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In patients who progress from acute hepatitis B virus (HBV) infection to a chronic HBV (CHB) infection, CD8+ T cells fail to eliminate the virus and become impaired. A functional cure of CHB likely requires CD8+ T cell responses different from those induced by the infection. Here we report preclinical immunogenicity and efficacy of an HBV therapeutic vaccine that includes herpes simplex virus (HSV) glycoprotein D (gD), a checkpoint modifier of early T cell activation, that augments CD8+ T cell responses. The vaccine is based on a chimpanzee adenovirus serotype 6 (AdC6) vector, called AdC6-gDHBV2, which targets conserved and highly immunogenic regions of the viral polymerase and core antigens fused to HSV gD. The vaccine was tested with and without gD in mice for immunogenicity, and in an AAV8-1.3HBV vector model of antiviral efficacy. The vaccine encoding the HBV antigens within gD stimulates potent and broad CD8+ T cell responses. In a surrogate model of HBV infection, a single intramuscular injection achieved pronounced and sustained declines of circulating HBV DNA copies and HBV surface antigen; both inversely correlated with HBV-specific CD8+ T cell frequencies in spleen and liver.

Hepatitis B virus (HBV) is a vaccine preventable disease. Sufficient post vaccination response is critical step to achieve infection eradication. Vaccine hypo-responsiveness is a major risk factor for HBV chronic infection. We aimed to evaluate the effectiveness of birth dose HBV vaccine in preventing perinatal HBV infection and to detect the rate of HBV surface antibody (HBs-Ab) seroconversion and its relation to interleukin-4 polymorphism (IL-4 PM) among a group of vaccinated Egyptian infants. This observational analytical study involved 77 infants aged 6 to 12 months who received 4 doses of HBV vaccine including a zero dose. We measured serum levels of HBV-DNA and hepatitis B surface antigen (HBsAg) as markers of infectivity, and the level of (HBsAb) to assess vaccine responsiveness. Cytokine gene analysis to detect IL-4 gene polymorphism and its association with vaccine un-responsiveness were investigated. We observed that none of the vaccinated infants acquired HBV infection. Of the included 77 infants, seroconversion against HBV was detected in 72 (93.5%), 28 (36.4%) had low response and 44 (57.1%) had high response. While 5 (6.5%) were non responders. There was significant association between IL-4 gene polymorphism and the poor seroconversion after HBV vaccination. (p=0.03). Furthermore, HBsAb titer was significantly lower in children who have IL-4 gene polymorphism (p=0.014). In conclusion, implementation of birth-dose HBV vaccination is effective for prevention of perinatal infection, but seroconversion rate may be insufficient to induce long term protection. IL-4 gene polymorphism is associated with poor response to HBV vaccine., (Copyright© by the Egyptian Association of Immunologists.)

Introduction: Updated data on the seroprevalences of hepatitis B and C viruses (HBV, HCV) are required to enable the adaptation of control strategies. In this study, we aimed to: (i) estimate the seroprevalences of HBsAg carriers and HCV exposure in the general population, and (ii) determine the impact of vaccination on HBV circulation since its introduction in 2006 in the Expanded Program on Immunization (EPI)., Methodology: From October 2020 to October 2022, a mass screening campaign was conducted in 10 cities across Burkina Faso. Individuals of all ages and genders who consented to participate were screened for viral markers (HBsAg, anti-HCV) using rapid diagnostic tests. The proportions of HBsAg carriers and HCV exposure were calculated using Stata, and logistic regression was used to assess the impact of HBV vaccination on HBsAg carriage., Results: A total of 15,650 participants were enrolled in the study. Of these, 51.4% were women and the age range was from 1 to 97 years. All participants were screened for HBsAg and 7,507 were also screened for anti-HCV. Overall, the seroprevalence of HBsAg was 8.8% and 2.6% for anti-HCV. The results indicated that age, gender, and place of residence were associated with HBV infection., Conclusions: The prevalence of HBV and HCV infections remains high in Burkina Faso. Prevention strategies, including initial mass screening with rapid diagnostic tests and vaccination, need to be intensified., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2024 Armel Moumouni SANOU, Delphine Napon-Zongo, Abou Coulibaly, Ina Marie Angèle Traoré, Ad Bafa Ibrahim Ouattara, Abdoul Kader Ilboudo, Abdou Azaque Zoure, Sylvie Zida, Mathuola Nina Geneviève Ouattara, Abdoulaye Dera, Djara Konaté, Eric Kyelem, Achille Sindimbasba Nikiema, David Lankoande, Dieudonné Ilboudo, Dramane Kania.)

As healthcare workers run a high and constant occupational risk of hepatitis B virus (HBV) infection through exposure to biological material, vaccination is mandatory as well as the monitoring of antibody levels one to two months after complete immunisation. The aim of this descriptive cross-sectional study was to determine HBV vaccine coverage of 200 primary and secondary healthcare workers (100 each) from Šabac, Serbia and their blood anti-HBs titre. We also wanted to identify factors that could predict the titre. Anti-HBV vaccination covered all participants, of whom 89.5 % were fully vaccinated, and 85 % had a protective antibody titre. We found a statistically significant association between antibody titre and the number of received vaccine doses, chronic jaundice, autoimmune disease, and cancer in our participants. The fact that 15 % did not achieve the protective antibody titre confirms the necessity of its control after immunisation, which is not routinely carried out in most countries, Serbia included. It is, therefore, necessary to develop a detailed strategy for monitoring vaccination and serological status of healthcare workers in order to improve their safety at work. An important role should also be given to continuous education of healthcare workers from the beginning of schooling to the end of their professional career., (© 2024 Slobodanka Bogdanović Vasić et al., published by Sciendo.)

Background: Premature infants have less physiologic reserve and often delayed vaccination compared to full-term infants. The birth dose of hepatitis B vaccine (HepB-BD) is an essential measure to achieve the goal of "zero infections" of hepatitis B virus in all newborns. However, there are few investigations of hepatitis B vaccination of preterm infants, leading to uncertainty of coverage and insufficient knowledge of factors influencing timely vaccination of this important population., Methods: We obtained hepatitis B vaccine (HepB) vaccination histories of premature infants born during 2019-2021 in three provinces from the respective provincial immunization information systems. Extracted data included date of birth, sex, region, and dates of HepB administration. We conducted descriptive analyses that included basic characteristics of the study subjects, HepB-BD administration, and full-series HepB vaccination. Factors potentially influencing HepB-BD and full series vaccination were analyzed by logistic regression., Results: There were 1623 premature infants included in the analytic data set. Overall HepB-BD coverage was 71.41%; coverage among premature infants born to mothers with unknown hepatitis B surface antigen (HBsAg) status was 69.57%; coverage was higher at county-level-and-above hospitals (72.02%) than hospitals below county level (61.11%). Full-series HepB coverage was 94.15%; full-series coverage among preterm infants weighing less than 2000 g at birth was 76.92%. Logistic regression showed that the HepB-BD vaccination rate was positively associated with being born to an HBsAg-positive mother and being preterm with high birth weight. Regression analysis for factors influencing full-series HepB coverage showed that being born prematurely was positively associated with full-series coverage and being premature with a very low birth weight was negatively associated with full-series coverage., Conclusions: HepB-BD coverage levels in three provinces of China were less than the target of 90%, especially among premature infants born to mothers with unknown HBsAg status and at hospitals below the county level. Screening of pregnant women should be a universal normal standard. Hepatitis B vaccination training should be strengthened in hospitals to improve the HepB-BD vaccination rate of premature infants and to effectively prevent mother-to-child transmission of hepatitis B virus., (© 2024. The Author(s).)

