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The WHO recommends hepatitis B birth-dose vaccination (HepB-BD), but it is not routinely given in most sub-Saharan African countries. We aimed to assess the immunogenicity of HepB-BD in addition to the existing hepatitis B vaccine (HepB3) schedule in Kinshasa, Democratic Republic of Congo among HBV-unexposed and HBV-exposed infants. Using an open-label, randomised, controlled design, HBV-unexposed infants were randomised (1:1) to receive the standard HepB3 vaccine series (group U3), or to receive HepB-BD in addition to HepB3 (group U4). A supplemental cohort of HBV-exposed infants (group E4) received HepB-BD and HepB3. We compared the proportion of infants with protective antibodies against HBV (HBV surface antibody ≥ 10 mIU/mL) between groups U3 and U4 and groups U4 and E4 at 12 months of age. Between August 20 and October 9, 2019, we enrolled 281 mother/infant dyads; 88 (31.3%) returned at 12 months. Most infants had protective antibodies against HBV at 12 months: 92.9% (75.7%-98.2%) in group U3, 85.7% (67.5%-94.5%) in group U4 and 96.9% (95% CI: 81.2%-99.6%) in group E4. Trends held in estimates adjusted for loss-to-follow-up (LTFU) and baseline imbalance across groups. In this first randomised trial assessing the addition of HepB-BD to the hepatitis B vaccine schedule in SSA, we found that HBV-unexposed infants who received the 3-dose and 4-dose vaccine series had similar immunogenicity against HBV at 12 months. A high proportion of infants, and notably HBV-exposed infants, had protective antibodies. Though extrapolation of findings may be limited by LTFU, this study adds real-world evidence regarding HepB-BD implementation in sub-Saharan Africa. Trial Registration: ClinicalTrials.gov identifier: NCT03897946., (© 2024 John Wiley & Sons Ltd.)

Using a systematic review and meta-analytic approach, this study determined the durability of HBV immunity and the prevalence of anamnestic response to a booster HBV vaccine dose in individuals previously vaccinated with a 3-dose HBV vaccine series as children or adolescents. Two researchers independently searched PubMed, Embase and Cochrane from inception to 6/1/2023 and performed data extraction. Studies that included individuals with significant comorbidities or < 5 years of follow-up were excluded. Of 2517 potential studies, we analysed 91 eligible studies (193,359 individuals from 208 cohorts [some studies provided data for more than one cohort]). Median age at vaccination was 0 years (range: 0-20.00). After a median follow-up of 10.15 years (range: 5-35), 63.2% (95% CI: 59.3-67.0) retained HBV immunity. HBV immunity declined by 6.62% per follow-up year (Ptrend < 0.0001). In meta-regression adjusting for vaccine type, follow-up time and geographic location, age at vaccination was significantly associated with retaining HBV immunity (adjusted odds ratio [aOR] 1.12 per year, p < 0.0001). Anamnestic response rate (44 studies, 66 cohorts, 29,040 patients) was 90.34% (95% CI: 86.84-92.98), with highest rates in Europe and Asia, but only study setting (clinical versus community-based: aOR 2.21, p = 0.034) was an independent factor. HBV immunity prevalence was about 60% after 10 years following childhood vaccination. Anamnestic response rate was about 90% and varied by study setting. Testing for immunity should be considered in individuals with high exposure risk and distant vaccination history with booster as needed., (© 2025 John Wiley & Sons Ltd.)

Dendritic cells are the most potent antigen-presenting cells in immune therapeutic approaches for chronic hepatitis B (CHB) infection. Here, we developed a clinical trial to evaluate the efficacy and safety of autologous HBV vaccine-pulsed DCs and their induced T cells (HPDCT) in CHB patients. This was a randomised, prospective, open-label, multicentre, superiority study and 309 treatment-naive CHB patients were divided into HPDCT plus nucleos(t)ide analogues (NAs) group (n = 84), NAs mono-therapy group (n = 82), HPDCT plus Peg-interferon (Peg-IFN) group (n = 69), Peg-IFN mono-therapy group (n = 74). Twelve times of HPDCT vaccinations were given intravenously, and all the patients were followed up for 72 weeks. In total, 1836 HPDCT infusions were administered with no obvious toxicity and side effect although few patients had self-limited low fever. More patients got HBsAg loss in those receiving HPDCT therapy. Patients of HPDCT plus Peg-IFN group with HBV DNA < 1 × 10 7  IU/mL at baseline exhibited earlier, stronger and longer lasting of viral response, especially HBV DNA < 20 IU/mL, than those patients of Peg-IFN mono-therapy group, from week 24 till week 72 (p < 0.05). Comparable efficacy was observed between the patients of HPDCT plus NAs group and NAs mono-therapy groups. In addition, CD25 on CD8 + T cells and HBV-specific CD8 + T cell increased significantly in patients of HPDCT combined antiviral drugs therapy. HPDCT combined with antiviral drugs was safe and able to enhance T cell immunity. Furthermore, HPDCT combined with Peg-IFN could provide an incremental benefit to patients with baseline levels of lower HBV DNA. Trial Registration: ClinicalTrials.gov identifier: NCT01935635., (© 2025 John Wiley & Sons Ltd.)

Recently, HLA class II loci, including HLA-DPB1, have been reported to be associated with interindividual variance in the hepatitis B (HB) vaccine response. In this study, we investigated significant single nucleotide polymorphisms (SNPs) for anti-HBs antibody levels in 6867 healthy Koreans using a genome-wide association study (GWAS). In GWAS, the top 20 SNPs that showed significant association with anti-HBs levels (P < 1.0 × 10 -29 ) all resided in HLA-DPB1. Utilizing PCR sequencing, we verified the relationship of the top 3 most significant SNPs (rs1042169, rs9277355 and rs9277356) from the GWAS and genotypes of HLA-DPB1 with the HB vaccine response in Korean infants who received a scheduled vaccination. The DPB1*04:02 allele has G, C and A nucleotides for the 3SNP sites, and was significantly more frequent in responders than in nonresponders (10.9% vs 1.0%, P c  = 0.018). DPB1*05:01 was significantly more frequent in nonresponders than in responders (49.0% vs 31.1%, P c  = 0.018). In multivariate logistic regression, DPB1*04:02 showed a significant association with both vaccine response (P = 0.037, OR = 8.465) and high-titre response (P = 0.027, OR = 9.860). The haplotypes rs1042169 G - rs9277355 C - rs9277356 A showed a significant association with a high-titre response only (P = 0.002, OR = 2.941). In conclusion, DPB1*04:02 possessing rs1042169 G - rs9277355 C - rs9277356 A is an independent predictor of the HB vaccine response in Koreans., (© 2019 John Wiley & Sons Ltd.)

Background: The long-term administration of nucleotide analogues (NAs) and hepatitis B immune globulin (HBIG) comprises standard prophylaxis for patients with hepatitis B virus (HBV)-related liver diseases to prevent HBV reinfection after liver transplantation (LT). However, prolonging the prophylaxis strategy involves safety issues, such as the development of escape mutations and/or emerging resistant strains, and is also associated with high costs; further, it remains unclear how long prophylactic treatment should be continued., Method: Liver transplantation recipients responding to hepatitis B vaccination due to HBV-related liver diseases were retrospectively analysed after stopping HBIG and/or NAs, administered to prevent HBV reinfection, after long-term follow-up. The safety and effectiveness of the strategy were then evaluated for these responders., Result: Seventy-eight responders were enrolled. All responders discontinued HBIG, among which 36 stopped both HBIG and NAs. During follow-up, four recipients experienced HBV reinfection, which was associated with HBV escape mutations, after the withdrawal of both HBIG and NAs. No death or graft loss occurred in recipients during the follow-up period., Conclusion: A careful withdrawal of HBIG and/or NAs is feasible and safe for responders to hepatitis B vaccination receiving transplants for HBV-related liver diseases., (© 2019 John Wiley & Sons Ltd.)

