higher parity., Competing Interests: None

The present review summarizes up-to-date evidence addressing the frequently discussed clinical controversies regarding the use of immune checkpoint inhibitors (ICIs) in cancer patients with viral infections, including AIDS, hepatitis B and C, progressive multifocal leukoencephalopathy, influenza, and COVID-19. In detail, we provide available information on (1) safety regarding the risk of new infections, (2) effects on the outcome of pre-existing infections, (3) whether immunosuppressive drugs used to treat ICI-related adverse events affect the risk of infection or virulence of pre-existing infections, (4) whether the use of vaccines in ICI-treated patients is considered safe, and (5) whether there are beneficial effects of ICIs that even qualify them as a therapeutic approach for these viral infections., Competing Interests: Competing interests: TG has received speakers and/or advisory board honoraria from BMS, Sanofi-Genzyme, MSD, Novartis Pharma, Roche, Abbvie, Almirall, Janssen, Lilly, Pfizer, Pierre Fabre, Merck-Serono, outside the submitted work. JR and CHS declare that they have no competing interests. JCB is receiving speaker’s bureau honoraria from Amgen, Pfizer, Merck-Serono, Recordati and Sanofi, is a paid consultant/advisory board member for Boehringer Ingelheim, eTheRNA, In ProTher, MerckSerono, Pfizer, 4SC and Sanofi. His group receives research grants from Bristol-Myers Squibb, Merck Serono, HTG, IQVIA, and Alcedis., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Hepatitis B (HepB) is one of the most common infectious diseases affecting over two billion people worldwide. About one third of all HepB cases are in China. In recent years, China made significant efforts to implement a nationwide HepB vaccination program and reduced the number of unvaccinated infants from 30 to 10%. However, many individuals still remain unprotected, particularly those born before 2003. Consequently, a catch-up retroactive vaccination is an important and potentially cost-effective way to reduce HepB prevalence. In this paper, we analyze a game theoretical model of HepB dynamics that incorporates government-provided vaccination at birth coupled with voluntary retroactive vaccinations. Given the uncertainty about the long-term efficacy of the HepB vaccinations, we study several scenarios. When the waning rate is relatively high, we show that this retroactive vaccination should be a necessary component of any HepB eradication effort. When the vaccine offers long-lasting protection, the voluntary retroactive vaccination brings the disease incidence to sufficiently low levels. Also, we find that the optimal vaccination rates are almost independent of the vaccination coverage at birth. Moreover, it is in an individual's self-interest to vaccinate (and potentially re-vaccinate) at a rate just slightly above the vaccine waning rate.

Background: The genetic variation and origin of Hepatitis B Virus (HBV) in Qinghai-Tibet Plateau were poorly studied. The coexistence of HBsAg and anti-HBs has been described as a puzzle and has never been reported in the indigenous population or in recombinant HBV sequences. This study aimed to report geographical distribution, genetic variability and seroepidemiology of HBV in southwest China., Methods: During 2014-2017, 1263 HBsAg positive serum were identified and 183 complete genome sequences were obtained. Serum samples were collected from community-based populations by a multistage random sampling method. Polymerase chain reaction (PCR) was used to amplify the HBV complete genome sequences. Then recombination, genetic variability, and serological analysis were performed., Results: (1) Of the 1263 HBsAg positive serum samples, there were significant differences between the distribution of seromarkers in Tibet and Qinghai. (2) Of 183 complete genome sequences, there were 130 HBV/CD1 (71.0%), 49 HBV/CD2 (26.8%) and four HBV/C2 isolates (2.2%). Serotype ayw2 (96.1%) was the main serological subtype. (3) Several nucleotide mutations were dramatically different in CD1 and CD2 sequences. Clinical prognosis-related genetic variations such as nucleotide mutation T1762/A1764 (27.93%), A2189C (12.85%), G1613A (8.94%), T1753C (8.38%), T53C (4.47%) T3098C (1.68%) and PreS deletion (2.23%) were detected in CD recombinants. (4) From the inner land of China to the northeast boundary of India, different geographical distributions between CD1 and CD2 were identified. (5) Twenty-seven (2.14%) HBsAg/HBsAb coexistence serum samples were identified. S protein amino acid mutation and PreS deletion were with significant differences between HBsAg/HBsAb coexistence group and control group., Conclusions: HBV/CD may have a mixed China and South Asia origin. Based on genetic variations, the clinical prognosis of CD recombinant seems more temperate than genotype C strains in China. The HBsAg/HBsAb coexistence is a result of both PreS deletion and aa variation in S protein. Several unique mutations were frequently detected in HBV/CD isolates, which could potentially influence the clinical prognosis.