Hepatitis B vaccination is the most effective means of interrupting HBV transmission. Although the hepatitis B vaccine is very effective and safe, adverse events following immunization do occur and need to be reported so that problems can be identified and appropriate corrective action can be taken. Most of the research on AEFI focuses on the safety observation of newly used vaccines, and there are few long-term studies on AEFI of the hepatitis B vaccine. This study retrospectively analyzes the reporting rate, clinical symptoms, and onset time of AEFI of the hepatitis B vaccine in Quzhou from 2011 to 2023, and compares the differences in AEFI reporting rates between different types of hepatitis B vaccines, different vaccination ages, and different doses. The surveillance results show that from 2011 to 2023, the AEFI reporting rate of hepatitis B Vaccines in Quzhou was 17.55/100,000 doses. 98.73% of reported AEFI were non-serious. The types of AEFI reported were vaccine product-related reactions, immunization anxiety-related reactions, and coincidental events. 94.12% of vaccine product-related reactions occurred within 3 days, and the main symptoms were fever, local reactions at the injection site, and rash. The AEFI reporting rate of the CHO vaccine was higher than that of the yeast vaccines, and the probability of AEFI in children under 1 year of age receiving the hepatitis B vaccine was higher in the latter dose than in the previous dose. The 13-year-long AEFI surveillance provides reliable evidence of the safety of the hepatitis B vaccine.

Infant hepatitis B vaccine coverage in China is high, with over 95% of infants immunized; however, high vaccine coverage can often mask low timeliness. The vaccination interval between the second and third doses is not clearly defined by immunization guidelines in China. This retrospective cohort study assessed the time interval distribution of hepatitis B vaccination among a cohort of randomly selected live births from the Centers for Disease Control and Prevention across four provinces or municipalities in China between January 2017 and December 2021. Among the infants analyzed, 163,224 received the first dose of hepatitis B vaccine with 146,905 (90.0%) and 135,757 (83.2%) infants receiving the second and third doses, respectively. A total of 132,577 (90.2%) infants received the second dose between 28 and 61 days after the first dose. Of the 119,437 (88.0%) infants that completed the hepatitis B series between 61 and 214 days after the second dose 87,067 (64.1%) infants were vaccinated with the third dose between 151 and 180 days after the second dose. The time interval distribution varied across the four provinces or municipalities ( p  < .001). Of the 58,077 infants who completed the hepatitis B vaccine series, 36,377 (62.6%) infants used the same type of hepatitis B vaccine for all three doses. Overall, the timeliness of hepatitis B vaccination for infants was lower than expected, with regional disparities observed. This highlights the need for improved timeliness through the introduction of a defined timeframe for the last two doses of vaccine and training for obstetricians and related personnel.

Since the introduction of Haemophilus Influenzae type b (Hib) conjugate vaccines, invasive Hib disease has strongly declined worldwide, yet continued control of Hib disease remains important. In Europe, currently three different hexavalent combination vaccines containing Hib conjugates are marketed. In this phase IV, single-blind, randomized, controlled, multi-country study (NCT04535037), we aimed to compare, in a 2 + 1 vaccination schedule, the immunogenicity and safety and show non-inferiority, as well as superiority, of DTPa-HBV-IPV/Hib (Ih group) versus DTaP5-HB-IPV-Hib (Va group) in terms of anti-polyribosylribitol phosphate (PRP) antibody geometric mean concentrations (GMCs) and proportion of participants reaching anti-PRP antibody concentrations greater than or equal to a threshold of 5 µg/mL. One month after the booster vaccination, the anti-PRP antibody GMC ratio (Ih group/Va group) was 0.917 (95% CI: 0.710-1.185), meeting the non-inferiority criteria. The difference in percentage of participants (Ih group - Va group) reaching GMCs ≥5 µg/mL was -6.3% (95% CI: -14.1% to 1.5%), not reaching the predefined non-inferiority threshold. Interestingly, a slightly higher post-booster antibody avidity was observed in the Ih group versus the Va group. Both vaccines were well tolerated, and no safety concerns were raised. This study illustrates the different kinetics of the anti-PRP antibody response post-primary and post-booster using the two vaccines containing different Hib conjugates and indicates a potential differential impact of concomitant vaccinations on the anti-PRP responses. The clinical implications of these differences should be further studied.

Chronic hepatitis B virus (HBV) infection is a global health problem that substantially increases the risk of developing liver disease. The development of a novel strategy to induce anti-HB seroconversion and achieve a long-lasting immune response against chronic HBV infection remains challenging. Here, we found that chronic HBV infection affected the signaling pathway involved in STING-mediated induction of host immune responses in dendritic cells (DCs) and then generated a lymph node-targeted nanovaccine that co-delivered hepatitis B surface antigen (HBsAg) and cyclic diguanylate monophosphate (c-di-GMP) (named the PP-SG nanovaccine). The feasibility and efficiency of the PP-SG nanovaccine for CHB treatment were evaluated in HBV-carrier mice. Serum samples were analyzed for HBsAg, anti-HBs, HBV DNA, and alanine aminotransferase levels, and liver samples were evaluated for HBV DNA and RNA and HBcAg, accompanied by an analysis of HBV-specific cellular and humoral immune responses during PP-SG nanovaccine treatment. The PP-SG nanovaccine increased antigen phagocytosis and DC maturation, efficiently and safely eliminated HBV, achieved a long-lasting immune response against HBV reinjection, and disrupted chronic HBV infection-induced immune tolerance, as characterized by the generation and multifunctionality of HBV-specific CD8 + T and CD4 + T cells and the downregulation of immune checkpoint molecules. HBV-carrier mice immunized with the PP-SG nanovaccine achieved partial anti-HBs seroconversion. The PP-SG nanovaccine can induce sufficient and persistent viral suppression and achieve anti-HBs seroconversion, rendering it a promising vaccine candidate for clinical chronic hepatitis B therapy., (© 2024. The Author(s).)

Identifying correlations between immune responses elicited via HIV and non-HIV vaccines could aid the search for correlates of HIV protection and increase statistical power in HIV vaccine-efficacy trial designs. An exploratory objective of the HVTN 097 phase 1b trial was to assess whether immune responses [focusing on those supported as correlates of risk (CoR) of HIV acquisition] induced via the RV144 pox-prime HIV vaccine regimen correlated with those induced via tetanus toxoid (TT) and/or hepatitis B virus (HBV) vaccines. We measured TT-specific and HBV-specific IgG-binding antibody responses and TT-specific and HBV-specific CD4+ T-cell responses at multiple time points in HVTN 097 participants, and we assessed their correlations at peak time points with HIV vaccine (ALVAC-HIV and AIDSVAX B/E)-induced responses. Four correlations were significant [false discovery rate-adjusted p -value (FDR) ≤ 0.2]. Three of these four were with IgG-binding antibody responses to TT measured one month after TT receipt, with the strongest and most significant correlation [rho = 0.368 (95% CI: 0.096, 0.588; p = 0.008; FDR = 0.137)] being with IgG-binding antibody responses to MN gp120 gDneg (B protein boost) measured two weeks after the second ALVAC-HIV and AIDSVAX B/E boost. The fourth significant correlation [(rho = 0.361; 95% CI: 0.049, 0.609; p = 0.021; FDR = 0.137)] was between CD4+ T-cell responses to a hepatitis B surface antigen peptide pool, measured 2 weeks after the third HBV vaccination, and IgG-binding antibody responses to gp70BCaseAV1V2 (B V1V2 immune correlate), measured two weeks after the second ALVAC-HIV and AIDSVAX B/E boost. These moderate correlations imply that either vaccine, TT or HBV, could potentially provide a moderately useful immunogenicity predictor for the ALVAC-HIV and AIDSVAX B/E HIV vaccine regimen.