According to international guidelines, healthcare workers and medical students immunized against HBV are periodically tested for anti-HBs IgG. Subjects who show an anti-HBs titre <10 mUI/mL must receive additional vaccine doses to induce a measurable antibody response. This study aimed to evaluate the long-time immunogenicity of anti-hepatitis B vaccination in a sample of medical students and residents of the University of Bari who attended the Hygiene Department for biological risk assessment (April 2014-June 2017). The strategy for the management of nonresponder subjects was evaluated. A total of 3676 students and residents were invited for testing according to a standardized protocol. Anti-HBs IgG was tested for in 3140 (85.4%) subjects: 1174/3140 (37.7%) subjects were negative. 14.6% (128/808) of subjects who received the vaccine during their 12th year of life and 45.8% (1056/2305) of subjects immunized during the first year of life (P < 0.0001) were negative. 1005/1174 (85.6%) seronegative subjects received a booster dose, and 903/1005 (89.9%) were tested for anti-HBs 1 month after the booster dose: 82/903 (9.1%) subjects were still negative. Of these, 56/82 (68.3%) received 2 additional doses of vaccine and 52/56 (92.9%) were tested 1 month after the third dose: 50/52 subjects (96.2%) developed a positive titre. In conclusion, several medical students, immunized at birth or at young age against HBV, did not develop protective titres against the virus. Our management strategy (booster retest; for negative subjects, 2 doses and retest) seems consistent with the purpose of evidencing immunological memory., (© 2018 John Wiley & Sons Ltd.)

Hepatitis B virus (HBV) infection is hyperendemic in Cameroon, and healthcare workers (HCWs) are at high risk of infection. We aimed to assess prevalence, risk factors and vaccine coverage of HBV infection among HCWs in Cameroon. We conducted a cross-sectional study in 16 hospitals across all regions of Cameroon. HCWs were tested for HBV using rapid diagnostic tests (RDT). We collected data on socio-demographics and HBV vaccination status. We estimated prevalence of HBV and used Poisson regression models with robust standard errors to model the prevalence ratios of HBV positivity between covariates. We enrolled 1824 of 1836 eligible HCWs (97.5%). The mean age was 34 (SD: 10) years, 65.3% (n = 1787) were women, and 11.4% (n = 1747) had three or more doses of the HBV vaccine. Overall, we found a HBV prevalence of 8.7% (95% CI: 5.2%-14.3%). Patient transporters had the highest crude prevalence (14.3%; 95%CI: 5.4%-32.9%), whereas medical doctors had the lowest (3.2%; 95%CI: 0.8%-12.1%). The Far North Region had the highest prevalence of HBV (24.0%; 95%CI: 18.3%-30.8%). HBV prevalence decreased with increasing doses of the HBV vaccine (10.3% for no doses vs 3.5% for three or more doses; P < 0.001). In conclusion, approximately 1 in 12 HCWs in Cameroon have evidence of HBV infection, yet fewer than 1 in 6 have been fully vaccinated. Our results illustrate the urgent need to scale up systematic HBV screening and targeted vaccination of HCWs in the region., (© 2018 John Wiley & Sons Ltd.)

Approximately 5% of the healthy adult population respond inadequately to the commercial recombinant hepatitis B vaccines. As the recombinant vaccines all have an aluminium-based adjuvant, we tried to enhance the immune response by adding a cytokine-based adjuvant. This new adjuvant AI20, containing 20 μg recombinant human IL-2 attached to 20 μg aluminium hydroxide, was added to HBVaxPro©-10 μg (HBAI20). In a double-blind randomized controlled trial (RCT), 24 naïve subjects were randomized to receive either HBAI20 or commercial HBVaxPro©-10 μg vaccine. In an open-label study, 10 nonresponders received HBAI20 vaccine. All participants received 3 vaccinations (0, 1 and 6 months). In the RCT, the occurrence of any adverse events or severe events was similar between the trial arms. At month 7, all naïve participants were seroprotected; moreover, 92% in the HBAI20 group had protective antibodies 10 days after the second vaccination vs 58% in the HBVaxPro©-10 μg group, P = .16. In the open-label study, no serious adverse events were noted. The HBAI20 vaccine was able to elicit protective anti-HBs titres in 90% of nonresponders, 1 month after the third vaccination. According to these results, the new HBAI20 vaccine seems safe, well-tolerated and may promote more rapid protection against hepatitis B infection., (© 2018 The Authors. Journal of Viral Hepatitis Published by John Wiley & Sons Ltd.)

Immunization with the hepatitis B vaccine is the most effective measure to prevent Hepatitis B Virus (HBV) infection. The aim of this study was to investigate the change in antibody levels induced by administration of the hepatitis B vaccine in children aged 1-16 year old in a large sample sized investigation. HBV markers were determined in 93 326 1- to 16-year-old hospitalized children who completed primary immunization as infants from south-west China, Chongqing. Analyses were performed on anti-HBs titre changes with increasing age, and the revaccination effect was evaluated in children aged 7-14. The percentage of protective antibody was between 45.29% and 63.33% in all age groups, but was higher in the 1-, 2- and 3-year-old groups (90.31%, 83.95% and 71.82%, respectively), and the rate of high-responder was 5.03%-10.56%, except in the 1-year-old group (23.33%). Additionally, 3.33%-25.79% of subjects had not seroconverted. There was no significant difference in antibody levels between girls and boys (P > .05). The Geometric Mean Titers in children with confirmed revaccination history were significantly higher than those with unknown or no revaccination history (P < .0001). In conclusion, the overall rate of protective anti-HBs was 67.10% with consecutive age groups from 1 to 16, it decreased from 90.31% to 45.29% for 1- to 8-year-old individuals, and interestingly, the rate increased from 45.46% to 63.33% for subjects aged 9-15. Anti-HBs titres were significantly improved after revaccination. Booster doses are recommended for those without seroconversion, especially children who live in school with other students or have family members with positive HBsAg., (© 2017 John Wiley & Sons Ltd.)

Hepatitis B virus (HBV) infection in the United States is the most common among Asians followed by non-Hispanic blacks. However, there have been few studies that describe HBV infection and immunity by racial group. Our study aimed to assess racial/ethnic disparities in the prevalence and awareness of HBV infection and immunity using nationally representative data. In the National Health and Nutrition Examination Survey 2011-2014, 14 722 persons had HBV serology testing. We estimated the prevalence of HBV infection, past exposure, and immunity by selected characteristics and calculated adjusted odds ratios using survey-weighted generalized logistic regression. Awareness of infection and vaccination history was also investigated. The overall prevalence of chronic HBV infection, past exposure and vaccine-induced immunity was 0.34% [95%CI 0.24-0.43], 4.30% [95%CI 3.80-4.81], and 24.4% [95%CI 23.4-25.4], respectively. The prevalence of chronic infection was 2.74% [95% CI 1.72-3.76] in Asians, 0.64% [95% CI 0.35-0.92] in non-Hispanic blacks, and 0.15% [95% CI 0.06-0.24] in non-Asian, non-blacks. Only 26.2% of those with chronic infection were aware of their infection. The prevalence of the past exposure was 21.5% [95%CI 19.3-23.7] in Asians, 8.92% [95%CI 7.84-9.99] in non-Hispanic blacks, 2.05% [95%CI 1.49-2.63] in non-Hispanic whites and 4.47% [95%CI 3.25-5.70] in Hispanics. Prevalence of vaccine-induced immunity by each race was 34.1% [95%CI: 32.0-36.2] in Asians, 25.5% [95%CI: 24.0-27.0] in non-Hispanic blacks, 24.0% [95%CI: 22.6-25.4] in non-Hispanic whites and 22.2% [95%CI: 21.3-23.3] in Hispanics. There are considerable racial/ethnic disparities in HBV infection, exposure and immunity. More active and sophisticated healthcare policies on HBV management may be warranted., (© 2017 John Wiley & Sons Ltd.)