We formulate and analyze a within-host hepatitis B viral mathematical model for hepatitis B in the acute phase of infection. The model incorporates hepatocytes, hepatitis B virus, immune system cells and cytokine dynamics using a system of ordinary differential equations. We use the model to demonstrate the trends of the hepatitis B infection qualitatively without the effects of immune cells and cytokines. Using these trends, we tested the effects of incorporating the immune cells only and immune cells with cytokine responses at low and high inhibitions on the hepatitis B virus infection. Our results showed that it is impossible to have the immune cells work independently from cytokines when there is an acute hepatitis B virus infection. Therefore, our results suggest that incorporating immune cells and cytokine dynamics in the acute hepatitis B virus infection stage delays infection in the hepatocytes and excluding such dynamics speeds up infection during this phase. Results from this study are useful in developing strategies for control of hepatocellular carcinoma which is caused by hepatitis B virus infection.

Objectives: Previous exposure to hepatitis B virus (HBV) may increase the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C. We aim to study the impact of previous HBV infection on the severity and outcomes of patients with nonalcoholic fatty liver disease (NAFLD)., Methods: This was a multicenter study of 489 patients with biopsy-proven NAFLD and 69 patients with NAFLD-related or cryptogenic HCC. Antihepatitis B core antibody (anti-HBc) was used to detect the previous HBV infection., Results: In the biopsy cohort, positive anti-HBc was associated with lower steatosis grade but higher fibrosis stage. 18.8% and 7.5% of patients with positive and negative anti-HBc had cirrhosis, respectively (P < 0.001). The association between anti-HBc and cirrhosis remained significant after adjusting for age and metabolic factors (adjusted odds ratio 2.232; 95% confidence interval, 1.202-4.147). At a mean follow-up of 6.2 years, patients with positive anti-HBc had a higher incidence of HCC or cirrhotic complications (6.5% vs 2.2%; P = 0.039). Among patients with NAFLD-related or cryptogenic HCC, 73.9% had positive anti-HBc. None of the patients had positive serum HBV DNA. By contrast, antihepatitis B surface antibody did not correlate with histological severity., Discussion: Positive anti-HBc is associated with cirrhosis and possibly HCC and cirrhotic complications in patients with NAFLD. Because a significant proportion of NAFLD-related HCC may develop in noncirrhotic patients, future studies should define the role of anti-HBc in selecting noncirrhotic patients with NAFLD for HCC surveillance.

Background: The incidence of hepatitis C virus (HCV) infection among patients with lichen planus (LP) varies considerably. Currently, there is more evidence for the association between hepatitic C and oral LP (OLP) than cutaneous LP (CLP). There is also lack of data on the Polish population. The study aimed at assessing the prevalence of HCV infection and liver test abnormalities among patients with CLP in south Poland., Methods: Eighty-four patients with CLP and 130 patients with other dermatoses (controls) were included in this retrospective case-control study. Medical records were reviewed for the presence of anti-HCV antibodies and hepatitis B surface antigen (HBsAg) and serum levels of liver function tests: aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glumatyltranspeptidase (GGT)., Results: Anti-HCV antibodies were not found in any of the patients in the study or control group. HBsAg was detected in one (1.19%) patient with CLP and none of the controls. Considering the prevalence of abnormal liver function parameters, there were no statistically significant differences in the frequencies of AST (P = 0.87), ALT (P = 0.9), and GGT (P = 0.81) above the upper limit between patients with CLP and patients with other dermatoses., Conclusions: Currently, there is no evidence confirming the relationship between HCV infection and CLP in southern Poland. There is also no increased incidence of liver function abnormalities compared to patients with other dermatoses. However, there is a need for further research on larger groups of patients., (© 2020 the International Society of Dermatology.)