Background: Antibody-mediated protection can depend on mechanisms varying from neutralization to Fc-dependent innate immune-cell recruitment. Adjuvanted vaccine development relies on a holistic understanding of how adjuvants modulate the quantity/titer and quality of the antibody response., Methods: A Phase 2 trial (ClinicalTrials.gov: NCT00805389) evaluated hepatitis B vaccines formulated with licensed adjuvants (AS01 B , AS01 E , AS03, AS04 or Alum) in antigen-naïve adults. The trial investigated the role of adjuvants in shaping antibody-effector functions, and identified an innate transcriptional response shared by AS01 B , AS01 E and AS03. We integrated previously reported data on the innate response (gene expression, cytokine/C-reactive protein levels) and on quantitative/qualitative features of the mature antibody response (Fc-related parameters, immunoglobulin titers, avidity). Associations between the innate and humoral parameters were explored using systems vaccinology and a machine-learning framework., Results: A dichotomy in responses between AS01/AS03 and AS04/Alum (with the former two contributing most to the association with the humoral response) was observed across all timepoints of this longitudinal study. The consistent patterns over time suggested a similarity in the impacts of the two-dose immunization regimen, year-long interval, and non-adjuvanted antigenic challenge given one year later. An innate signature characterized by interferon pathway-related gene expression and secreted interferon-γ-induced protein 10 and C-reactive protein, which was shared by AS01 and AS03, consistently predicted both the qualitative antibody response features and the titers. The signature also predicted from the antibody response quality, the group of adjuvants from which the administered vaccine was derived., Conclusion: An innate signature induced by AS01- or AS03-adjuvanted vaccines predicts the antibody response magnitude and quality consistently over time., Competing Interests: AE, VB, and WB are employees of and hold shares in GSK. YS and ST received financial support from GSK for the conduct of the present study through their institution VIB-Ghent University. The authors declare GSK funded this study (GSK study identifier: 112115/ClinicalTrials.gov identifier: NCT00805389) and all costs related to the development of the publication. The funder was involved in study design, data collection and analysis, and covered the fees related to the preparation of the manuscript., (Copyright © 2024 Tasdighian, Bechtold, Essaghir, Saeys and Burny.)

Background: This study aimed to determine the prevalence and factors associated with susceptibility to hepatitis B virus (HBV) among cisgender men who have sex with men (MSM) on HIV pre-exposure prophylaxis (PrEP) in Northeastern Brazil., Methods: This was a cross-sectional, analytical study conducted between September 2021 and June 2023. Participants underwent structured interviews to collect sociodemographic and clinical information, including hepatitis B vaccination history, HIV PrEP use and sexual health history. Blood samples were collected for hepatitis B serologic testing: HBV surface antigen (HBsAg), HBV surface antibody (anti-HBs), total and IgM HBV core antibody (anti-HBc). HBV susceptibility was defined as nonreactive results for all these serological markers., Results: A total of 287 participants were enrolled into the study. The median age of the individuals was 31 years (interquartile range: 27; 36). HBV susceptibility was found in 58 out 286 individuals (20.3%; 95% CI: 15.9-25.2). Seventy-six percent of the participants reported completing the three-dose hepatitis B vaccine schedule. Susceptibility was significantly associated with a monthly income ≤ 5 minimum wages (PR: 2.02; 95% CI: 1.01-4.05), lack of complete hepatitis B vaccination schedule (PR: 4.52; 95% CI: 2.89-7.06), initiation of HIV PrEP (PR: 2.18; 95% CI: 1.21-3.94), duration of six months of HIV PrEP (PR: 2.16; 95% CI: 1.19-3.91), absence of tattoos (PR: 1.55; 95% CI: 1.00-2.40) and no history of sexually transmitted infections (PR: 1.65; 95% CI: 1.07-2.54)., Conclusion: Our findings highlight the significant burden of HBV susceptibility among MSM on HIV PrEP in Northeastern Brazil. Socioeconomic factors, vaccination status, PrEP use and sexual health behaviors play critical roles in determining susceptibility to HBV. Integrating hepatitis B screening and vaccination into PrEP services is critical for identifying and addressing HBV susceptibility among MSM. Interventions aimed at increasing vaccination coverage and promoting safer sexual practices are essential for mitigating the burden of HBV infection in this population., (© 2024. The Author(s).)

The hepatitis B vaccination-induced immune response has been demonstrated to be associated with a number of factors, including age, sex, BMI, and the presence of comorbidities. Additionally, modifiable determinants such as smoking have been identified as influencing the response to vaccination. However, despite the evidence that smokers are at an increased risk of not responding to vaccination, the long-term effects of smoking on antibody persistence remain poorly understood. This study aims to assess the impact of smoking habits on long-term immunity following the primary vaccination cycle. Participants were required to have received a standard three-dose vaccine schedule in childhood, without subsequent doses, and to be between 18 and 24 years of age. Data on age, sex, BMI, age of administration of the first vaccine dose, and time between doses were collected. An antibody concentration < 10 IU/L was considered as non-protective. A total of 2133 individuals were included, 14.2% of whom were smokers. The mean age was 20.28 ± 0.92 years. The probability of having a non-protective antibody concentration was significantly higher in smokers than in non-smokers (AOR: 1.287; 95% CI: 1.002-1.652). The detrimental effects of smoking extend beyond the immediate effects on the vaccine response, also impairing the long-term immune response in individuals who received vaccinations during childhood.

Background:  The hepatitis B virus (HBV) is one of the most important biological occupational hazards for healthcare workers. A high percentage of HBV infections are attributable to percutaneous occupational exposure. This study aimed to describe the HBV immunisation and current immune status of all the nurses employed in a regional hospital in central South Africa., Methods:  A descriptive record review included all the nurses (N = 388) employed in a regional hospital in central South Africa from 01 January 2018 to 31 January 2020. A total of 289 health records were included in the study. Data were analysed using descriptive statistics. Logistic regression analysis was used to establish factors associated with full immunisation., Results:  Most nurses were females (87.9%), working in medical (27.0%) wards. Only 20.4% of nurses received one dose of vaccine, while 51.2% received the three prescribed doses. However, 91.2% of nurses did not receive the vaccine at the correct intervals. Most of the tested nurses (71.0%) were immune. Immunisation status was significantly associated with religion (p  0.001) and schedule (p = 0.003). Nurses who were non-Christians were 35.9% less likely to be fully vaccinated compared to Christians., Conclusion:  Half of the nursing staff received three doses as prescribed. All nurses should receive the vaccine against HBV and their immune status monitored to minimise the risk of an infection. It is therefore recommended that proof of immunity should be a requirement.Contribution: This study found a high percentage of nurses with HBV antibodies, which will ensure workplace safety.

Despite the availability of a vaccine against hepatitis B virus (HBV), this infection still causes public health problems, particularly in susceptible populations. In Portugal, universal free vaccination started in 1994, and most HBV infections are diagnosed in immigrants from high-prevalence countries. Our aim was to assess the pattern of HBV genotypes/subgenotypes in samples collected between 2017 and 2021 from a convenience sample of 70 infected residents in Portugal. The HBV pol/HBsAg region was amplified and sequenced, allowing the analysis of RT sequences submitted to phylogenetic analysis and mutations assessment. A total of 37.1% of samples were from native Portuguese, aged 25-53 years (mean: 36.7 years), and the remaining samples were from individuals born outside of Portugal. A high diversity of HBV was identified: subgenotypes A1-A3 in 41.0% (16/39); D1, D3, and D4 in 30.7% (12/39); E in 23.1% (9/39); and F4 in 2.6% (1/39). Besides genotypes A and D, Portuguese were also infected with genotypes E and F, which are prevalent in Africa and South America, respectively. Resistance mutations in RT sequences were not found. The findings provide valuable insights for updating the HBV molecular epidemiology in Portugal. However, successful strategies to prevent and control the infection are still needed in the country, especially among susceptible and vulnerable populations.