In this study, anti-hepatitis B virus (HBV) immunity was evaluated in mice using several regimens of the HBV recombinant protein vaccine HBSS1 that expressed in CHO cells containing S (1-223 aa) and preS1 (21-47 aa) and recombinant adenovirus rAdSS1 vaccine. Further, the protective efficacy of these vaccine regimens was studied in a mouse model. High titres of antigen-specific antibodies and neutralizing activity were elicited in mice after vaccination. However, robust multi-antigen (preS1 and S)-specific cell-mediated immunity (CMI) was only detected in mice primed with HBSS1 and boosted with rAdSS1. Moreover, functional T-cell responses with high levels of cytokines and antigen-specific cytotoxic T-cell responses (CD107a + CD8 + ) were also detected in the mice. Rapid clearance of hepatitis B surface antigen and HBV DNA in blood and significantly decreased hepatitis B envelope antigen levels were observed in mice immunized with the heterogeneous prime-boost vaccine after hepatitis B virus challenge by hydrodynamic injection (HI) of pCS-HBV1.3. The clearance of HBV correlated well with antigen-specific CMI (Th1 and CTL responses) and cytokine profiles (IFN-γ, TNF-α, IL-2) elicited by vaccination. Taken together, our results might contribute to the development of new human HBV vaccines and a better understanding of the mechanisms underlying immune protection and clearance of hepatitis B virus infection., (© 2016 John Wiley & Sons Ltd.)

A persistent hepatitis B virus (HBV) infection is characterized by a lack of or a weak immune response to HBV, which may be reflective of tolerance to HBV. Efficient induction of HBV-specific immune response leads to the clearance of HBV in patients with a chronic HBV infection. CpG oligodeoxynucleotides (ODN) has a powerful adjuvant effect in HBV vaccination. A recent report demonstrated that the immunization by B/K CpG ODN (K3) wrapped by the nonagonistic Dectin-1 ligand, schizophyllan (SPG), namely K3-SPG, was more effective in the induction of antigen-specific immune response than that by K3. In this study, we examined the efficacy of K3-SPG as a HBV vaccine adjuvant. Wild-type (WT) mice and HBV transgenic (HBV-Tg) mice were subcutaneously immunized with hepatitis B surface antigen (HBsAg) alone, HBsAg and K3, or HBsAg and K3-SPG. The vaccination with HBsAg and K3-SPG significantly enhanced humoral and cellular immune response to HBV antigen compared to the other vaccinations in WT and HBV-Tg mice. K3-SPG induced the accumulation of dendritic cells (DCs) into draining lymph node and the activation of DCs. The expression of cytokines and chemokines related to Th1 and Th2 responses was upregulated after the vaccination including with K3-SPG. In conclusion, these results indicated that the vaccination using K3-SPG may overcome tolerance even in patients with chronic HBV infection., (© 2016 John Wiley & Sons Ltd.)

It is still controversial whether maternal anti-HBV antibodies (anti-HBVs) affect the infants' immune response to hepatitis B virus (HBV) vaccination. This multicentre study aims to address this question. First, we determined whether the transplacental transfer of maternal anti-HBVs occurs by measuring the titres of 90 anti-HBVs-positive pregnant women and their newborns. The anti-HBVs-positive rates of newborns ranged from 89.7% to 100.0%, depending on the maternal anti-HBVs titres. Secondly, we investigated the effects of maternal anti-HBVs on the immune response of infants to HBV vaccination. A total of 1063 mother-and-infant pairs were enrolled and divided into three groups with maternal anti-HBVs titres of <10 IU/L (negative - 37.9%), 10-499 and ≥500 IU/L. The infants' anti-HBVs-positive rate and titres were negatively correlated with maternal anti-HBVs titres: the anti-HBVs-positive rate of infants were 88.9% (360/405), 84.5% (381/451) and 77.3% (160/207) in mothers with low, intermediate and high antibody titres, respectively, P<.0001. Median titres of anti-HBVs (IU/L) among infants were 169.1, 141.0 and 79.4, respectively, P=.020. One hundred and sixty-two infants were negative for anti-HBVs after the standard vaccination, and 120 of 131 of these infants (91.6%) reached anti-HBVs positivity after the first "booster" dose. The maternal anti-HBVs titres did not significantly affect infant response to this booster. In summary, transplacental transfer of anti-HBVs occurs and high titres of maternal anti-HBVs may suppress the immune response of infants to the standard HBV vaccination. The current schedule of the 0, 1 and 6 month may not be the optimal choice of infants with anti-HBVs-positive mothers., (© 2016 John Wiley & Sons Ltd.)

We evaluated the immune response to neonatal HBV immunization in children of infected parents 10-18 years after primary vaccination. Healthy individuals immunized with an infantile course of three doses of HBV vaccine were tested for persistence of anti-HB surface antibody (HBsAb). Those with an HBsAb level of <10 IU/mL received a booster dose of the vaccine with subsequent doses to those without protective titres. HBsAb concentrations were determined 4 weeks after each dose of the booster vaccine. The data were analysed separately for three age groups: 10-11, 12-14 and 15-18 years old. A total of 541 healthy individuals were studied. The highest seroprotection rate of 48% was observed in the youngest vaccinees (10-11 years old). This declined to 26.5% in the oldest (15-18 years old) group (P = 0.008). The youngest vaccinees showed the highest rate of anamnestic immune responses (96%). However, 25% of oldest individuals failed to mount an anamnestic immune response in challenge with a booster dose of the vaccine (P = 0.005), suggesting waning immunity with increasing age. Age (OR: 0.80; P = 0.01) and prebooster HBsAb levels (OR: 0.37; P = 0.01) identified responders to first booster doses of the vaccine by logistic regression analysis. The majority of high-risk vaccinees showed anamnestic immune response 10-11 years after primary immunization. However, we found a significant proportion (25%) of older individuals with no anamnetic response, which suggests a waning of immune memory. Detailed long-term follow-up studies are necessary to determine the risk of natural infection among these individuals before a booster schedule can be recommended., (© 2016 John Wiley & Sons Ltd.)

DNA vaccine targeting delivery to DC represents one effective strategy to improve the immunogenicity of the vaccine. In a previous study, we developed a novel DC-targeting recombinant protein that can deliver plasmid DNA to DCs by an electrostatic coupling effect and can thus improve the uptake efficiency of DCs, improving the expression of plasmid DNA in DCs. In this study, we coupled the protein with the HBV DNA vaccine pSVK-HBVA and investigated whether the immunogenicity and antiviral ability of the vaccine can be improved in HBV transgenic mice. The results show that a stronger specific immune response can be induced in mice after immunization with the coupling vaccine. The HBV DNA copy number and circulating antigen HBsAg in the serum of HBV transgenic mice were significantly decreased. Therefore, this study has demonstrated that the DC-targeting protein has the ability to improve the immunogenicity and the antiviral activity of the HBV DNA vaccine pSVK-HBVA. These findings indicate that this DC-targeting protein can be a potential method for the delivery of DNA vaccines directly to DCs., (© 2016 John Wiley & Sons Ltd.)

It is an honour to be invited to recount the progress in our understanding and management of hepatitis B 50 years after the discovery of Australia antigen (Au Ag). During this half century, we have gone from identifying the causative agent--hepatitis B virus (HBV), understanding its biology and the disease it causes, to having vaccines that can prevent HBV infection and antiviral therapy that can suppress HBV replication and prevent progression of HBV-related liver disease. As a result of the progress, prevalence of HBV infection and morbidity and mortality from chronic HBV infection has declined., (© 2015 John Wiley & Sons Ltd.)