Objective: This article analyzes the effectiveness of a super-accelerated immunization schedule against hepatitis B in patients who have received a liver transplantation., Methods: This is a quantitative and retrospective study based on secondary data of medical records from 177 patients who have received a liver transplantation at the Hospital de Base in São José do Rio Preto, São Paulo State, Brazil, between 1998 and 2016., Results: From the total number of participants, 72.89% were male, 39.55% had a cirrhosis diagnosis with associated causes, 23.16% had hepatocellular carcinoma, 53.11% were classified according to Child-Turcotte-Pugh C score, 58.76% had the hepatitis C virus, 97.18% had received an unconventional immunization schedule, and seroconversion was 36.63% among those with an unconventional schedule. The fact that the patient had the hepatitis C virus was statistically significant considering the lack of protection of the vaccine against the hepatitis B virus; their chances were 5 times higher of not seroconverting at the end of the immunization schedule., Conclusion: The need for high immediate protection in a short term may justify using unconventional immunization schedules in patients who make it to the transplantation waiting list without any previous immunization., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In patients with HBV and HCV coinfection, HBV reactivation leading to severe hepatitis has been reported with the use of direct-acting antivirals (DAAs) to treat HCV infection. Here we studied the molecular mechanisms behind this viral interaction. In coinfected cell culture and humanized mice, HBV replication was suppressed by HCV coinfection. In vitro, HBV suppression was attenuated when interferon (IFN) signaling was blocked. In vivo, HBV viremia, after initial suppression by HCV superinfection, rebounded following HCV clearance by DAA treatment that was accompanied by a reduced hepatic IFN response. Using blood samples of coinfected patients, IFN-stimulated gene products including C-X-C motif chemokine 10 (CXCL10), C-C motif chemokine ligand 5 (CCL5), and alanine aminotransferase (ALT) were identified to have predictive value for HBV reactivation after HCV clearance. Taken together, our data suggest that HBV reactivation is a result of diminished hepatic IFN response following HCV clearance and identify serologic markers that can predict HBV reactivation in DAA-treated HBV-HCV-coinfected persons.

Hepatitis B virus ( HBV) chronic infection is a critical risk factor for hepatocellular carcinoma. The innate immune response to HBV infection is a matter of debate. In particular, viral escape mechanisms are poorly understood. Our study reveals that HBV RNAs are not immunostimulatory in immunocompetent myeloid cells. In contrast, HBV DNA from viral particles and DNA replication intermediates are immunostimulatory and sensed by cyclic GMP-AMP Synthase (cGAS) and Stimulator of Interferon Genes (STING). We show that primary human hepatocytes express DNA sensors to reduced levels compared to myeloid cells. Nevertheless, hepatocytes can respond to HBV relaxed-circular DNA (rcDNA), when transfected in sufficient amounts, but not to HBV infection. Finally, our data suggest that HBV infection does not actively inhibit the DNA-sensing pathway. In conclusion, in infected hepatocytes, HBV passively evades recognition by cellular sensors of nucleic acids by (i) producing non-immunostimulatory RNAs, (ii) avoiding sensing of its DNAs by cGAS/STING without active inhibition of the pathway.