Background: Health care workers (HCWs) are at increased risk of exposure to hepatitis B virus (HBV). The most effective prevention measure is vaccination, with a serum hepatitis B surface antibody (HBsAb) titre > 10 mIU/ml considered protective. To date, the sociodemographic and occupational characteristics related to HBV serosusceptibility and factors associated with booster hesitancy remain unclear. Therefore, this study aimed to identify factors associated with maintaining a protective HBsAb titre in a large sample of HCWs and to evaluate factors potentially associated with hesitancy towards vaccine boosters., Methods: A cross-sectional study was conducted among HCWs who underwent a health surveillance visit between 2017 and 2022. If the serum HBsAb titre was < 10 MIU/ml, a vaccine booster dose was offered. Based on their willingness to be vaccinated, employees were classified into three groups: acceptance, hesitation, and refusal. Uni- and multivariable analyses were performed to assess the association of demographic and occupational characteristics with serosusceptibility and attitudes towards vaccination., Results: A total of 1632 (27%) employees were shown to be nonimmune. A lower median age and being a physician were significantly associated with a protective HBsAb titre. A total of 706 nonimmune employees (43.3%) accepted the vaccination, 865 (53%) hesitated, and 61 (3.7%) refused. The median age of those who refused vaccination was significantly higher than that of those who hesitated and those who were vaccinated. Acceptance of vaccination was significantly higher among nurses, while nurse aides hesitated more; among nonmedical graduate staff both hesitation and refusal were higher than expected. In the multivariable analysis, higher age, female sex, and employment as an allied health care professional were shown to be significantly associated with hesitation/refusal, while being born abroad turned out to be protective., Conclusions: Our study showed that approximately a quarter of HCWs were not immune to HBV infection, and of these, more than half were hesitant towards or refused the booster dose. The risk of hesitation/refusal was higher with age in women and among allied health care staff. Based on these findings, further studies are needed to prospectively evaluate HBV seroprevalence, vaccination adherence, factors associated with hesitancy, and the effectiveness of health surveillance strategies in a high-risk population susceptible to infection., Competing Interests: Declaration of Competing Interest We have no conflict of interest to declare., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background/purpose: This study aims to investigate the prevalence of isolated core antibodies against hepatitis B (IAHBc) in different birth cohorts using a large medical record database., Methods: Hepatitis B viral serological test data were collected from a chart cloud database at a medical center in Taiwan between January 2006 and December 2018. The data collected included birth year, sex, hepatitis B viral markers (HBsAg, anti-HBs or anti-HBc), and hepatitis B vaccination records. Enrolled patients were grouped according to their birth year into three categories: ≤ 1986, 1987-1992, and ≥ 1993, which correspond to no neonatal hepatitis B immunization, plasma-derived HB vaccine (PDHBV), and recombinant hepatitis B vaccine (RHBV), respectively. Prevalence of hepatitis B viral seromarkers, including IAHBc, was calculated by sex, age groups, and birth cohorts. Those who underwent repeated hepatitis B serology tests were included for further analysis to follow up their serostatus., Results: A total of 117,335 adults with complete hepatitis B serologic data were analyzed. Among them, 6641 individuals (5.7 %) were found to have IAHBc. The prevalence of IAHBc was 11.4 %, 0.8 %, and 0.3 % among those born before 1986, between 1987 and 1992, and after 1992, respectively. Among the 690 subjects with repeated blood tests and complete hepatitis B serologic data, 551 cases (79.9 %) remained IAHBc. The other cases included resolved infection status (13.9 %), seronegativity for three HB seromarkers (3 %), and carrier of hepatitis B virus (2.3 %)., Conclusion: The management of individuals with IAHBc should be tailored to their age, vaccination status, and risk factors for occult hepatitis B viral infection., Competing Interests: Declaration of competing interest All of the authors disclose no conflict of interest in this work., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

How human genetic variation contributes to vaccine effectiveness in infants is unclear, and data are limited on these relationships in populations with African ancestries. We undertook genetic analyses of vaccine antibody responses in infants from Uganda (n = 1391), Burkina Faso (n = 353) and South Africa (n = 755), identifying associations between human leukocyte antigen (HLA) and antibody response for five of eight tested antigens spanning pertussis, diphtheria and hepatitis B vaccines. In addition, through HLA typing 1,702 individuals from 11 populations of African ancestry derived predominantly from the 1000 Genomes Project, we constructed an imputation resource, fine-mapping class II HLA-DR and DQ associations explaining up to 10% of antibody response variance in our infant cohorts. We observed differences in the genetic architecture of pertussis antibody response between the cohorts with African ancestries and an independent cohort with European ancestry, but found no in silico evidence of differences in HLA peptide binding affinity or breadth. Using immune cell expression quantitative trait loci datasets derived from African-ancestry samples from the 1000 Genomes Project, we found evidence of differential HLA-DRB1 expression correlating with inferred protection from pertussis following vaccination. This work suggests that HLA-DRB1 expression may play a role in vaccine response and should be considered alongside peptide selection to improve vaccine design., (© 2024. The Author(s).)

Introduction: Limited data were available on the effectivenessfour years after Homo or Hetero prime-boost with 10 μg Hansenulapolymorpha recombinant hepatitis B vaccine (HepB-HP) and 20 μgChinese hamster ovary cell HepB (HepB-CHO)., Methods: A crosssectional study was performed in maternalhepatitis B surface antigen (HBsAg)-negative children whoreceived one dose of 10 μg HepB-HP at birth, Homo or Heteroprime-boost with 10 μg HepB-HP and 20 μg HepB-CHO at 1 and 6months. HBsAg and hepatitis B surface antibody (anti-HBs) fouryears after immunization were quantitatively detected by achemiluminescent microparticle immunoassay (CMIA)., Results: A total of 359 children were included; 119 childrenreceived two doses of 10 μg HepB-HP and 120 children receivedtwo doses of 20 μg HepB-CHO, called Homo prime-boost; 120children received Hetero prime-boost with 10 μg HepB-HP and 20μg HepB-CHO. All children were HBsAg negative. The geometricmean concentration (GMC) and overall seropositivity rate (SPR) ofanti-HBs were 59.47 (95%CI: 49.00 - 72.16) mIU/ml and 85.51%(307/359). Nearly 15% of the study subjects had an anti-HBsconcentration < 10 mIU/ml and 5.01% had an anti-HBsconcentration ≤ 2.5 mIU/ml. The GMC of the 20 μg CHO Homoprime-boost group [76.05 (95%CI: 54.97 - 105.19) mIU/ml] washigher than that of the 10 μg HP Homo group [45.86 (95%CI:31.94 - 65.84) mIU/ml] ( p = 0.035). The GMCs of the Heteroprime-boost groups (10 μg HP-20 μg CHO and 20 μg CHO-10 μgHP) were 75.86 (95% CI: 48.98 - 107.15) mIU/ml and 43.65(95%CI: 27.54 - 69.18) mIU/ml, respectively ( p = 0.041). Aftercontrolling for sex influence, the SPR of the 20 μg CHO Homoprime-boost group was 2.087 times than that of the 10 μg HPHomo group., Discussion: The HepB booster was not necessary in the generalchildren, Homo/Hetero prime-boost with 20 μg HepB-CHO wouldincrease the anti-HBs concentration four years after immunization,timely testing and improved knowledge about the self-pay vaccinewould be good for controlling hepatitis B., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yin, Wen, Fu, Li, Fang, Gong, You, Wang and Zheng.)