A serologic response to hepatitis B virus (HBV) defined as 'anti-HBc alone' is commonly observed, but its significance remains unclear. This study aimed to define the relationship between 'anti-HBc alone' serostatus and HBV infection, including HBV-specific T- and B-cell memory responses. We enrolled 31 'anti-HBc alone' patients. Total HBV DNA and cccDNA were tested by nested polymerase chain reaction (PCR) analysis in liver samples from 22 'anti-HBc alone' patients vs controls (chronic or resolved HBV infection), followed by HBsAg/HBcAg immunohistochemical (IHC) staining. IFN-γ secretion by HBV-specific T cells was compared in individuals who were 'anti-HBc alone' (n = 27), resolved HBV (n = 21), chronic HBV (n = 24) and 12 healthy controls using enzyme-linked immunospot (ELISpot) assays. An HBsAg-IgG B-cell ELISpot assay was performed in 'anti-HBc alone' patients before and after one dose of recombinant HBsAg vaccine. The majority (23/31, 74.2%) of the 'anti-HBc alone' individuals were co-infected with HCV. Infrequent intrahepatic total HBV DNA (2/22, 9.1%) and cccDNA (1/22, 4.5%) were detected in biopsies; HBsAg and HBcAg IHC staining was negative. HBV-specific T-cell responses were similar between 'anti-HBc alone' individuals and HBV resolvers. Circulating HBV-memory B-cell responses were detected in all 'anti-HBc alone' individuals, consistent with an HBsAg-specific memory pool. After one HBV vaccine dose, increased anti-HBs antibody levels were observed, accompanied by an expansion of HBsAg-specific memory B cells (P = 0.0226). 'Anti-HBc alone' individuals showed HBV-specific T-cell and memory B-cell responses typical of previous viral exposure and protective memory, suggesting a resolved infection., (© 2015 John Wiley & Sons Ltd.)

Infants infected with hepatitis B virus (HBV) face the risk of developing severe complications. Unfortunately, in spite of universal vaccination programmes, 5% or more of vaccinated newborns still do not achieve protective levels of anti-hepatitis B virus surface antigen titres (anti-HBs). The aim of this study was to use animal experiments and population-based research to determine whether maternal vaccination against HBV affects the outcome of neonatal vaccination. Six sows and 53 newborn piglets were used for this study and randomly assigned to the vaccination group (three 20 μg doses of recombinant HBV vaccine). All the piglets were followed up to 10 weeks of age, and peripheral blood was withdrawn for measurement of anti-HBs. A cross-sectional study was also conducted on 449 mothers with infants. A structured questionnaire was used to collect demographic, medical and maternal data, and their peripheral blood was collected for measurement of anti-HBs. The results of animal experiments demonstrated that nonvaccinated piglets born to vaccinated sows and nonvaccinated piglets born to nonvaccinated sows were negative for anti-HBs. Repeated measures analysis of variance showed that the titres of anti-HBs in vaccinated piglets born to vaccinated sows were significantly higher than in vaccinated piglets born to nonvaccinated sows (P < 0.05). In a population-based study, a cumulative logistic regression analysis showed that the strongest influences on neonatal anti-HBs titres were delay of the first vaccination dose [OR = 3.02(95% CI: 1.72-5.30)] and maternal anti-HBs titres [OR = 2.48(95% CI: 2.03-3.04)]. In conclusion, high maternal anti-HBs titres can enhance the response to HBV vaccination in infants., (© 2013 John Wiley & Sons Ltd.)

DNA-based vaccination appears of promise for chronic hepatitis B immunotherapy, although there is an urgent need to increase its efficacy. In this preclinical study, we evaluated the therapeutic benefit of cytokine (IL-2, IFN-γ) genes co-delivery with DNA vaccine targeting hepadnaviral proteins in the chronic duck hepatitis B virus (DHBV) infection model. Then, we investigated the persistence of replication-competent virus in the livers of apparently resolved animals. DHBV carriers received four injections of plasmids encoding DHBV envelope and core alone or co-delivered with duck IL-2 (DuIL-2) or duck IFN-γ (DuIFN-γ) plasmids. After long-term (8 months) follow-up, viral covalently closed circular (ccc) DNA was analysed in duck necropsy liver samples. Liver homogenates were also tested for in vivo infectivity in neonatal ducklings. Co-delivery of DuIFN-γ resulted in significantly lower mean viremia starting from week 21. Viral cccDNA was undetectable by conventional methods in the livers of 25% and 57% of animals co-immunized with DuIL-2 and DuIFN-γ, respectively. Interestingly, inoculation of liver homogenates from 7 such apparently resolved animals, exhibiting cccDNA undetectable in Southern blotting and DHBV expression undetectable or restricted to few hepatocytes, revealed that three liver homogenates transmitted high-titre viremia (3-5×10(10) vge/mL) to naïve animals. In conclusion, our results indicate that IFN-γ gene co-delivery considerably enhances immunotherapeutic efficacy of DNA vaccine targeting hepadnaviral proteins. Importantly, we also showed that livers exhibiting only minute amounts of hepadnaviral cccDNA could induce extremely high-titre infection, highlighting the caution that should be taken in occult hepatitis B patients to prevent HBV transmission in liver transplantation context., (© 2012 Blackwell Publishing Ltd.)

Most hepatitis B virus (HBV) vaccines consist of viral small surface (S) protein subtype adw2 expressed in yeast cells. In spite of good efficacy, HBV-genotype and subtype differences, escape mutants and insufficient Th1 activation remain potential problems. To address these problems, we generated recombinant Semliki Forest virus (rSFV) vectors encoding S protein, subtype adw2 or ayw2, or a fragment of the large surface protein, amino acids 1-48 of the pre-S1 domain, fused to S (pre-S1.1-48/S). The antigen loop in S protein and the selected pre-S1 sequences are known targets of neutralizing antibodies. BALB/c mice were immunized intravenously with 10(7) rSFV particles and 10(8) rSFV particles 3 weeks later. Antibodies induced by rSFV encoding S proteins reacted preferentially with subtype determinants of yeast-derived S antigen but equally well with patient-derived S antigen. Immunization with rSFV encoding pre-S1.1-48/S resulted in formation of pre-S1- and S-specific immunoglobulin G (IgG), while immunization with the isogenic mutant without S start codon induced pre-S1 antibodies only. Neutralizing antibodies were determined by mixing with plasma-derived HBV/ayw2 and subsequent inoculation of susceptible primary hepatocyte cultures from Tupaia belangeri. S/adw2 antisera neutralized HBV/ayw2 as effectively as antisera raised with S/ayw2. The pre-S1 antibodies also completely neutralized HBV infectivity. The IgG1/IgG2a ratios ranged from 0.28 to 0.88 in the four immunized groups and were lowest for the pre-S1.1-48/S vector, indicating the strongest Th1 response. This vector type may induce subtype-independent and S-escape-resistant neutralizing antibodies against HBV., (© 2012 Blackwell Publishing Ltd.)

A DNA vaccine against the hepatitis B virus (HBV), enhanced by IL-2/IFN-γ fusion protein expression from a plasmid construct and mediated by in vivo electroporation, was evaluated in a total of 39 HBeAg-positive patients with chronic hepatitis B (CHB). The six of 39 patients with a serum alanine aminotransferase (ALT) value of 1-2 times upper limit of normal (ULN) were assigned to the open-label arm (Group01) receiving vaccine monotherapy; the remaining 33 patients with an ALT of more than two times ULN were enroled to the randomized and controlled arm (Group02) receiving lamivudine (LAM) monotherapy (LAM+placebo) or combined therapy (LAM+DNA vaccine) in 1:2 ratio. In Group01, a significant elevation of HBV-specific IFN-γ-secreting T-cell counts in comparison with baseline was observed. In Group02, the proportion of patients with HBV DNA suppression was higher with LAM+DNA vaccine than with LAM monotherapy at each visit time point after the final injection of DNA vaccine at week 36, revealing a significant difference between the two groups (P = 0.03) at week 60. The incidence of dual-site mutations of rtM204/I/S+rtL180M was significantly lower (P = 0.03) with an identified lower virological breakthrough (VBT) rate (P = 0.03) in patients receiving LAM+DNA vaccine than LAM monotherapy, accompanied with a significant higher positive T-cell response rate in patients receiving LAM+DNA vaccine (P = 0.03). In conclusion, this study provides evidence that HBV DNA vaccination is safe and immunologically effective, and that the HBV-specific T-cell responses induced by DNA vaccination under LAM chemotherapy showed a correlation with the suppression of viral replication in patients with CHB., (© 2012 Blackwell Publishing Ltd.)