Woodchuck infected with woodchuck hepatitis virus (WHV) represents the pathogenically nearest model of hepatitis B and associated hepatocellular carcinoma (HCC). This naturally occurring animal model also is highly valuable for development and preclinical evaluation of new anti-HBV agents and immunotherapies against chronic hepatitis (CH) B and HCC. Studies in this system uncovered a number of molecular and immunological processes which contribute or likely contribute to the immunopathogenesis of liver disease and modulation of the systemic and intrahepatic innate and adaptive immune responses during hepadnaviral infection. Among them, inhibition of presentation of the class I major histocompatibility complex on chronically infected hepatocytes and a role of WHV envelope proteins in this process, as well as augmented hepatocyte cytotoxicity mediated by constitutively expressed components of CD95 (Fas) ligand- and perforin-dependent pathways, capable of eliminating cells brought to contact with hepatocyte surface, including activated T lymphocytes, were uncovered. Other findings pointed to a role of autoimmune response against hepatocyte asialoglycoprotein receptor in augmenting severity of liver damage in hepadnaviral CH. It was also documented that WHV in the first few hours activates intrahepatic innate immunity that transiently decreases hepatic virus load. However, this activation is not translated in a timely manner to induction of virus-specific T cell response which appears to be hindered by defective activation of antigen presenting cells and presentation of viral epitopes to T cells. The early WHV infection also induces generalized polyclonal activation of T cells that precedes emergence of virus-specific T lymphocyte reactivity. The combination of these mechanisms hinder recognition of virus allowing its dissemination in the initial, asymptomatic stages of infection before adaptive cellular response became apparent. This review will highlight a range of diverse mechanisms uncovered in the woodchuck model which affect effectiveness of the anti-viral systemic and intrahepatic immune responses, and modify liver disease outcomes. Further exploration of these and other mechanisms, either already discovered or yet unknown, and their interactions should bring more comprehensive understanding of HBV pathogenesis and help to identify novel targets for therapeutic and preventive interventions. The woodchuck model is uniquely positioned to further contribute to these advances., (Copyright © 2020 Michalak.)

Previously, a telomerase-derived 16-mer peptide, GV1001, developed as an anticancer vaccine, was reported to exert antiviral effects on human immunodeficiency virus or hepatitis C virus in a heat shock protein-dependent manner. Here we investigated whether GV1001 exerts antiviral effects on hepatitis B virus (HBV) and elucidated its underlying mechanisms. GV1001 inhibited HBV replication and hepatitis B surface antigen (HBsAg) secretion in a dose-dependent manner, showing synergistic antiviral effects with nucleos(t)ide analogs (NAs) including entecavir and lamivudine. This peptide also inhibited viral cccDNA and pgRNA. The intravenous GV1001 treatment of transgenic mice had anti-HBV effects. Our mechanistic studies revealed that GV1001 suppresses HBV replication by inhibiting capsid formation via type I interferon-mediated induction of heme oxygenase-1 (HO-1). GV1001 promoted the mitochondrial DNA stress-mediated release of oxidized DNA into the cytosol, resulting in IFN-I-dependent anti-HBV effects via the STING-IRF3 axis. We found that the anti-HBV effect of GV1001 was due to its ability to penetrate into the cytosol via extracellular heat shock protein, leading to phagosomal escape-mediated mtDNA stress. We demonstrated that the cell-penetrating and cytosolic localization capacity of GV1001 results in antiviral effects on HBV infections via mtDNA stress-mediated IFN-I production. Thus, GV1001, a peptide proven to be safe for human use, may be an anti-HBV drug that can be synergistically used with nucleot(s)ide analog., (Copyright © 2020 Choi, Kim, Lee, Lee and Kim.)