Introduction: since the introduction of the anti-HBV vaccine into the Expanded Program on Immunization (EPI) in 2005 in Cameroon, vaccination coverage has reached 99.0%. This coverage would indicate an increase in the number of children immune to Hepatitis B Virus (HBV) and a decrease in susceptibility to HBV-infection. This study was conducted to evaluate the effect of the HBV vaccine on pediatric HBV-infection in Yaounde, Cameroon., Methods: this school-based cross-sectional study was conducted from February to May 2016 among 180 children from Nkomo public school. The study population was stratified into two groups: vaccinated (n=95) versus (vs) unvaccinated (n=85). Screening for HBV biomarkers was done using a rapid panel test for detection (HBsAg, HBeAg and anti-HBc) and anti-HBs titer using enzyme linked immunosorbent assay (ELISA). Statistical analyses were done using SPSS v. 22 with p < 0.05 considered significant., Results: the mean age was 9.65 years. HBsAg (p=0.019) and anti-HBc (p=0.001) rates were detected in children aged ≥10 years and children aged < 10 years (95.95% [71/74]) were vaccinated vs 22.64% (24/106) for those aged ≥10 years (OR: 80.86; 95% CI: 23.36%-279.87%, p < 0.0001). According to anti-HBV vaccination status, HBsAg rate varied from [9.41% (8/85) to 1.05% (1/95), p=0.025], HBeAg rate varied from [2.35% (2/85) to 0% (0/95), p= 0.42] and anti-HBc rate ranged from [12.94% (11/85) to 2.10% (2/95), p= 0.011]., Conclusion: despite the variability of the anti-HBs titer, vaccination against HBV has a positive effect on the reduction of HBV-infection in children in tropical settings such as Cameroon., Competing Interests: The authors declare no competing interests., (Copyright: Philippe Salomon Nguwoh et al.)

Background: Pentavalent vaccines (DTP-HepB-Hib) have been introduced in many countries in their routine public immunization programmes to protect against diphtheria (D), tetanus (T), pertussis (P), hepatitis B (Hep B) and Hemophilus influenzae type b (Hib) diseases. This study compared the safety and immunogenicity of a new formulation of a whole-cell Bordetella pertussis (wP) based pentavalent vaccine (DTwP-HepB-Hib). The new formulation was developed using well-characterized hepatitis B and pertussis whole cell vaccine components., Methods: This was a phase III, observer-blind, randomized, non-inferiority, multi-center study conducted in India among 460 infants who were followed up for safety and immunogenicity for 28 days after administration of three doses of either investigational or licensed comparator formulations at 6-8, 10-12 and 14-16 weeks of age., Results: The investigational formulation of DTwP-HepB-Hib vaccine was non-inferior to the licensed formulation in terms of hepatitis B seroprotection rate (% of subjects with HepB antibodies ≥10mIU/mL were 99.1% versus 99.0%, respectively, corresponding to a difference of 0.1% (95% CI, -2.47 to 2.68)) and pertussis immune responses (adjusted geometric mean concentrations of antibodies for anti-PT were 76.7 EU/mL versus 63.3 EU/mL, with a ratio of aGMTs of 1.21 (95% CI, 0.89-1.64), and for anti-FIM were 1079 EU/mL versus 1129 EU/mL, with a ratio of aGMTs of 0.95 (95% CI, 0.73-1.24), respectively). The immune responses to other valences (D, T, and Hib) in the two formulations were also similar. The safety profile of both formulations was found to be similar and were well tolerated., Conclusions: The investigational DTwP-HepB-Hib vaccine formulation was immunogenic and well-tolerated when administered as three dose primary series in infants., Clinical Trial Registration: Clinical Trials Registry India number: CTRI/2018/12/016692., Competing Interests: PM reports grants and non-financial support from Sanofi Pharma, during the conduct of the study; JC reports grants from Sanofi Pharma, during the conduct of the study; NADC, EV, BNP, AM, VJM, SP and FN are Sanofi employees and own stocks of the company. DMP and SRJ were employees of Sanofi at the time of study. PS, SM, SMD, SK, PIV have nothing to disclose, (Copyright: © 2023 Aloysia D’Cor et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Immunization is recommended for people with diabetes mellitus (DM), but little information is available on their seropositivity rates. To determine the impact of glucose tolerance state on seropositivity rate after hepatitis B vaccination, we included 7645 adult participants from the National Health and Nutrition Examination Survey 2005-2016 who reported three doses of hepatitis B vaccine and were seropositive for anti-hepatitis B surface antibody (≥ 12.0 mIU/mL), after exclusion of those positive for anti-hepatitis B core antibody and/or hepatitis B surface antigen. We classified the states of glucose tolerance as normal glucose tolerance (NGT, 61.68%), abnormal glucose tolerance (AGT, 26.02%), or DM (13.30%). We observed a stepwise decline in hepatitis B seropositivity rate from NGT (53.64%) to AGT (45.52%) to DM (28.84%) (P < 0.0001). We confirmed these results after standardization for age and BMI (P < 0.0001 for all subgroup analyses) and in subgroup analyses by gender and racial/ethnic group. Dysregulated glucose metabolism is associated with a decreased seropositivity rate after hepatitis B vaccination. Our observations suggest that regular follow-up screening for anti-hepatitis B surface antibody, with additional booster vaccination as necessary, is especially important in patients with DM. Whether a similar phenomenon exits for other vaccines, especially COVID-19, remains to be investigated., (© 2022. The Author(s).)

Humans are a major reservoir of the hepatitis B virus (HBV), therefore promising treatment and control vaccination strategies are needed to eradicate the virus. Though promising drugs and vaccines are available against HBV, still efforts are required to enrich the therapy options. Herein, the HBV assembly protein was explored to identify novel targets for future use against HBV. Computer-aided drug designing and immune-informatics techniques were employed for the identification of putative inhibitors and vaccine ensemble against HBV using capsid assembly protein. The identified drug molecule binds with high affinity to the active pocket of the protein, and several epitopes are scanned in the protein sequence. The drug molecule, besides being a good putative inhibitor, has acceptable drug-like properties. A multi-epitope vaccine is also constructed to overcome the limitations of weakly immunogenic epitopes. In contrast to the MHC II level, the set of predicted epitopes has been recognized to interact with significant numbers of HLA alleles of MHC I. Selected epitopes are extremely virulent, antigenic, nontoxic, nonallergic, have suitable affinity to bind with the prevailing DRB*0101 allele, and also spectacle 86% mediocre population coverage. A multi-epitope peptide-based vaccine chimera having 73 amino acids was designed. It emerged as substantially immunogenic, thermally stable, robust in producing cellular as well as humoral immune responses, and had competent physicochemical properties to analyze in vitro and in vivo studies. The capsid assembly protein is a in more stable nature in the presence of the drug molecule compared to the TLR3 receptor in the vaccine presence. These particulars were confirmed by exposing the docked molecules to absolute and relative binding free energy approaches of MMGBSA/PBSA. The purpose to investigate the interactions between the vaccine and a representative TLR3 immune receptor can reveal the intermolecular affinity and possible presentation mechanism of the vaccine by TLR3 to the host immune system. It was revealed that the vaccine is showing a very good affinity of binding for the TLR3 and forming a network of hydrophobic and hydrophilic interactions. Overall, the findings of this study are promising and might be useful for further experimental validations., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Hepatitis B vaccine has contributed to the reduction in hepatitis B virus infections and chronic disease globally. Screening to establish extent of vaccine induced immune response and provision of booster dose are limited in most low-and-middle income countries (LMICs). Our study investigated the extent of protective immune response and breakthrough hepatitis B virus infections among adult vaccinated healthcare workers in selected health facilities in northern Uganda. A cross-sectional study was conducted among 300 randomly selected adult hepatitis B vaccinated healthcare workers in Lira and Gulu regional referral hospitals in northern Uganda. Blood samples were collected and qualitative analysis of Hepatitis B surface antigen (HBsAg), Hepatitis B surface antigen antibody (HBsAb), Hepatitis B envelop antigen (HBeAg), Hepatitis B envelop antibody (HBeAb) and Hepatitis B core antibody (HBcAb) conducted using ELISA method. Quantitative assessment of anti-hepatitis B antibody (anti-HBs) levels was done using COBAS immunoassay analyzer. Multiple logistic regression was done to establish factors associated with protective anti-HBs levels (≥ 10mIU/mL) among adult vaccinate healthcare workers at 95% level of significance. A high proportion, 81.3% (244/300) of the study participants completed all three hepatitis B vaccine dose schedules. Two (0.7%, 2/300) of the study participants had active hepatitis B virus infection. Of the 300 study participants, 2.3% (7/300) had positive HBsAg; 88.7% (266/300) had detectable HBsAb; 2.3% (7/300) had positive HBeAg; 4% (12/300) had positive HBeAb and 17.7% (53/300) had positive HBcAb. Majority, 83% (249/300) had a protective hepatitis B antibody levels (≥10mIU/mL). Hepatitis B vaccine provides protective immunity against hepatitis B virus infection regardless of whether one gets a booster dose or not. Protective immune response persisted for over ten years following hepatitis B vaccination among the healthcare workers., Competing Interests: The authors have declared that no competing interests exist.

