CpG-C ODN M362 as an immunoadjuvant for HBV therapeutic vaccine reverses the systemic tolerance against HBV.

Chronic Hepatitis B virus (CHB) infection is a global public health problem. Oligodeoxynucleotides (ODNs) containing class C unmethylated cytosine-guanine dinucleotide (CpG-C) motifs may provide potential adjuvants for the immunotherapeutic strategy against CHB, since CpG-C ODNs stimulate both B cell and dendritic cell (DC) activation. However, the efficacy of CpG-C ODN as an anti-HBV vaccine adjuvant remains unclear. In this study, we demonstrated that CpG M362 (CpG-C ODN) as an adjuvant in anti-HBV vaccine (cHBV-vaccine) successfully and safely eliminated the virus in HBV-carrier mice. The cHBV-vaccine enhanced DC maturation both in vivo and in vitro, overcame immune tolerance, and recovered exhausted T cells in HBV-carrier mice. Furthermore, the cHBV-vaccine elicited robust hepatic HBV-specific CD8+ and CD4+ T cell responses, with increased cellular proliferation and IFN-γ secretion. Additionally, the cHBV-vaccine invoked a long-lasting follicular CXCR5+ CD8+ T cell response following HBV re-challenge. Taken together, CpG M362 in combination with rHBVvac cleared persistent HBV and achieved long-term virological control, making it a promising candidate for treating CHB.

Immunogenicity and Safety of a 3-Antigen Hepatitis B Vaccine vs a Single-Antigen Hepatitis B Vaccine: A Phase 3 Randomized Clinical Trial.

Importance: There is a need for improved immunogenicity of hepatitis B virus (HBV) vaccines among young adults with risk of infection. Objectives: To demonstrate manufacturing equivalence of a 3-antigen (3A) HBV vaccine, evaluate noninferiority of seroprotection rate (SPR) of 3A-HBV vs single-antigen (1A) HBV after 2 and 3 vaccine doses, and compare safety and reactogenicity between 3A-HBV and 1A-HBV vaccines. Design, Setting, and Participants: This phase 3, double-blinded, randomized clinical trial included healthy adults aged 18 to 45 years randomized to 1 of three 3A-HBV groups or 1 control group receiving 1A-HBV. The trial was conducted at 37 community clinics and academic hospitals in Canada, Europe, the United Kingdom, and the United States between December 2017 and October 2019. Participants were followed up for 48 weeks after the first vaccination. Interventions: Intramuscular administration of 3A-HBV (10 µg) or 1A-HBV (20 µg) on days 0, 28, and 168. Main Outcomes and Measures: Geometric mean concentration (GMC) of serum hepatitis B surface antibodies (anti-HBs) and proportion of participants achieving seroprotection. Results: Of 2838 participants, 1638 (57.8%) were women, 2595 (91.5%) were White, and 161 (5.7%) were Black or African American. A total of 712 participants (25.1%) were randomized to the 1A-HBV group and 2126 (74.9%) to 3A-HBV. The mean (SD) age at informed consent was 33.5 (8.0) years. The study demonstrated 3A-HBV lot-to-lot consistency, as the 2-sided 95% CIs for each pairwise comparison for the anti-HBs GMC ratios were within 0.67 and 1.50 (eg, adjusted GMC ratio, lot A vs lot B: 0.82; 95% CI, 0.67-1.00; lot A vs lot C: 0.95; 95% CI, 0.78-1.15; lot B vs lot C: 1.16; 95% CI, 0.95-1.41). The SPR of the pooled 3A-HBV was noninferior to 1A-HBV and higher than 1A-HBV after 2 vaccinations at day 168 (90.4% [95% CI, 89.0%-91.8%] vs 51.6% [95% CI, 47.5%-55.6%]) and 3 vaccinations at day 196 (99.3% [95% CI, 98.7%-99.6%] vs 94.8% [95% CI, 92.7%-96.4%]). The mean GMC of anti-HBs with 3A-HBV was 7.9 times higher after 2 vaccinations at day 168 and 3.5 times higher after 3 vaccinations at day 196 compared with 1A-HBV (after 2 vaccinations, 3A-HBV: GMC, 118.7 mIU/mL; 95% CI, 108.0-129.0 mIU/mL; SE, 1.0 mIU/mL; 1A-HBV: GMC, 15.0 mIU/mL; 95% CI, 12.9-17.5 mIU/mL; SE, 1.0 mIU/mL; after 3 vaccinations, 3A-HBV: GMC, 5442.4 mIU/mL; 95% CI, 4967.0-5963.0 mIU/mL; SE, 1.0 mIU/mL; 1A-HBV: 1567.2 mIU/mL; 95% CI, 1338.0-1834.0 mIU/mL; SE, 1.0 mIU/mL). Rates of local and systemic reactogenicities were higher with 3A-HBV compared with 1A-HBV (local: 1805 of 2124 [85.0%] vs 469 of 712 [65.9%]; systemic: 1445 [68.0%] vs 428 [60.1%]). Vaccine discontinuation due to adverse events (AE) was uncommon, and serious AEs were infrequent, reported in 42 participants (2.0%) and 3 participants (0.4%) in the 3A-HBV and 1A-HBV groups, respectively. Conclusions and Relevance: In this study, consistently higher antibody concentrations and SPRs were found with 3A-HBV after 2 and 3 doses vs 1A-HBV in adults aged 18 to 45 years old. The safety and efficacy of 3A-HBV shows its usefulness for the prevention of hepatitis B in young healthy adults. Trial Registration: Clinicaltrials.gov Identifier: NCT03408730; EU Clinical Trials Number: 2017-001820-22.