We previously identified that hepatitis B virus (HBV) encodes a microRNA (HBV-miR-3) that restrains HBV replication by targeting the HBV transcript. However, whether HBV-miR-3 affects host innate immunity to modulate HBV replication remains unclear. Here, we examined the vital functions of HBV-miR-3 in the innate immune response after HBV infection. We found that HBV-miR-3 expression gradually increased in a dose- and time-dependent manner in HBV-infected HepG2-NTCP cells. HBV-miR-3 activated the JAK/STAT signaling pathway by downregulating SOCS5 in hepatocytes, thereby enhancing the IFN-induced anti-HBV effect. In addition, HBV-miR-3 in exosomes facilitated the M1 polarization of macrophages. Furthermore, exosomes containing HBV-miR-3 enhanced the secretion of IL-6 via inhibiting the SOCS5-mediated ubiquitination of EGFR. In short, these results demonstrate that HBV-miR-3 activates the innate immune response to restrain HBV replication by multiple pathways, which may suppress HBV-induced acute liver cell injury and affect the progression of persistent HBV infection., (© The Author(s) (2019). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS.)

Introduction: Antibody to hepatitis B core antigen (HBcAb) is known to be related with the prognosis for patients with hepatocellular carcinoma (HCC). This study aims to evaluate the prognostic capacity of HbcAb and other donor/recipient hepatitis B seroepidemiological indexes in transplantation for HCC., Methods: Based on the national liver transplant registry, we analyzed the prognostic capacity of HBcAb in liver transplantation for patients with HCC of different etiological backgrounds. The hepatitis B virus (HBV)-related HCC cohort was further studied regarding donor/recipient hepatitis B seroepidemiology, and then divided into a training cohort (n = 1,222) and a validation cohort (n = 611) to develop a pretransplant recurrence-risk predicting nomogram., Results: Positive HbcAb in recipients was related to an increased risk of post-transplant tumor recurrence in HBV-related (n = 1,833, P = 0.007), HCV-related (n = 79, P = 0.037), and non-B non-C HCC (n = 313, P = 0.017). In HBV-related HCC (n = 1,833), donor hepatitis B surface antigen (HbsAg) was also associated with post-transplant tumor recurrence (P = 0.020). Multivariate analysis showed that the matching status of recipient HbcAb and donor HbsAg (MSHB) was an independent prognostic factor (P = 0.017). HbcAb-positive recipients matched with HbsAg-positive donors displayed the worst post-transplant outcomes (P < 0.001). In the training cohort (n = 1,222), a risk-predicting nomogram was established based on α-fetoprotein, Milan criteria, and MSHB. The model showed excellent prognostic capacity and safely expanded Milan criteria in both training and validation cohorts (P < 0.001)., Discussion: Positive HbcAb in recipients increases the risk of post-transplant tumor recurrence in HCC with different etiological backgrounds. The nomogram based on MSHB is effective in predicting tumor recurrence after transplantation for HBV-related HCC.