Background: There is conflicting evidence about whether a double dose of the hepatitis B virus (HBV) vaccine induces better immunity than the standard-dose vaccine for people living with HIV (PLWH). This study provides a meta-analysis that summarizes the efficacy of HBV vaccine regimens among HIV-infected patients, clarifying the role of particular factors such as dose and frequency of vaccination in vaccine responsiveness and highlighting the need for evidence-based practice to assess HBV vaccination among PLWH., Methods: Randomized clinical trials (RCTs) and prospective studies reporting vaccination response rates among PLWH were found through a search of PubMed, Cochrane, and the Web of Science. The key outcome was vaccine response. A random-effects model was used to estimate the pooled response rate. Subgroup analysis was conducted to evaluate key factors and explore sources of heterogeneity. Possible biases were assessed using quality and publication bias assessment., Results: Eligible studies included controlled trials that examined the effects of 17 interventional studies with 1,821 participants. Among PLWH who received the HBV vaccine, the pooled response rate of HBV vaccination was 71.5% (95% CI 64.0%-77.9%, p < 0.001). Compared with the standard dose (65.5%, 95% CI 53.1%-76.1%), the double dose (75.2%, 95% CI 66.2%-82.5%) was associated with a better response rate [ Q (1) = 19.617, p < 0.001]. When stratified by schedule, the four-dose schedule (89.7%, 95% CI 83.1%-93.9%) had a higher response rate than the three-dose schedule (63.3%, 95% CI 56.6%-69.4%) and the difference was significant [ Q (1) = 88.305, p < 0.001]. PLWH with higher CD4 + T-cell counts (>500 cells/mm 3 ) at the time of vaccination had better response rates [ Q (1) = 88.305, p < 0.001]., Conclusions: In this meta-analysis, the double dose of the HBV vaccine and multiple injections were associated with better immune responses than the standard HBV vaccine regimen in PLWH. Higher seroconversion rates were observed in PLWH with high CD4 + T-cell levels, indicating that individuals infected with HIV should receive the HBV vaccine as soon as possible after diagnosis., Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tian, Hua, Wu, Zhang, Wang, Wu, Guo and Huang.)

The role of Myeloid-Derived Suppressor Cells (MDSC) in infant immune ontogeny is unknown. Here, we evaluated MDSC frequency and relationship with infant vaccine responses throughout the first year of life in a prospective cohort study. Ninety-one South African infant-mother pairs were enrolled at delivery, and blood samples were collected at 0, 6, 10, and 14 weeks, 6 months, 9 months, and 1 year. MDSC frequencies were quantified, and immune responses to the childhood vaccines Bacillus Calmette-Guérin (BCG), hepatitis B (HepB), and combination diphtheria, tetanus, and pertussis (dTaP) were measured by Ag-specific CD4 + T cell proliferation and interferon gamma (IFN-γ) production. Vaccine-specific Ab responses to HepB, dTaP, and Haemophilus influenzae type b (Hib) were quantified via Enzyme-Linked Immunosorbent assay (ELISA). MDSC frequency in mother-infant pairs was strongly correlated; the frequency of MDSC decreased in both mothers and infants during the months after delivery/birth; and by 1 year, infant MDSC frequencies rebounded to birth levels. Higher MDSC frequency at vaccination was associated with a lack of subsequent IFN-γ release in response to vaccine Ags, with the exception of BCG. With the exception of a weak, positive correlation between MDSC frequency at 6 weeks (time of initial vaccination) and peak Hepatitis B surface antigen Ab titer, Polymorphonuclear Myeloid-Derived Suppressor Cells (PMN-MDSC) was not correlated with T cell proliferation or Ab responses in this study. The potential for MDSC-mediated suppression of vaccine Ag-specific IFN-γ responses should be explored further, and considered when evaluating candidate infant vaccines., (©2021 Society for Leukocyte Biology.)

Vaccination to prevent infectious disease is one of the most successful public health interventions ever developed. And yet, variability in individual vaccine effectiveness suggests that a better mechanistic understanding of vaccine-induced immune responses could improve vaccine design and efficacy. We have previously shown that protective antibody levels could be elicited in a subset of recipients with only a single dose of the hepatitis B virus (HBV) vaccine and that a wide range of antibody levels were elicited after three doses. The immune mechanisms responsible for this vaccine response variability is unclear. Using single cell RNA sequencing of sorted innate immune cell subsets, we identified two distinct myeloid dendritic cell subsets (NDRG1-expressing mDC2 and CDKN1C-expressing mDC4), the ratio of which at baseline (pre-vaccination) correlated with the immune response to a single dose of HBV vaccine. Our results suggest that the participants in our vaccine study were in one of two different dendritic cell dispositional states at baseline - an NDRG2-mDC2 state in which the vaccine elicited an antibody response after a single immunization or a CDKN1C-mDC4 state in which the vaccine required two or three doses for induction of antibody responses. To explore this correlation further, genes expressed in these mDC subsets were used for feature selection prior to the construction of predictive models using supervised canonical correlation machine learning. The resulting models showed an improved correlation with serum antibody titers in response to full vaccination. Taken together, these results suggest that the propensity of circulating dendritic cells toward either activation or suppression, their "dispositional endotype" at pre-vaccination baseline, could dictate response to vaccination., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Aevermann, Shannon, Novotny, Ben-Othman, Cai, Zhang, Ye, Kobor, Gladish, Lee, Blimkie, Hancock, Llibre, Duffy, Koff, Sadarangani, Tebbutt, Kollmann and Scheuermann.)

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.

Background: The cellular mechanisms involved in the lack of protective antibody response after hepatitis B vaccination are still rather unclear. Regulatory B cells (Breg) known as modulators of B-and T-cell responses may contribute to poor vaccine responsiveness. The current study aimed to investigate the role of regulatory B cells (Breg) in hepatitis B vaccine non-responsiveness after immunization with second- or third-generation hepatitis B vaccines., Method: We performed comparative phenotypic and frequency analysis of Breg subsets (CD24 + CD27 + and CD24 high CD38 high Breg) in second-generation hepatitis B vaccine non-responders (2 nd HBvac NR, n = 11) and responders (2 nd HBvac R, n = 8) before (d0), on day 7 (d7), and 28 (d28) after booster vaccination. Cryopreserved peripheral blood mononuclear cells were stimulated ex vivo with a combination of CpG, PMA, and Ionomycin (CpG+P/I) and analyzed for numbers and IL-10 expression levels of Breg by flow cytometry-based analyses., Results: Flow cytometry-based analyses revealed elevated frequencies of CD24 + CD27 + Breg at all time points and significantly higher frequencies of CD24 high CD38 high Breg on d0 ( p = 0.004) and 28 ( p = 0.012) in 2 nd HBvac NR compared to 2 nd HBvac R. In parallel, we observed significantly lower levels of CpG+P/I-induced IL-10 expression levels of CD24 + CD27 + and CD24 high CD38 high Breg (d0: p < 0.0001; d7: p = 0.0004; d28: p = 0.0003 and d0: p = 0.016; d7: p = 0.016, respectively) in 2 nd HBvac NR compared to 2 nd HBvac R before and after booster immunization. Frequencies of CD24 + CD27 + and CD24 high CD38 high Breg significantly decreased after third-generation hepatitis B booster vaccination (d7: p = 0.014; d28: p = 0.032 and d7: p = 0.045, respectively), whereas IL-10 expression levels of both Breg subsets remained stable., Conclusion: Here we report significantly higher frequencies of CD24 high CD38 high Breg in parallel with significantly lower IL-10 expression levels of CD24 + CD27 + and CD24 high CD38 high Breg in 2 nd HBvac NR compared to 2 nd HBvac R. Anti-HBs seroconversion accompanied by a decrease of Breg numbers after booster immunization with a third-generation hepatitis B vaccine could indicate a positive effect of third-generation hepatitis B vaccines on Breg-mediated immunomodulation in hepatitis B vaccine non-responders., Competing Interests: UP received funding for the project from the Helmholtz Association in context of the iMed initiative and the Helmholtz-Alberta-Initiative in Infectious Disease Research. UP serves as scientific advisor for Gilead, Leukocare, Abbvie, MSD, Arbutus, GSK, Vaccitech, Biontech, and Dicerna. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Körber, Pohl, Weinberger, Grubeck-Loebenstein, Wawer, Knolle, Roggendorf, Protzer and Bauer.)