Humoral Response after SARS-CoV-2 mRNA Vaccination in a Cohort of Hemodialysis Patients and Kidney Transplant Recipients.

BACKGROUND: Kidney transplant recipients and patients receiving hemodialysis are immunocompromised populations that are prioritized for COVID-19 vaccination but were excluded from clinical trials of SARS-CoV-2 mRNA vaccines. Antibody titers and rates of seroconversion after vaccination are lower among patients with CKD and those taking immunosuppressants compared with controls. Data are lacking regarding their humoral response to vaccination to prevent COVID-19. METHODS: This investigation of early serological response after COVID-19 vaccination with the Pfizer/BioNTech (BNT162b2) mRNA vaccine included 78 patients undergoing hemodialysis, 74 kidney transplant recipients, and seven healthy controls. We recorded data from the medical file for various clinical parameters, including response to hepatitis B vaccination, and measured antibody titers against SARS-CoV-2 at 0, 14, 28, 36, and 58 days after the first injection. RESULTS: In controls, we detected antibodies at a positive level (>13 arbitrary units per ml; AU/ml) at day 14 postinjection, which increased progressively to peak at day 36 (1082 AU/ml; interquartile range [IQR], 735.0-1662.0). Patients undergoing hemodialysis had lower titers that peaked at day 58 (276 AU/ml; IQR, 83.4-526.0). We detected a positive antibody level in only three transplant recipients at day 36. In patients on hemodialysis, those aged <75 years had a higher antibody response versus those aged >75 years, and serum albumin and Kt/V were positively correlated with serological response (P<0.04 and P<0.0, respectively); nonresponders to HBV vaccine had the lowest anti-SARS-CoV-2 antibody titers. CONCLUSIONS: Our results suggest that the postvaccination humoral response is strongly inhibited by immunosuppressant therapy in kidney transplant recipients, and is reduced by the uremic condition in patients undergoing hemodialysis.

Association of Routine Hepatitis B Vaccination and Other Effective Factors with Hepatitis B Virus Infection: 25 Years Since the Introduction of National Hepatitis B Vaccination in Iran.