Background & Aims: Non-cytolytic cure of HBV-infected hepatocytes by cytokines, including type I interferons (IFNs), is of importance for resolving acute and chronic infection. However, as IFNs stimulate hundreds of genes, those most relevant for HBV suppression remain largely unknown. Amongst them are the large myxovirus resistance (Mx) GTPases. Human MX1 (or MxA) is active against many RNA viruses, while MX2 (or MxB) was recently found to restrict HIV-1, HCV, and herpesviruses. Herein, we investigated the anti-HBV activity of MX2., Methods: The potential anti-HBV activity of MX2 and functional variants were assessed in transfected and HBV-infected hepatoma cells and primary human hepatocytes, employing multiple assays to analyze the synthesis and decay of HBV nucleic acids. The specific roles of MX2 in IFN-α-driven inhibition of HBV transcription and replication were assessed by MX2-specific shRNA interference (RNAi)., Results: Both MX2 alone and IFN-α substantially inhibited HBV replication, due to significant deceleration of the synthesis and slight acceleration of the turnover of viral RNA. RNAi knockdown of MX2 significantly reduced the inhibitory effects of IFN-α. Strikingly, MX2 inhibited HBV infection by reducing covalently closed circular DNA (cccDNA), most likely by indirectly impairing the conversion of relaxed circular DNA to cccDNA rather than by destabilizing existing cccDNA. Various mutations affecting the GTPase activity and oligomerization status reduced MX2's anti-HBV activity., Conclusion: MX2 is an important IFN-α inducible effector that decreases HBV RNA levels but can also potently inhibit HBV infection by indirectly impairing cccDNA formation. MX2 likely has the potential for therapeutic applications aimed at curing HBV infection by eliminating cccDNA., Lay Summary: This study shows that the protein MX2, which is induced by interferon-α, has important anti-hepatitis B virus (HBV) effector functions. MX2 can reduce the amount of covalently closed circular DNA, which is the form of DNA that HBV uses to maintain viral persistence within hepatocytes. MX2 also reduces HBV RNA levels by downregulating synthesis of viral RNA. MX2 likely represents a novel intrinsic HBV inhibitor that could have therapeutic potential, as well as being useful for improving our understanding of the complex biology of HBV and the antiviral mechanisms of interferon-α., Competing Interests: Conflict of interest The authors declare that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Design and application of epitope-based polyvalent vaccines have recently garnered attention as an efficient alternative for conventional vaccines. We previously have reported the in silico design of HHP antigen which encompasses the immune-dominant epitopes of Hepatitis B surface antigen (HBsAg), Hepatitis C core protein (HCVcp) and Poliovirus viral proteins (VPs). It has been shown that the HHP has desirable conformation to expose the epitopes, high antigenicity and other desired physicochemical and immunological properties. To confirm the accuracy of these predictions, the ex-vivo immunogenicity of the HHP was assessed. The HHP gene was chemically synthesized in pET28a and expressed in E. coli (BL21). The expressed protein was purified and its immunological potency was evaluated on dendritic cells (DCs) as antigen presenting cells (APCs). Functional analysis was assessed in co-cultivation of autologous T-cells with matured DCs (mDCs). T-cell activation, proliferation and cytokines secretion were evaluated using flowcytometry and ELISA methods. Our results indicated that the HHP could induce the DC maturation. The mDCs were able to trigger T-cell activation and proliferation. In silico design and ex-vivo confirmation of immunological potential could pave the way to introduce efficient immunogens for further analysis. The ability of HHP in DC maturation and T-cell activation makes it an amenable vaccine candidate for further in-vivo studies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier Inc.)

There have been various estimates of the prevalence of hepatitis B and C infections in Nigeria. Recent studies have shown the prevalence to be lower than previously reported. The different populations studied might be responsible for this. It is important to have a real population data that would inform the policies to be adopted for eradication. We set out to determine the prevalence, risk factors, and pattern of hepatitis B and C in Benue State, Central Nigeria. Four thousand and five (4,005) subjects, aged 1 year and older, were selected through a multistage random sampling to represent all parts of the state. Trained health workers administered a validated questionnaire. Rapid test kits were standardized and used in determining the prevalence of the respective viruses. Hepatitis B surface antigen (HBsAg) and antibodies to hepatitis C virus (anti-HCV) were found to be positive in 5% and 1%, respectively, of subjects screened. The prevalence varied from one local government area to another, with HBsAg being 8% in the highest to 2% in the lowest LGC, and anti-HCV being 3% in the highest and 0% in the lowest. Age, previous close contact with a patient, and multiple sex partners were the most important risk factors for hepatitis B virus (HBV) infection, whereas age and previous blood transfusion were the most important risk factors for hepatitis C virus (HCV) infection. HBV immunization may be having an impact in reducing the prevalence of the virus. Nigeria appears to be moving from high endemicity to the intermediate one.