The neonatal hepatitis B vaccination (HBVac) was implemented 35 years ago in Taiwan, but many vaccinees exhibit inadequate long-term vaccine-induced seroprotective hepatitis B surface antibody (anti-HBs) levels. We investigated the association of the human leukocyte antigen (HLA) alleles (DPA1, DPB1, DQA1, and DQB1) with the long-term immunological response to the neonatal HBVac and adolescent booster HBVac in a Taiwanese cohort. We divided 281 Han students (median age 22, age range 17-29 years) into the following groups: (1) Group A ( n  = 61): anti-HBs titer ≥ 10 mIU/mL at the beginning of the study; (2) Group B ( n  = 75): anti-HBs level > 1000 mIU/mL after the first booster; (3) Group C ( n  = 37): anti-HBs level < 10 mIU/mL after the first booster; and (4) Group D ( n  = 5): anti-HBs level < 10 mIU/mL after three boosters. DQA1, DQB1, DPA1, and DPB1 typing of the participants was performed using sequence-specific oligonucleotides. Associations of HLA alleles and haplotypes with effects on neonatal HBVac and booster HBVac were examined through logistic regression analysis and Fisher's exact test. A false discovery rate-based measure of significance, the q-value, was used for multiple comparisons, and an association was considered significant if the corresponding q-value was < 0.1. DPA1 alleles were associated with the long-term immunological response to the neonatal HBVac. The estimated odds ratio (OR) of the lack of HBV protective immunity when carrying an additional DPA1*01 and DPA1*02 was 0.36 [95% confidence interval (CI) = 0.17-0.76, p = 0.0076] and 2.39 (95% CI = 1.17-4.87, p = 0.016), respectively. DPB1 and DQB1 alleles were associated with a response to the adolescent booster vaccination. The estimated ORs of being nonresponsive to the first booster when carrying an additional DPB1*05 and DQB1*02 were 2.11 (95% CI = 1.13-3.93, p = 0.019) and 3.73 (95% CI = 1.43-9.71, p = 0.0070), respectively. All DPB1*03 carriers responded to the first booster (p of Fisher's exact test = 0.0045). In our study, we discovered that HLA-DPA1 was primarily associated with the long-term response of primary infantile HBVac, and HLA-DPB1 and HLA-DQB1 exhibited associations with the HBV booster vaccination., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wang, Lin, Chang, Yeh, Su, Wu and Su.)

Chronic hepatitis B infection remains a serious global health threat, contributing to a large number of deaths through liver cirrhosis and hepatocellular carcinoma. Current treatment does not eradicate disease, and therefore new treatments are urgently needed. In acute hepatitis B virus (HBV) a strong immune response is necessary to clear the virus, but in chronic infection the immune response is weakened and dysfunctional. Therapeutic vaccination describes the process of inoculating individuals with a non-infective form of viral antigen with the aim of inducing or boosting existing HBV-specific immune responses, resulting in sustained control of HBV infection. In this review we outline the rationale for therapeutic vaccination in chronic HBV infection, discuss previous and ongoing trials of novel HBV therapeutic vaccine candidates and outline strategies to improve vaccine efficacy going forward., (© 2021 The Authors. Clinical & Experimental Immunology published by John Wiley & Sons Ltd on behalf of British Society for Immunology.)

Although aluminum-containing adjuvants are widely used in human vaccination due to their excellent safety profile, they exhibit low effectiveness with many recombinant antigens. This study investigated the adjuvanticity of snail mucin with recombinant Hepatitis B Vaccine (rHBsAg). Twenty-five (25) female mice distributed unbiasedly into 5 groups were used in the study and were administered different rHBsAg/Mucin formulation at 7 days intervals. Blood samples were collected a day following the administration for analysis. The results of liver function and body weight analysis were indications that snail mucin had no adverse effect on the mice. The treatment group (administer mucin and rHBsAg) showed significantly (P<0.05) higher mean titres of anti-HBsAg antibodies when compared with the negative controls and the positive control administered with two doses of rHBsAg after the boost doses (day 28). Furthermore, a comparable immune response to positive control administered with three doses rHBaAG was recorded. In silico prediction, studies of the protein-protein interaction of a homology modelled snail mucus protein and HBsAg gave an indication of enhanced HBV antigen-antibody interaction. Therefore, this study has shown that snail mucin possesses some adjuvant properties and enhances immune response towards rHBsAg vaccine. However, there is a need for further molecular dynamics studies to understand its mechanism of action., Competing Interests: The authors have declared that no competing interests exist

Background: Despite completion of the vaccine schedule for hepatitis B virus (HBV), children may display levels of HBV surface antibodies (anti-HBs) that are considered inadequate for sufficient protection (<10 IU/L)., Aims: Our aim was to investigate if age and gap time between HBV vaccine doses may negatively affect the levels of anti-HBs in children, and if these relationships are modified by sex., Methods: In a high-endemic HBV region of the western Brazilian Amazon we enrolled children who had completed the HBV vaccine schedule. All children underwent analysis of anti-HBs and a clinical examination., Results: We included 522 children (mean age 4.3 ± 0.8 years; 50% male). Median anti-HBs was 28.4 [interquartile range (IQR) 5.4 to 128.6] IU/L and 32% had anti-HBs <10 IU/L. The median gap time from last to preceding dose was 2.4 [IQR 2.1 to 3.3] months. Levels of anti-HBs decreased with higher age (-42% per year increase [95%CI -56% to -24%], p<0.001), but not with longer gap time (+23% per month increase [95%CI -16% to +62%], p = 0.249). After adjusting for relevant confounders, gap time became significant (p = 0.032) and age remained a significant predictor of anti-HBs (p<0.001)., Conclusion: One third of assessed children displayed anti-HBs <10 IU/L. Levels of anti-HBs decreased with higher age and increased with longer gap time between the last two doses., Competing Interests: The authors have declared that no competing interests exist.