Background: One of the main health problems in the world is hepatitis B virus (HBV) infection. Vaccination and other factors can affect HBV infection. As various effective factors have been reported in different regions and studies, this study aimed to investigate the association between HBV infection and routine vaccination and other effective factors 25 years since the launch of the national vaccination program in Iran. Methods: This cross-sectional study, conducted in 2017 in Shiraz (Iran), investigated factors such as demographic variables such as gender, education, and occupation, vaccination status, and the potential risk factors for HBV infection. Hepatitis B surface antigen (HBsAg) and anti-hepatitis B core antibody (HBc Ab) tests were performed to determine HBV infection status. The data were analyzed using R software (version 3.5.2), using multivariate logistic regressions and machine learning methods. The level of significance was considered below 0.05. Results: A total of 2720 individuals were enrolled in the study (194 cases with HBV infection). Based on the logistic regression analyses, factors such as a family history of the disease (OR=2.53, P<0.001), vaccination (OR=0.57, P=0.004), a history of high-risk behaviors (OR=1.48, P=0.022), and occupation (OR=1.80, P=0.035) were significantly associated with HBV infection. Based on the conditional tree method, a family history of infection (P<0.001) and vaccination (P=0.023) were two important factors in classifying individuals for HBV infection. Conclusion: Based on the different methods applied in this study, HBV infection was affected by factors such as a family history of the disease, national HBV vaccination, and occupation. It appears that HBV vaccination, launched by the Iranian Ministry of Health and Medical Education in 1993, has reduced HBV infection.

Decrease in the prevalence of hepatitis B and D virus infections in an endemic area in Peru 23 years after the introduction of the first pilot vaccination program against hepatitis B.

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.

Prevalence of viral hepatitis B in Ghana between 2015 and 2019: A systematic review and meta-analysis.

Chronic hepatitis B (HBV) remains a significant public health problem in Ghana and past reviews conducted could not calculate a nationwide prevalence of the disease due to lack of primary research for some regions of the country. We therefore conducted this study to summarize and update the available information on HBV infection burden (prevalence) in Ghana from 2015-2019.We systematically searched PubMed, Embase, ScienceDirect, and Google Scholar to retrieve primary studies published in peer-reviewed journals from November 2015 to September 2019, assessing the prevalence of HBV among the Ghanaian populace. The review included 21 studies across all ten old regions of Ghana with a total sample population of 29 061. The HBV prevalence was estimated for subpopulations as follows: 8.36% in the adult population, 14.30% in the adolescent population, and 0.55% in children under five years (pre-school). Among adults, HBV infection prevalence was the highest in the special occupation group (14.40%) and the lowest prevalence rate of 7.17% was recorded among blood donors. Prevalence was lower in the north than in the southern part of the country. The Ashanti region had the most studies at 6/21 (29%), while no study was identified for the Upper West region. Across the country, the highest HBV infection prevalence rates were recorded in the age group of 20-40 years. The burden of hepatitis B is enormous and remains an important public health issue in Ghana. Addressing the issue will require an integrated public health strategy and rethinking of the implementation gaps in the current HBV infection control program. This will help propel the country towards eliminating the disease by 2030.

Novel Hepatitis B Virus Capsid Assembly Modulator Induces Potent Antiviral Responses In Vitro and in Humanized Mice.

Hepatitis B virus (HBV) affects an estimated 250 million chronic carriers worldwide. Though several vaccines exist, they are ineffective for those already infected. HBV persists due to the formation of covalently closed circular DNA (cccDNA)-the viral minichromosome-in the nucleus of hepatocytes. Current nucleoside analogs and interferon therapies rarely clear cccDNA, requiring lifelong treatment. Our group identified GLP-26, a novel glyoxamide derivative that alters HBV nucleocapsid assembly and prevents viral DNA replication. GLP-26 exhibited single-digit nanomolar anti-HBV activity, inhibition of HBV e antigen (HBeAg) secretion, and reduced cccDNA amplification, in addition to showing a promising preclinical profile. Strikingly, long term combination treatment with entecavir in a humanized mouse model induced a decrease in viral loads and viral antigens that was sustained for up to 12 weeks after treatment cessation.

DTaP-IPV-HepB-Hib Vaccine (Hexyon®): An Updated Review of its Use in Primary and Booster Vaccination.