It is well known that the seroconversion rate of patients following hepatitis B virus (HBV) vaccination is lower in uraemic than healthy subjects. A variety of inherited or acquired factors have been implicated in this diminished response, and the high prevalence of hepatitis C virus (HCV) infection among patients on maintenance dialysis has been suggested to play a role. However, the impact of HCV on the immune response to HB vaccine in patients receiving long-term dialysis is not entirely understood. Here, we evaluate the influence of HCV infection on the immunological response to HBV vaccine in dialysis population by performing a systematic review of the literature with a meta-analysis of clinical studies.We used the random-effects model of DerSimonian and Laird with heterogeneity and sensitivity analyses. The end-point of interest was the rate of patients showing seroprotective anti-hepatitis B titres at completion of HBV vaccine schedule among HCV-positive versus HCV-negative patients on chronic dialysis. We identified eight studies involving 520 unique patients on long-term dialysis. Aggregation of study results did not show a significant decrease in response rates among HCV-infected versus noninfected patients [pooled odds ratio = 0.621 (95% CI, 0.285; 1.353)]. The P-value was 0.007 for our test of study heterogeneity. Stratified analysis in various subgroups of interest did not meaningfully change our results. Our meta-analysis showed no association between immunological response to hepatitis B vaccine and HCV infection in individuals on long-term dialysis. These results support the use of recombinant vaccine against hepatitis B in patients on regular dialysis with HCV infection., (© 2011 Blackwell Publishing Ltd.)

Chronic dialysis patients are at risk of contracting hepatitis B virus infection and have a diminished immune response to hepatitis B virus vaccine. Recent reports support intradermal administration of hepatitis B virus vaccine in patients on regular dialysis but the efficacy and safety of this approach remain unclear. We conducted a meta-analysis of randomized, controlled clinical trials to compare seroprotection achieved by intradermal vs intramuscular hepatitis B vaccine, in patients on maintenance dialysis. Meta-analysis of data from 718 adults (14 trials) on long-term dialysis demonstrated that intramuscular hepatitis B vaccination was less likely to achieve seroprotection than intradermal vaccination, the pooled odds ratio was 0.454 (95% CI, 0.3; 0.67), P = 0.001. The test of study heterogeneity was not significant. This difference did not persist during follow-up (6-60 months after completing vaccine schedule), the pooled odds ratio being 0.718 (95% CI, 0.36; 1.47), NS. Some evidence of significant heterogeneity including publication bias was present but stratified analysis in various subgroups showed that this issue did not meaningfully change our results. Intradermal hepatitis B vaccine was safe and well tolerated. We conclude that intradermal hepatitis B vaccine induces a superior response rate compared to intramuscular route at completion of vaccine cycle, despite a lower vaccine dose. No significant advantage was found over longer follow-up. It remains unclear whether the higher seroprotection rate achieved with intradermal route translates into a lower frequency of de novo hepatitis B among patients on maintenance dialysis., (© 2010 Blackwell Publishing Ltd.)

Mother-to-child transmission of hepatitis B virus (HBV) continues to occur despite immunoprophylaxis. We examined maternal factors contributing to transmission in infants receiving adequate immunoprophylaxis in Alberta, Canada. Prenatal specimens from HBsAg-positive women whose babies developed HBV infection despite immunoprophylaxis (cases) and HBsAg-positive mothers whose babies did not (controls) were tested for HBsAg, HBeAg and HBV DNA. Specimens with detectable DNA underwent HBV genotyping. Routinely collected surveillance data and laboratory test results were compared between cases and controls. Twelve cases and 52 controls were selected from a provincial registry from 2000 to 2005. At the time of prenatal screening, median maternal age was 31 years [interquartile range (IQR): 27.5-34.5], and median gestational age was 12 weeks (IQR 10.0-15.5). Cases were more likely than controls to test positive for HBeAg (77.8% vs. 23.1%; P < 0.05). Of all mothers with detectable viral load (n = 51), cases had a significantly higher median viral load than did controls (5.6 × 10(8)  IU/mL vs. 1750 IU/mL, P < 0.0001). Of the two cases who were HBeAg negative, one had an undetectable viral load 8 months prior to delivery and a sP120T mutation. The viral load in the other case was 14,000 IU/mL. The majority of isolates were genotype B (31.3%) and C (31.3%) with no significant differences in genotype between cases or controls. In this case-control study, transmission of HBV to infants was more likely to occur in mothers positive for HBeAg and with high HBV DNA., (© 2010 Blackwell Publishing Ltd.)

Vaccination against hepatitis B virus (HBV) immediately after birth prevents neonatal infection by vertical transmission from HBV carrier mothers. There is an ongoing debate whether infant vaccination is sufficient to protect against infection when exposed to HBV later in life. We studied 222 Thai infants born to HBsAg -/+ and HBeAg -/+ mothers who were vaccinated with recombinant hepatitis B vaccine at 0-1-2-12 months of age. A subset of 100 subjects received a booster dose at age 5 years. Blood samples collected yearly for 20 years were examined for anti-HBs antibodies and serological markers of hepatitis B infection (anti-HBc, HBsAg, and in selected cases HBeAg, anti-HBe, HBV DNA). During the 20-year follow-up, no subject acquired new chronic HBV infection or clinical hepatitis B disease. During the first decade, possible subclinical breakthrough HBV infection (anti-HBc seroconversion) was only observed in subjects born to HBsAg +/HBeAg + mothers (6/49 [12.2%]). During the second decade, breakthrough HBV infections were detected in all groups (18/140 [12.8%]). Increases in anti-HBs concentrations that were unrelated to additional HBV vaccination or infection were detected in approximately 10% of subjects in each decade. Primary infant vaccination with a recombinant hepatitis B vaccine confers long-term protection against clinical disease and new chronic hepatitis B infection despite confirmed hepatitis B exposure., (© 2010 Blackwell Publishing Ltd.)

In 1996, a combined vaccine against both hepatitis A and B was licensed and commercialized and has been recommended for healthcare personnel in Belgium. This study compares the immunogenicity against hepatitis B virus (HBV) and safety of two vaccination schedules (0-1-12 months and 0-1-6 months) with this vaccine. This is a randomized, stratified and controlled study in healthy adult workers, who are not occupationally exposed to HBV. Seroconversion (≥1 IU/L) and seroprotection (≥10 IU/L) rates were compared using Fisher's exact test; geometric mean concentrations (GMCs) of anti-HBs were compared using one-way ANOVA. All statistical analyses were carried out with SPSS 11 on Apple Macintosh. A total of 399 subjects were enrolled in the study, and 356 were analysed according to the protocol. The rate of ≥10 IU/L at 6 months was 70.6% in the group 0-1-12 and 79.9% in the group 0-1-6; this rate decreased to 55.9% at 12 months in the first group. Seroconversion and seroprotective rates against HBV measured at month 13 in group 0-1-12 (98.9% and 95.6%) and measured at month 7 in group 0-1-6 (99.4% and 97.1%) were not statistically significantly different. GMC of anti-HBs after the 0-1-12 schedule was more than two fold higher than after 0-1-6 schedule (P < 0.001). Reported side effects were comparable in both groups with a slight tendency to fewer side effects in the 0-1-12 group after the third dose. The results from our study show that the completed schedule 0-1-12 offers at least equal protective immunogenicity against HBV as the completed 0-1-6 schedule. People not receiving their third dose at 6 months can be given this dose up to 12 months after the first dose. The drawback of this flexibility, however, is the longer time period before the protection becomes effective., (© 2010 Blackwell Publishing Ltd.)

Coinfection with hepatitis B virus (HBV) is an important and preventable cause of chronic liver disease among HIV-infected patients. We calculated the prevalence of chronic HBV infection annually from 1996 to 2007 by age, gender, race/ethnicity, and HIV transmission risk in a multisite observational cohort study of HIV-infected patients. Prevalence of chronic HBV infection was calculated as the number of patients with a positive HBsAg or detectable HBV DNA divided by the number of patients tested using either one of these assays. Among 4467 (59%) patients tested for chronic HBV infection from a total of 7618 patients active during 1996-2007, median age was 38.5 years, 77% were men, 49% were white, 35% were black, 13% were Hispanic, and 53% were men who had sex with men (MSM). Overall, 8.4% tested positive for HBsAg or detectable HBV DNA. Annual chronic HBV prevalence during 1996-2007 ranged from 7.8% to 8.6% without a statistically significant trend. Overall, prevalence was greater among men compared with women; among whites, blacks, and persons of other race compared with Hispanics; among MSM compared with injection drug users and high-risk heterosexuals; and among patients aged 35-44 years compared with younger or older patients. MSM constituted the greatest fraction (63-72%) of all HBV-infected patients in the HIV Outpatient Study (HOPS) over the period. Of eligible patients, 5.8%, 23.4%, and 31.6% had received at least one dose of HBV vaccine by years 1996, 2002, and 2007, respectively. Despite the availability of an effective HBV vaccine for over two decades and long-standing recommendations for immunization of persons (with or without HIV infection) at risk for HBV, the prevalence of chronic HBV infection in this study has been largely unchanged over the past decade among patients in all groups, and overall was 20 times as high as the national population prevalence., (© 2010 Blackwell Publishing Ltd.)