Objective: To determine the outcome of the vaccination against hepatitis, we determined the prevalence of hepatitis B virus (HBV) and hepatitis D virus (HDV) infections, eight years after introduction of the vaccination., Materials and Methods: A cross-sectional study was performed in 2 944 participants of 67 Kandozi and Chapra indigenous peoples in April 2010. Serological screening for hepatitis B surface antigen (HBsAg), antibody anti-HBc IgM and IgG, antibody anti-HBs and anti-HDV were determined by ELISA tests., Results: The prevalence rates of HBsAg, anti-HBc total, anti- HBs ≥10 mlUI/ml and anti-HDV were 2.3, 39.13, 50.95 and 2.11%, respectively. The prevalence rate of HBsAg in children <11 years was 0%. Among carriers of HBsAg, the prevalence rates of HDV and acute HBV infections were 2.11% (all were >14 years) and 11.94%, respectively. HBsAg and anti-HBc total were associated with individuals ≥10 years (p<0.001)., Conclusions: These findings show the elimination of HBVmcarriers in children <11 years, eight years following introduction of the vaccination against HBV., Competing Interests: Declaration of conflict of interests. The authors declare that they have no conflict of interests.

Background & Aims: Quantification of anti-HBs and anti-HBc predicts the risk of HBV reactivation (HBVr) in lymphoma patients receiving rituximab treatment. However, it remains unclear whether the quantification is predictive of HBVr in leukemia patients undergoing immunosuppression., Methods: and patients: Clinical and laboratory data of the leukemia patients with resolved HBV infection diagnosed between January 2013 and March 2018 were retrospectively collected. Data series of HBV seromarkers and HBV DNA levels before the patients receiving chemotherapy and/or hematopoietic stem cell transplantation (HSCT) and during follow-up duration were analyzed., Results: In total, 533 leukemia patients with resolved HBV infection were included. The incidences of HBVr were 5.7% (25/441) and 2.2% (2/92) in patients receiving HSCT and chemotherapy, respectively. In patients receiving HSCT, acute lymphoid leukemia had a significantly higher incidence of HBVr than acute myeloid leukemia (8.9% vs 3.9%, P < 0.05). The incidence varied almost zero to 40% due to the differences in the profiles of HBV antibodies. High anti-HBs (cut-off of 79.2 IU/L) or low anti-HBc levels (cut-off of 4.475, S/CO) at baseline were associated with a low risk of HBVr. Anti-HBe status did not affect the incidence of HBVr. However, the cut-offs were only predictive of HBVr in the patients who had negative anti-HBe., Conclusion: The baseline profiles of HBV antibodies are predictive of the risk of HBVr in leukemia patients undergoing immunosuppression. However, seronegative anti-HBe is a prerequisite for using baseline anti-HBs and anti-HBc quantification to predict HBVr risk., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Hepatitis B virus (HBV) infection is still a concern in vulnerable populations. In a study performed by our team in 1999-2003 in two Afro-Brazilian communities, Furnas dos Dionísios (FD) and São Benedito (SB), high prevalence rates of HBV exposure (42.7% and 16.0%, respectively), high susceptibility to HBV (55.3% and 63.0%) and low HBV vaccination like profile rates (2.0% and 21.0%) were observed. In 2015-2016, we reassessed HBV epidemiological and molecular features in these two communities to verify the impact of health actions adopted in the last years. The prevalence rate of HBV exposure among the enrolled 331 subjects was 35.3% in FD and 21.8% in SB. HBV chronic infection (5.8% in FD, 4.9% in SB) remained high. The rate of HBV vaccination like profile increased from 10.7% to 43.5% (2.0% to 45.9% in FD, 21.0% to 39.5% in SB) while susceptible subjects declined from 58.9% to 26.3% (55.3% to 18.8% in FD, 63.0% to 38.7% in SB). Among 18 HBsAg positive samples, 13 were successfully sequenced (pre-S/S region). Phylogenetic analyses showed that all isolates belong to HBV subgenotype A1, clustering within the Asian-American clade. Despite the maintenance of high prevalence rate of HBV exposure over these 13 years of surveillance, significant improvements were observed, reinforcing the importance of facilitated HBV vaccination to difficult-to-access population to close gaps in prevention.