Hexyon® is a fully-liquid, ready-to-use, hexavalent vaccine approved in the EU since 2013 for primary and booster vaccination in infants and toddlers from age 6 weeks against diphtheria, tetanus, pertussis, hepatitis B (HB), poliomyelitis, and invasive diseases caused by Haemophilus influenzae type b (Hib). While the source of HB antigen in Hexyon® is different from other vaccines, the rest of its valences have been extensively used in other approved vaccines. Hexyon® is highly immunogenic for all its component toxoids/antigens when used as primary and booster vaccine in infants and toddlers, irrespective of vaccination schedule. It provides durable protection against hepatitis B. Hexyon® can be used for a mixed primary series of hexavalent-pentavalent-hexavalent vaccines or as a booster in infants primed with Infanrix hexa™ or pentavalent (whole-cell or acellular pertussis) vaccines. Coadministration of Hexyon® with other common childhood vaccines did not affect immune response to any vaccines. Hexyon® has a good reactogenicity/safety profile. The immunogenicity and safety profile of Hexyon® was similar to that of several approved vaccines, including Infanrix hexa™. However, Hexyon® offers the convenience of full-liquid, ready-to-use formulation, which may minimize vaccination errors and preparation time. Thus, Hexyon® is a convenient, useful option for vaccination against childhood diseases caused by six major pathogens.

Molecular Evaluation of Oral Immunogenicity of Hepatitis B Antigen Delivered by Hydrogel Microparticles.

The development of oral vaccine formulation is crucial to facilitate an effective mass immunization program for various vaccine-preventable diseases. In this work, the efficacy of hepatitis B antigen delivered by bacterial nanocellulose/poly(acrylic acid) composite hydrogel microparticles (MPs) as oral vaccine carriers was assessed to induce both local and systemic immunity. Optimal pH-responsive swelling, mucoadhesiveness, protein drug loading, and drug permeability were characterized by MPs formulated with minimal irradiation doses and acrylic acid concentration. The composite hydrogel materials of bacterial nanocellulose and poly(acrylic acid) showed significantly greater antigen release in simulated intestinal fluid while ensuring the integrity of antigen. In in vivo study, mice orally vaccinated with antigen-loaded hydrogel MPs showed enhanced vaccine immunogenicity with significantly higher secretion of mucosal immunoglobulin A, compared to intramuscular vaccinated control. The splenocytes from the same group demonstrated lymphoproliferation and significant increased secretion of interleukin-2 cytokines upon stimulation with hepatitis B antigen. Expression of CD69 in CD4+ T lymphocytes and CD19+ B lymphocytes in splenocytes from mice orally vaccinated with antigen-loaded hydrogel MPs was comparable to that of the intramuscular vaccinated control, indicating early activation of lymphocytes elicited by our oral vaccine formulation in just two doses. These results demonstrated the potential of antigen-loaded hydrogel MPs as an oral vaccination method for hepatitis B.

Evaluation of response to hepatitis B virus vaccine in adults with human immunodeficiency virus.

INTRODUCTION AND AIM: Viral hepatitis is a serious public health problem. The risk of progression to chronic hepatitis in hepatitis B virus (HBV) infection occurs in 5-10% of adults and is a leading cause of cirrhosis and hepatocellular carcinoma worldwide. Individuals infected with human immunodeficiency virus (HIV) may have coinfection with HBV. The existence of unvaccinated groups represents a significant risk not only individually but also at the community level. The aim of this study was to evaluate HBV vaccine response in adults with HIV infection. MATERIALS AND METHODS: A retrospective, descriptive study of the cross-sectional type was carried out in an outpatient HIV referral center in southern Brazil. All medical records of adult HIV patients seen during January 2006 to December 2015 were selected. In statistical analysis, a significance level of 5% was used. RESULTS: Of the 201 patients evaluated with a complete vaccination scheme, 55.72% were males, with a mean age of 43.86±12.68 years. Vaccine response occurred in 80.10% (161/201) of the patients, and it did not correlate with age, CD4+ cell count or viral load. CONCLUSION: HBV vaccine response in a HIV population was satisfactory, highlighting the importance of vaccination for prevention, cost reduction and better prognosis in preventing HBV/HIV coinfection.

Effectiveness of a hepatitis B vaccination program at two tertiary hemodialysis centers.