Combined passive and active immunization for newborns very effectively prevents perinatal hepatitis B virus (HBV) infections. In the Netherlands, babies born to hepatitis B surface antigen (HBsAg)-positive women receive passive immunization with hepatitis B and at least three active HBsAg vaccinations. Serological testing for the presence of HBV markers was offered for all infants born to HBsAg-positive mothers between January 2003 and July 2007, after completion of their vaccination schedule. About 75% of the infants (n = 1743) completed their HB-vaccination schedule and participated in the serologic evaluation. Twelve of them (0.7%) were found to be HBV infected. Furthermore, we identified three older children with high levels of anti-HBc, anti-HBs and anti-HBe, while they were HBsAg and HBV DNA negative. This serologic profile is evidence for a resolved HBV infection. In the group of older children (1.5-5 years of age, n = 728), about half of the HBV-infected children (3 of 7) had already cleared their infection at the time of sampling. For a proper evaluation of the efficacy of a new intervention programme to prevent vertical HBV transmission, it is also important to analyse the HBV markers in serum collected when the children are older than 1.5 years. In a programmatic setting, all children born to HBV-infected mothers should be tested not only for the level of anti-HBs but also for the absence of HBsAg, because 2 of the 12 HBV-infected children (17%) had a high level of anti-HBs., (© 2009 Blackwell Publishing Ltd.)

Hepatitis B virus (HBV) infection and its sequelae remain a major health problem for Taiwan. The national hepatitis B (HB) vaccination programme was first launched in 1984 to combat the spread of this infection. This study examined the status of HBV infection amongst students at a Taiwanese university in 2005, 18 years after the implementation of a nation-wide mass HB vaccination programme. In 2005, 5875 new university entrants, who were born during the period 1 July 1976 to 30 June 1988, were subdivided into one of 12 one-year-interval birth-year cohorts. Each student was individually tested for serum hepatitis B surface antigen (HBsAg), Antibody to hepatitis B surface antigen (anti-HBs) and antibody to hepatitis B core antigen (anti-HBc) status. We observed a declining trend of past exposure to HB infection from 48.7% (1976 birth-year cohort) to 5.2% (1987 birth-year cohort). The prevalence of chronic HB infection also declined from 14.5% (1976 birth-year cohort) to 1.9% (1987 birth-year cohort). The prevalence of persistent HB immunity through (earlier) active vaccination declined from 72% (1984 birth-year cohort) to 41.6% (1987 birth-year cohort). The prevalence of HB infection-naïve individuals increased from 18.2% (1984 birth-year cohort) to 53.1% (1987 birth-year cohort). This study demonstrates that as the implementation of the mass HB vaccination programme in 1984, the incidence of HB infection in Taiwan has declined, although a 'waning-off' effect of serum anti-HBs to low or undetectable levels, which may not provide protection, amongst this student population has arisen, 18 years following the implementation of the nation-wide HB vaccination programme. Such a situation may mean that these individuals may not be effectively protected against future HB infection. A booster dose of HB vaccine, given 18 years following HB vaccination, perhaps even earlier, should be considered.

Both hepatitis B and hepatitis C viruses (HBV and HCV) cause chronic infections worldwide that are associated with development of liver diseases ranging from mild liver inflammation to hepatocellular carcinomas. While efficient preventive vaccines are available for HBV, efforts are ongoing to develop one in case of HCV. Yet, both infections share the fact that therapeutic agents available to treat already established infections are yet poorly efficient, toxic or associated with development of resistance. Thus, novel immune-based therapies are actively being developed to complement or replace standard antiviral treatments. Among those, development of therapeutic vaccines represents a major effort. Peptide-, recombinant protein- or viral vector-based vaccines have been engineered and tested at preclinical and clinical levels. Means to adjuvant these vaccines are being pursued, including approaches based on combining vaccines of different nature. This review will outline major advances in the field of both HBV and HCV therapeutic vaccine development with a particular focus on candidates presented at the 12th International Symposium on Viral Hepatitis and Liver Disease (July 2006, Paris, France).

Interferon-alpha and nucleoside analogues are available for the treatment of chronic hepatitis B virus (HBV) infection but do not lead to a satisfactory result. New findings about the immunological control of HBV during acute infection suggest the pivotal role of T-cell mediated immune responses. Several preclinical and clinical trials were undertaken to explore the possibility of stimulating specific immune responses in chronically infected animals and patients by vaccination. However, vaccination with commercially available HBV vaccines in patients and immunization in woodchucks with core or surface proteins of woodchuck hepatitis virus (WHV) did not result in effective control of HBV and WHV infection, suggesting that new formulations of therapeutic vaccines are needed. Some new approaches combining antiviral treatments with nucleoside analogues, DNA vaccines and protein vaccines were tested in the woodchuck model. It could be shown that therapeutic vaccinations are able to stimulate specific B- and T-cell responses and to achieve transient suppression of viral replication. These results suggest the great potential of therapeutic vaccination in combination with antivirals to reach an effective and sustained control of HBV infection.

The introduction and implementation of hepatitis B vaccination programmes in areas of high endemicity has been very stressful. However, this initial accomplishment has led to the reassessment of priorities in some countries which could undermine these early successes. Work still remains to be done to support and implement interventions that will bring us closer to the WHO goal and to the control of hepatitis B in the community at large. Hepatitis A vaccine strategy for immunizing toddlers is shifting to those countries with intermediate endemicity where increasing morbidity in adults is being observed. Accumulating evidence indicates that such programmes can result in impressive reductions in the incidence of hepatitis A by herd immunity. Monitoring of these populations to determine durability of protection will be important to avoid shifting the infection to the older age population, when symptoms are more likely to occur. National policies need to consider hepatitis A vaccination in the context of other public health priorities.

Liver transplantation is often the ultimate option of therapy for chronically hepatitis B virus (HBV) infected patients. Adoptive transfer of HBV immunity with the liver after vaccination of living liver donors (LLD) could be a new approach to prevent reinfection in the recipients. The time to achieve HBV immunity in LLD is usually short (1-2 months). Therefore, we established a short time immunization protocol (four injections in 2 weeks intervals) using Hepimmune, a recombinant vaccine that contains the L, M and S proteins of HBV. We examined cellular and humoral immune responses after immunization with Hepimmune and compared its immunogenicity to that of a standard HBV vaccine containing only the S protein (HBVAXPRO). Cellular immunity was measured by interferon (IFN)-gamma ELISpot and proliferation assay. HBV-specific T cells were detectable in the Hepimmune group after the second and in the standard group after the third vaccination. IFN-gamma production of T cells was significantly higher (P < 0.001) after the third vaccination with Hepimmune. Proliferative responses were also significantly (P < 0.01) higher in the Hepimmune group after the second to fourth vaccination. The humoral immune response could already be detected after the first immunization in nine of 15 Hepimmune vaccinated test persons while it was only observed in one of 15 probands of the later group. Titres differed significantly (P < 0.01) following all four vaccinations. Thus, Hepimmune appears to be a good candidate for short time immunization protocols.