INTRODUCTION: Hemodialysis (HD) patients are at increased risk of hepatitis B infection in comparison to the general population. Despite a more intensified hepatitis vaccination regimen, response rates in HD patients are typically low. The study was conducted to quantify response rate to a new hepatitis B vaccination protocol initiated in late 2015, determine risk factors affecting response rate, and assess adherence to protocol. METHODS: This retrospective chart review evaluated all HD patients eligible for hepatitis B vaccination in two large dialysis clinics from initiation of the hepatitis B protocol to July 2017. Recombinant hepatitis vaccine (Recombivax® HB) 40 µg was administered in a 3-dose regimen at months 0, 1, and 6 to patients with hepatitis B surface antibodies (anti-HBs) <10 mIU/mL. A repeat series was given if anti-HBs levels remained below 10 mIU/mL after the first series. A booster dose was given if anti-HBs titers fell below 10 mIU/mL after initial response to a second series vaccination. FINDINGS: Of 411 patients at the two HD centers, 142 patients received hepatitis B vaccination with a total of 168 vaccine courses given, series 1: n = 86, series 2: n = 60 and booster: n = 22. Response rates to vaccination were 61.4%, 58.3%, and 81.8%, respectively. In univariate analysis, adherence to protocol significantly affected response rate (P = 0.035). A multivariate analysis assessing response rates to series 1, 2 or booster confirmed that adherence was a significant risk factor (OR = 2.2; 95% CI 1.4-3.4; P = 0.0005). DISCUSSION: This was the first study to examine adherence to regimen and identified adherence as an important predictor of vaccine response. Adherence is one of the few modifiable risk factors that can be optimized in an effort to improve response to hepatitis B vaccination.

Contribution of sex­based immunological differences to the enhanced immune response in female mice following vaccination with hepatitis B vaccine.

Hepatitis B virus (HBV) vaccination is regarded as the most economical and effective method for the prevention and control of HBV infection, a major global health problem. Previous studies have suggested that there may be sex­specific differences regarding the immune response to the HBV vaccine in humans; however, the mechanisms associated with these sex­specific differences are yet to be elucidated. In the present study, sex­based immunological differences in mice following HBV vaccination were investigated to determine the mechanisms underlying sexual dimorphism, with the aim of identifying potential targets for clinical intervention. Balb/c mice (n=6) were vaccinated intramuscularly on 3 different days (days 0, 14 and 28) with the HBV vaccine. Sera were analyzed via ELISA for the presence of HBV surface antigen (HBsAg)­specific immunoglobulin G (IgG), and of different IgG subtypes, 3 weeks following the third injection. Enzyme­linked immunosorbent spot assays were conducted to determine interleukin­4/interferon­Î³ secretion. Immunological memory stimulated by the vaccine was detected via flow cytometry analysis and ELISA 1 week following the booster immunization. The seroconversion of the treated female group was higher compared with the male group at one week following the second vaccination. Female mice exhibited significantly increased HBsAg antibody titers compared with males at 1­5 weeks following the third vaccination. Sera obtained from vaccinated female mice exhibited markedly increased titers of IgG1 and IgG2b compared with those from male mice. Furthermore, female mice exhibited elevated cytotoxic T lymphocyte responses and immune memory. Collectively, the results of the present study indicated that sex­based immunological differences affected the dynamics and characteristics of the immune response in mice immunized with the HBV vaccine.

Glucan Particles Are a Powerful Adjuvant for the HBsAg, Favoring Antiviral Immunity.

The lack of vaccine adjuvants that are able to induce robust T cell responses fosters the search for more powerful options. Pathogen-like particles are a promising approach. The adjuvant activity of pathogen-like particles is highly influenced by size and surface composition. This study aimed to evaluate the adjuvant potential of two different ß-glucan-based particles, blend chitosan/ß-glucan particles (ChiGluPs), which are positively charged and have mean size of 1276 nm, and neutral yeast-derived glucan particles (GPs), with a mean size of 3 µm. Additionally, chitosan particles (ChiPs) were used to understand the effect of ß-glucan addition (ChiGluPs). Mouse spleen cells responded through the production of either TNF-α or RANTES, following in vitro stimulation with particles containing either ß-glucan (ChiGluPs and GPs) or chitosan (ChiGluPs and ChiPs). Human monocytes responded to all particles through TNF-α secretion. Subcutaneous vaccination of mice with the hepatitis B surface antigen (HBsAg) showed increased serum IgG for all particles compared to HBsAg alone (435-, 4500-, or 2500-fold increase for either ChiPs, ChiGluPs, or GPs). Interestingly, only GPs elicited the secretion of HBsAg-specific Th1, Th2, Th9, Th17, Th22, and Treg-related cytokines. This study demonstrates, for the first time, that GPs can have a significant role against the hepatitis B virus by favoring antiviral immunity.

Could hepatitis B vaccine act as an adjuvant to lower risk and relapses of cancer?

In this review article, we hypothesize that Hepatitis B Virus Vaccine (HBV-V) and certain antigens of Hepatitis B Virus (HBV) could act as anticancer immunoadjuvants in addition to their role of preventing HBV-associated liver cancer. Evidence suggests that in animal breast cancer and melanoma models, combining hepatitis B-surface antigen (HBsAg) with other cancer antigens resulted in enhanced antitumour activity. HBsAg shares antigenic mimicry with healthy and malignant cells including squamous epithelia, thymic epithelia, bladder- and colon cancer cells. There exist anecdotal reports and small case series about spontaneous remission of leukaemias and neuroblastoma following acute HBV-infection. Recent studies also exist showing HBV-carrier state is a good prognostic factor for intrahepatic cholangiocarcinoma. Further epidemiological studies and animal experiments are necessary whether HBV-Vs exert additional immunoadjuvant benefits besides lowering the risk of liver cancer.

Adjuvant effect of Vernonia amygdalina leaf extract on host immune response to hepatitis B virus subunit vaccine.

Aim of the study: Adjuvants can increase the efficiency and reduce the number of required doses for hepatitis B vaccination. Thus the study was designed to investigate whether V. amygdalina leaf extract may be used as an adjuvant to the conventional hepatitis B surface antigen-based vaccine through humoral response analyses. Methodology: The toxicity/safety margin of V. amygdalina was determined using Lorke's method. Immunization was carried out in mice in two phases, phase 1 employed a 3-times vaccination schedule while phase 2 tested 2-times vaccination schedule. The humoral immune response was determined using ELISA test. The total white blood count, different white blood count, aspartate aminotransferase level, alanine aminotransferase level were determined and the body weight of the mice periodically monitored. Results: Our data show that V. amygdalina was not toxic up to the dose of 5000 mg/kg bodyweight (bw). At a concentration of 250 mg/kg bw as an adjuvant in a three times vaccination schedule, it increased IgM, IgG1 and IgA antibody responses. In a 2-times vaccination schedule, 1000 mg/kg of V. amygdalina as an adjuvant to hepatitis B vaccine was able to elicit effective antibody production (0.174±0.002) significantly (P <0.05) higher than the conventional hepatitis B vaccine group (0.109±0.002) which received 3-times vaccine dose. It equally enhanced innate cell-mediated immune response by increasing total white blood cell, neutrophil and lymphocyte counts. The adjuvant-vaccine combination did not produce side effects as the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were within the normal ranges. The liver excised from the sacrificed mice at the end of the vaccination series showed no sign of congestion, inflammation or colour change. Periodic mice body weight monitoring showed similar growth pattern between the treatment and control groups. Conclusion: Results obtained suggest that V. amygdalina may serve as an effective adjuvant to hepatitis B virus vaccine.

HBV vaccination and PMTCT as elimination tools in the presence of HIV: insights from a clinical cohort and dynamic model.