Hepatitis B virus surface antigen (HBsAg), a specific antigen on the membrane of hepatitis B virus (HBV)-infected cells, provides a perfect target for therapeutic drugs. In order to mediate successful targeted delivery of these therapies, it is essential to have antibodies that recognize HBsAg with high specificity and affinity. In this report, we constructed a natural immune antigen binding fragments (Fab) antibody phage display library against HBsAg and after three rounds of panning, five Fab fragments with significant HBsAg binding ability were selected and analysed. DNA sequencing revealed that all the light chains had the same sequence, while all the Fd genes exhibited different sequences. For further application, all of the Fab antibodies were reconstructed into single chain antibodies (scFvs) and expressed in Escherichia coli BL21 cells. Indirect enzyme-linked immunosorbent assay analysis demonstrated that all five scFvs maintained a high affinity for HBsAg and could bind HBsAg on the membrane of HBV-infected cells. Indirect fluorescent staining analysis revealed that one of the scFvs (scFv15) could be internalized into HBsAg-positive HepG2.2.15 cells through clathrin-mediated endocytosis pathway. The internalizing scFv15 antibody would have great potential for the targeted delivery of therapeutics to HBV-infected cells.

The aim of the European Sero-Epidemiology Network 2 was to coordinate and standardize the serological surveillance of vaccine-preventable diseases in Europe. In this study, the standardization of hepatitis B virus (HBV) results is described. The 15 participating national laboratories tested a unique panel of 172 sera established by the Greek reference centre for HBV surface antigen (HBsAg), antibodies to HBsAg (anti-HBs) and/or to the HBV core antigen (anti-HBc) by assay methods of their choice. Country-specific quantitative measurements for anti-HBs and anti-HBc were transformed into common units using standardization equations derived by regressing each country's panel results against the reference centre's results, thus adjusting for interassay and interlaboratory variability. For HBsAg, a qualitative analysis (positive/negative) showed at least 99% agreement with the reference laboratory for all countries. By combining these standardized and qualitative results for the markers mentioned earlier, it was possible to achieve comparable estimates of the proportion of the population susceptible to HBV, vaccinated against HBV, with a past HBV infection, and with a current infection or chronic carrier state. Standardization is a very important tool that allows for international serological comparisons to assess the current vaccination policies and the progress of HBV control in Europe.

This review analyses the cumulated data from a number of long-term follow-up studies among infants, children and adults vaccinated against hepatitis B in industrialised and developing countries. Despite low or undetectable antibody responses years after vaccination, the development of HBsAg was a rarity and, if present, only transient. Some vaccinees developed anti-HBc responses but none developed an HB carrier state or clinical manifestations of disease. Studies demonstrating anamnestic responses among those with low or undetectable anti-HBs levels following challenge with HB vaccine, together with the production of anti-HBs in circulating B-cells by spot ELISA, confirmed the presence of immune memory among vaccinees. Anamnestic anti-HBs responses all correlate close in kinetics and magnitude with proliferative T-cell responses. The accumulated data from studies assessed in this Review indicate that protection is dependent on immune memory, rather than declining anti-HBs responses and add additional weight to the European Consensus recommendations (12) that following a complete course of vaccination, booster doses are unnecessary in immunocompetent persons. If implemented, this recommendation will have considerable cost benefits world-wide.

Among 1081 persons testing positive for hepatitis B surface antigen, 106 (10%) tested positive for antibodies to surface antigen (anti-HBs) in the same blood sample. Thirty of these persons were studied in detail: seven tested positive for hepatitis B e-antigen, nine were apparently healthy blood donors, and in 14 chronic infection could be demonstrated in follow-up samples. Frozen samples of 14 persons were available for additional quantitative anti-HBs testing using another anti-HBs assay: three showed no anti-HBs reactivity, seven showed borderline anti-HBs levels (1-5 IU/L), and anti-HBs titres ranged from 23 to 66 IU/L in four HBsAg-positive persons, including an apparently healthy blood donor. Thus, after hepatitis B vaccination of medical personnel, presence of anti-HBs may erroneously suggest immunity, while in fact chronic infection with hepatitis B virus is present.

Hepatitis B virus (HBV) vaccination is recommended for individuals with chronic liver disease. However, the response to standard doses of hepatitis B vaccines in such individuals has been poor. The aim of the present study was to assess the response to high-dose short-interval HBV vaccination in individuals with chronic liver disease of different aetiologies. A total two hundred and 24 subjects with chronic liver disease (138 chronic active hepatitis and 86 cirrhosis) and 26 healthy controls were vaccinated using a high-dose (40 microg) short-interval (monthly for 3 consecutive months) HBV vaccination schedule. One hundred and thirty-eight of the 224 subjects with chronic liver disease (62%) seroconverted to anti-HBs antibody positivity (>10 mIU/mL) after the third dose of vaccine as compared with 24 of the 26 controls (92%) (P < 0.01). The response rate was reduced in individuals with cirrhosis (36/86, 42%), particularly in alcohol-induced cirrhosis (2/17, 12%), as compared with individuals with chronic hepatitis (102/138, 74%) (P < 0.001). No significant HBV vaccination-related adverse effects were seen in individuals with or without cirrhosis as well as in the controls. High-dose short-interval HBV vaccination is safe and efficacious in individuals with chronic liver disease. The response to HBV vaccination is reduced in cirrhotics, particularly those with alcoholic cirrhosis. These data suggest that HBV vaccination should be accomplished early in an individual cause of chronic liver disease prior to the development of cirrhosis.

The response to vaccination with recombinant hepatitis B virus (HBV) vaccine is poor in haemodialysis patients. A defect in the antigen-presenting cells may be responsible for this hyporesponsiveness. To overcome this and to improve the response to HBV vaccine in dialysis patients, we used granulocyte-macrophage colony-stimulating factor (GM-CSF) as a vaccine adjuvant. Fifteen consecutive patients with chronic renal failure (CRF), commenced on dialysis, were stratified to receive either 40microg HBV vaccine (Engerix-B) at 0, 1, 2 and 6 months (group A, n=9) or 3microg kg-1 GM-CSF (Leucomax) on day 1 followed by the vaccination schedule described above (group B, n=6). All patients were negative for hepatitis B surface antigen (HBsAg), antibodies to hepatitis C virus (anti-HCV) and human immunodeficiency virus (HIV) serology. Titres of antibody to HBsAg (HBsAb) were quantitatively assayed, using enzyme-linked immunosorbent assay (ELISA), at 1, 2, 6 and 7 months from the first dose of vaccination. Only 44% of the patients in group A developed protective antibody levels (mean HBsAb: 22 IU l-1) Fifty per cent of responders developed protective antibody levels (HBsAb >10 IU l-1) only after the fourth dose of vaccination. In contrast, all six patients (100%) in group B developed protective levels of HBsAb (mean HBsAb: 70 IU l-1) (P<0.02). Sixty-seven per cent of the responders were protected after only the second dose of vaccination (P=0.046). No serious adverse effects of GM-CSF were observed in group B. Hence, haemodialysis patients respond poorly to HBV vaccine. GM-CSF is a safe vaccine adjuvant capable of stimulating an earlier and a stronger antibody response to HBV vaccine in haemodialysis patients.

The high prevalence of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) in pregnant women is considered to be the most important factor contributing to the high carrier rate of HBsAg in some populations. Several factors, including the age at which infection occurs, predispose to the acquisition and frequency of the carrier state. The proportion of infected people who become chronic carriers ranges from about 80 to 95% for babies born to HBsAg/HBeAg-positive mothers. In this study of Indonesian infants receiving only active immunization against HBV, we measured the HBV markers passively acquired from their HBsAg-positive mothers. The relationship of these markers with vaccination response and with HBV infection status was studied longitudinally in the infants. In the exposed neonates from the HBsAg-positive mothers (n=61), the seroconversion rate to hepatitis B surface antibody (HBsAb) positivity was 95% after the first booster vaccination, with a geometric mean titre (GMT) of 2017 IUl-1. After 60 months, the GMT in this group decreased to 50 IUl-1. Four newborns in this group became HBsAg carriers. Of the four vaccination failures, three newborns were HBsAg/HBeAg positive at birth, suggesting that they had been infected in utero. No vaccination strategy (active alone, or passive/active) can prevent this transmission from occurring. One carrier was HBsAg negative at birth and up to month 4 but was HBsAg positive at month 12 and subsequently, suggesting a postnatal infection. Vaccination early in life can, to a large extent, prevent perinatal transmission and hepatitis B virus (HBV) infection later in infancy and childhood. In this study, the protective efficacy of the vaccination was 85% in the subcohort of neonates from HBeAg-positive mothers and 100% in the subcohort of neonates from HBeAg-negative mothers. Lack of maternal antibodies to hepatitis B core antigen (HBcAb) correlated strongly with transmission of HBV infection.