BACKGROUND: Sustainable Development Goals set a challenge for the elimination of hepatitis B virus (HBV) infection as a public health concern by the year 2030. Deployment of a robust prophylactic vaccine and enhanced interventions for prevention of mother to child transmission (PMTCT) are cornerstones of elimination strategy. However, in light of the estimated global burden of 290 million cases, enhanced efforts are required to underpin optimisation of public health strategy. Robust analysis of population epidemiology is particularly crucial for populations in Africa made vulnerable by HIV co-infection, poverty, stigma and poor access to prevention, diagnosis and treatment. METHODS: We here set out to evaluate the current and future role of HBV vaccination and PMTCT as tools for elimination. We first investigated the current impact of paediatric vaccination in a cohort of children with and without HIV infection in Kimberley, South Africa. Second, we used these data to inform a new parsimonious model to simulate the ongoing impact of preventive interventions. By applying these two approaches in parallel, we are able to determine both the current impact of interventions, and the future projected outcome of ongoing preventive strategies over time. RESULTS: Existing efforts have been successful in reducing paediatric prevalence of HBV infection in this setting to < 1%, demonstrating the success of the existing vaccine campaign. Our model predicts that, if consistently deployed, combination efforts of vaccination and PMTCT can significantly reduce population prevalence (HBsAg) by 2030, such that a major public health impact is possible even without achieving elimination. However, the prevalence of HBV e-antigen (HBeAg)-positive carriers will decline more slowly, representing a persistent population reservoir. We show that HIV co-infection significantly reduces titres of vaccine-mediated antibody, but has a relatively minor role in influencing the projected time to elimination. Our model can also be applied to other settings in order to predict impact and time to elimination based on specific interventions. CONCLUSIONS: Through extensive deployment of preventive strategies for HBV, significant positive public health impact is possible, although time to HBV elimination as a public health concern is likely to be substantially longer than that proposed by current goals.

Dynamical analysis for a hepatitis B transmission model with immigration and infection age.

Hepatitis B virus (HBV) is responsible for an estimated 378 million infections worldwide and 620, 000 deaths annually. Safe and effective vaccination programs have been available for decades, but coverage is limited due to economic and social factors. We investigate the effect of immigration and infection age on HBV transmission dynamics, incorporating age-dependent immigration flow and vertical transmission. The mathematical model can be used to describe HBV transmission in highly endemic regions with vertical transmission and migration of infected HBV individuals. Due to the effects of immigration, there is no disease-free equilibrium or reproduction number. We show that the unique endemic equilibrium exists only when immigration into the infective class is measurable. The smoothness and attractiveness of the solution semiflow are analyzed, and boundedness and uniform persistence are determined. Global stability of the unique endemic equilibrium is shown by a Lyapunov functional for a special case.

Vaccination with a DNA vaccine encoding CD317-targeting HBs antigen elicits enhanced immunity in mice.

BACKGROUND: Conventional hepatitis B virus (HBV) vaccines fail to induce protective antibody titers in 5-10% of immune-competent vaccines. Therefore, safe and effective HBV vaccines are still clinically needed. METHODS: In this study, we developed a plasmid DNA vaccine encoding CD317 single-chain fragment variable (α317scFv) linked with the hepatitis B surface antigen (HBsAg) and detected the humoral and cellular immune responses elicited by this vaccine in BALB/c mice. RESULTS: Vaccination with this fusion DNA vaccine in BALB/c mice induced more robust antiviral T cell and antibody immunity against HBsAg. Compared with mice vaccinated with control vaccine encoding HBsAg, the level of serum-circulating anti-HBsAg antibody (HBsAb) was nearly double in fusion DNA-vaccinated mice. More interesting, splenic lymphocytes isolated from fusion DNA-vaccinated mice showed more potent proliferation and IFN-γ production after being re-stimulated with recombinant HBsAg in vitro. And not only that, the cytotoxicity of fusion DNA vaccine-sensitized splenocytes was ∼3-fold higher than that of controls. CONCLUSION: Taken together, our results reveal that the fusion DNA vaccine can induce more effective immunological protection against HBV, and is a promising candidate for preventing HBV infection.

Towards the elimination of hepatitis B and hepatocellular carcinoma.

Hepatitis B (HBV) remains a global health problem despite the availability of effective vaccines since 1982 and effective antiviral therapy. The global burden of disease is substantial, with HBV resulting in 887 220 deaths in 2015: acute hepatitis (87 076), cirrhosis (462 690) and hepatocellular carcinoma (337 454). The World Health Organization has a vision to eliminate viral hepatitis as a public health threat by 2030. Although HBV and its associated complications of cirrhosis, liver failure and hepatocellular carcinoma are entirely vaccine preventable, there is no cure for chronic hepatitis B as yet. HBV elimination strategies will need to focus on effective and implementable preventive and therapeutic strategies such as upscaling HBV birth-dose vaccination, full HBV vaccine coverage, vaccination of high-risk groups, prevention of mother-to-child transmission, and identification of HBV-infected individuals and linkage to care with sustainable access to antiviral therapy.