Hepatitis B virus causes a chronic infection in a large proportion of cases. One possible mechanism whereby hepatitis B avoids the host defences is by mutation of antigenic epitopes. This article reviews current views in the area.

A new triple-S containing recombinant hepatitis B vaccine was evaluated in terms of immunogenicity and reactogenicity in a cohort of healthy healthcare professionals who were persistent non-responders to the currently licensed hepatitis B vaccines. One hundred subjects were allocated randomly to receive two doses of 5, 10, 20 or 40 micrograms of a new hepatitis B vaccine 2 months apart. The overall seroconversion rate was 70% with a single dose of 20 micrograms of the vaccine being as effective as two doses of either 20 micrograms or 40 micrograms of the vaccine formulation in terms of seroconversion, seroprotection and geometric mean titres.

In the murine model the immune response to both the hepatitis B envelope and nucleocapsid antigens are linked to the MHC class II haplotype but they are independently restricted. Although in a human outbred population non-response is less likely, the host genetic environment may be important in determining the level of response to vaccine and inclusion of antigens apart from the S antigen may improve protection. The inclusion of HBcAg in vaccine remains controversial since, despite its high immunogenicity, the Th-cell response to this antigen may have a role in the down regulation of the immune response to HBV so promoting persistence.

The lack of response to hepatitis B vaccination remains a problem for those individuals directly at risk of hepatitis B infection, particularly those who work in the health care industry. The factors associated with non-response to hepatitis B vaccination have been investigated in 86 non-responder health care workers who had received multiple 'S' vaccinations without sustained production of anti-HBs. This group received a recently developed hepatitis B vaccine, Hepagene, which included proteins derived from the envelope region of HBV, not present in currently licensed vaccines. The pre-S1 and pre-S2 proteins were included in Hepagene in order to circumvent anti-HBs non-responsiveness which had previously been demonstrated in the inbred mouse model. The inclusion of these additional proteins in Hepagene enabled some seroconverion, from non-responder to responder; however, a proportion of the vaccinees remained non-responders and the reasons for this have been investigated here, with reference to HLA alleles and the demographic predisposition. Here the mechanisms that underlie hepatitis B vaccine non-response have considered the distribution of HLA alleles, age, sex, height and weight in addition to the T-cell responses to Hepagene derived antigens.

Hepagene is a novel recombinant particle consisting of the pre-S1, pre-S2 and small surface (SHBs) antigens (Ag) of the hepatitis B virus (HBV) and is adjuvanted with alhydrogel in the final formulation. It has been primarily developed to enhance anti-SHBs antibody titres in inadequate responders, to conventional SHBsAg vaccines. Since non-compliance is also a problem with existing HBV vaccine schedules, the ability to accelerate current immunization regimens to provide more rapid protection has also been an important objective. Here we describe the T- and B-cell responses to Hepagene in two strains of responder mouse (BALB/c and SWR/J). Hepagene induced high in vitro spleen T-cell proliferative responses in both strains (max. Stimulation Index = 43), following intraperitoneal immunization. High concentrations of interferon-gamma (max. = 5000 pg/mL) were detected in the media of spleen cells cultured with non-adjuvanted Hepagene particles. SWR/J mice showed the highest serum antibody (Ab) titres to non-adjuvanted Hepagene. The presence of alhydrogel adjuvant in the vaccine formulation significantly improved the titres. Anti-pre-S1 Ab was detected in both strains of mouse but anti-pre-S2 Ab was only detected in the SWR/J strain. In BALB/c mice, the anti-Hepagene (non-adjuvanted) IgG1 Ab subclass was predominant but in SWR/J mice IgG1, IgG2a and IgG2b subclasses were of a similar magnitude. In BALB/c mice, Hepagene induced higher anti-SHBs Ab responses than Engerix-B (11097 IU/mL and 1276 IU/mL, respectively), following two doses of vaccine (10 micrograms/mouse). The vaccine therefore, induces strong cellular and humoral immune responses and these data suggest that Hepagene is an improved hepatitis B vaccine.

Mutations occurring on the major antigenic 'a' determinant of hepatitis B surface antigen (HBsAg) have been detected in immunized Singapore children, despite immunoprophylaxis with hepatitis B immune globulin and HBV vaccine. These vaccine-escape HBsAg mutants display a predominance of the Gly145-to-Arg145 mutation in the antigenic 'a' determinant. Our latest follow-up studies indicate the stability of this as well as other vaccine-escape HBsAg mutants over time. We have also identified HBsAg mutants in immunized children with amino acid substitutions outside the 'a' determinant. Transmission of various vaccine-escape HBsAg mutants have been shown in our epidemiological studies. Detection of HBsAg mutants, carrying amino acid changes at various position of the 'a' determinant in random population, points to their emergence in Singapore before the implementation of the vaccination programme. Of significant interest is the recent identification of vaccine-escape HBsAg mutants in hepatocellular carcinoma.

We present a deterministic model of the possible emergence of a vaccine escape variant of hepatitis B virus (HBV). The model identifies the key unknowns determining this process: the protection afforded by the current vaccines against particular HBV variants; the infectiousness of these variants; and the current prevalence of individuals infectious with the variants (each factor relative to wild-type). By making pessimistic assumptions about these unknowns we show that even a highly infectious variant, under a vaccine programme that affords no protection against the variant, would still take decades to emerge. Thus the current low prevalence of variants is not evidence for the cross-reactivity of the current vaccines or for a lack of infectiousness in the variants. As any vaccine failure will be inapparent for decades it may be sensible to recommend vaccine modifications now rather than later.

Hepatitis B virus (HBV) infection is the leading cause of chronic hepatitis and cirrhosis in Turkey. The prevalence of hepatitis B surface antigen (HBsAg) positivity in Turkey is 5 to 10%. HBV is almost completely preventable with the use of hepatitis B vaccines. The most commonly used vaccine is that which contains the predominant viral surface (S) polypeptide. It elicits protective antibodies in greater than 90% of healthy subjects. A vaccine containing the PreS1 and PreS2 antigenic domains has recently been reported as being more efficient in achieving successful immunization in individuals who have not previously responded to the isolated S-antigen vaccine. In this study, the efficacy of a S and PreS-containing vaccine was compared with that of two different standard isolated S-antigen-containing vaccines in terms of the immunization protection produced against HBV in normal healthy adults who had not previously been immunized. Seventy-six young adults (aged 17-22) were randomly assigned to receive 1 ml (20 micrograms) of either one of two standard S-subunit recombinant hepatitis B vaccines (Engerix B. or Hepavax) or the combined S and PreS subunit vaccine (Gen Hevac B) intramuscularly in the deltoid muscle at 0, 1 and 2 months. Hepatitis B surface antigen antibody titres were measured at 1, 2 and 12 months. A titre > or = 10 IU ml-1 was considered to be protective. All subjects receiving the two standard isolated S-antigen-containing vaccines responded to the vaccination with reasonable antibody titres. One-half to two-thirds of those vaccinated developed high antibody titres (> 100 IU ml-1). In contrast, 9% of those receiving the combined PreS1 and PreS2 plus S antigens failed to respond, as demonstrated by antibody titres below the level considered to be protective. The mean titres at 12 months were 107 +/- 12 IU ml-1 (Engerix B), 102 +/- 12 IU ml-1 (Gen Hevac B) and 117 +/- 12 IU ml-1 (Hepavax Gene). Hence, no important difference in term of response to vaccination was found between the two different types of vaccines. As recombinant S-subunit vaccines are less expensive than those that combine S and PreS antigens, it is suggested that, when immunizing normal healthy adults, a standard isolated S-antigen-containing vaccine should be used.