Background: Refugees are frequently not immune to vaccine-preventable infections. Adherence to consensus guidelines on vaccination and infectious diseases screening among refugees resettling in the U.S. is unknown. We sought to determine rates of vaccine completion and infectious diseases screening in refugees following resettlement., Methods: We conducted a retrospective cohort study of refugees resettling in a region in the U.S. using medical data from June 2013-April 2015. We determined the proportion of vaccine-eligible refugees vaccinated with measles-mumps-rubella (MMR), hepatitis A/B, tetanus, diphtheria, and acellular pertussis (Tdap), and human papillomavirus (HPV) following resettlement. We also determined the proportion of refugees who completed HIV and hepatitis C (HCV) screening., Results: One hundred and eleven subjects were included, primarily from Iraq (53%), Afghanistan (19%), and Eritrea (11%). Of the 84 subjects who were vaccine-eligible, 78 (93%) initiated and 42 (50%) completed vaccinations within one year of resettlement. Odds of completing vaccination were higher for men (OR: 2.38; 95%CI:1.02-5.71) and for subjects with English proficiency (OR: 3.70; 95%CI:1.04-17.49). Of the 78 subjects (70%) completing HIV screening, two (3%) were diagnosed with HIV. Nearly all subjects completed screening for HCV, and one had active infection., Conclusion: While most refugees initiate vaccinations, only 50% completed vaccinations and 70% completed HIV screening within 1 year of resettlement. There is a need to emphasize vaccine completion and HIV screening in refugee patients following resettlement.

Hepatitis B virus (HBV) vaccines are composed of surface antigen HBsAg that spontaneously assembles into subviral particles. Factors that impede its humoral immunity in 5% to 10% of vaccinees remain elusive. Here, we showed that the low-level interleukin-1 receptor antagonist (IL-1Ra) can predict antibody protection both in mice and humans. Mechanistically, murine IL-1Ra-inhibited T follicular helper (Tfh) cell expansion and subsequent germinal center (GC)-dependent humoral immunity, resulting in significantly weakened protection against the HBV challenge. Compared to soluble antigens, HBsAg particle antigen displayed a unique capture/uptake and innate immune activation, including IL-1Ra expression, preferably of medullary sinus macrophages. In humans, a unique polymorphism in the RelA/p65 binding site of IL-1Ra enhancer associated IL-1Ra levels with ethnicity-dependent vaccination outcome. Therefore, the differential IL-1Ra response to particle antigens probably creates a suppressive milieu for Tfh/GC development, and neutralization of IL-1Ra would resurrect antibody response in HBV vaccine nonresponders., Competing Interests: The authors declare no competing interest.

Background: Vaccination is the best way to protect children under 5 years from death or disability. Children with biliary atresia (BA), which is the most common pediatric cholestatic end-stage liver disease (PELD), are more vulnerable to infectious diseases. However, the vaccination coverage and factors modulating vaccine responses in children with BA are largely unknown., Methods: In this study, 288 children (median age: 7 months) diagnosed with BA before liver transplantation were enrolled for the evaluation of vaccination status and the factors affecting the immune response to the hepatitis B (HBV) vaccine. Moreover, 49 BA children (median age: 4 months) were enrolled for flow cytometric analysis of CD4 + T cells and CD19 + B cell subsets and correlations with serum bile acid levels., Results: Generally, these children had very low routine vaccination rates for the meningococcal serogroup AC (Men AC) (41.2%), measles-mumps-rubella (MMR) (31.3%), poliomyelitis (Polio) (25.3%), hepatitis A (HAV) (25.0%), Japanese encephalitis (JE) (15.0%), diphtheria-tetanus-pertussis (DTP) (14.2%), meningococcal serogroup A (Men A) (13.5%) and varicella (VAR) (10.8%) vaccines, but not for the HBV (96.2%) and bacillus Calmette-Guérin (BCG) (84.7%) vaccines. Remarkably, 19.8% (57/288) of the patients had HBV infection. Out of 220 patients vaccinated for HBV, 113 (51.4%), 85 (38.6%) and 22 (10%) had one, two or three doses of the HBV vaccine, respectively. Furthermore, logistic regression analysis revealed that the bile acid level was an independent factor associated with poor HBV vaccine response ( p = 0.03; OR = 0.394; 95% CI = 0.170-0.969). Immunophenotyping showed that bile acids were only negatively correlated with the CD19 + CD27 + IgG + post-class-switched memory B cell ratio ( p = 0.01)., Conclusion: This study reveals the overall vaccination rates of routine vaccines in Chinese BA children are very low and the poor HBV vaccine responses are associated with bile acids, possibly via the inhibition of CD19 + CD27 + IgG + post-class-switched memory B cell response., Clinical Trial Registration: http://www.chictr.org.cn, identifier ChiCTR1800019165., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Liu, Fei, Zhou, Ji, Wu, Gu, Luo, Zhu, Feng, Wan, Qiu, Lu, Yang, Deng, Zhou, Gong, Deng, Xue and Xia.)

Background: The role of the HLA-DRB1 and HLA-DQB1 genes in the antibody response to hepatitis B (HB) vaccine has been well established; however, the involvement of the HLA-DPB1 allele in the HB vaccine immune response remained to be clarified by a systematic review., Methods: A meta-analysis was performed in which databases were searched for relevant studies published in English or Chinese up until June 1, 2020. Six studies were identified and a total of 10 alleles were processed into statistical processing in this meta-analysis., Results: Three thousand one hundred forty four subjects (including 2477 responders and 667 non-responders) were included in this research. Alleles HLA-DPB1∗02:02, DPB1∗03:01, DPB1∗04:01, DPB1∗04:02, and DPB1∗14:01 were found to be associated with a significant increase in the antibody response to HB vaccine, and their pooled odds ratios (ORs) were 4.53, 1.57, 3.33, 4.20, and 1.79, respectively; whereas DPB1∗05:01 (OR = 0.73) showed the opposite correlation., Conclusions: These findings suggested that specific HLA-DPB1 alleles are associated with the antibody response to HB vaccine., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Invasive meningococcal disease has high morbidity and mortality, with infants and young children among those at greatest risk. This phase III, open-label, randomised study in toddlers aged 12-23 months evaluated the immunogenicity and safety of meningococcal tetanus toxoid-conjugate vaccine (MenACYW-TT), a tetanus toxoid conjugated vaccine against meningococcal serogroups A, C, W and Y, when coadministered with paediatric vaccines (measles, mumps and rubella [MMR]; varicella [V]; 6-in-1 combination vaccine against diphtheria, tetanus, pertussis, polio, hepatitis B and Haemophilus influenzae type b [DTaP-IPV-HepB-Hib] and pneumococcal conjugate vaccine [PCV13])(NCT03205371). Immunogenicity to each meningococcal serogroup was assessed by serum bactericidal antibody assay using human complement (hSBA). Vaccine safety profiles were described up to 30 days post-vaccination. A total of 1183 participants were enrolled. The proportion with seroprotection (hSBA ≥1:8) to each meningococcal serogroup at Day 30 was comparable between the MenACYW-TT and MenACYW-TT + MMR + V groups (≥92 and ≥96%, respectively), between the MenACYW-TT and MenACYW-TT + DTaP-IPV-HepB-Hib groups (≥90% for both) and between the MenACYW-TT and MenACYW-TT + PCV13 groups (≥91 and ≥84%, respectively). The safety profiles of MenACYW-TT, and MMR + V, DTaP-IPV-HepB-Hib, and PCV13, with or without MenACYW-TT, were generally comparable. Coadministration of MenACYW-TT with paediatric vaccines in toddlers had no clinically relevant effect on the immunogenicity and safety of any of the vaccines.

Introduction: The humoral response to vaccinations varies widely between individuals. There is no data available on the correlation between responses to different vaccines. In this study, we investigated the correlation of antibody responses between routine vaccine antigens in infants., Methods: One and seven months after the 6-month vaccinations and one month after the 12-month vaccinations, antibody concentrations to diphtheria, tetanus, pertussis, polio (serotypes 1-3), Haemophilus influenzae type b (Hib), pneumococcus (13 serotypes), meningococcus C, measles, mumps and rubella were measured using fluorescent bead-based multiplex immune-assays. For the correlation of antibody responses, Spearman's rank correlation coefficients (ρ) with 95% confidence intervals (CI) were calculated between responses to each vaccine antigen., Results: The correlation between concentrations of antibodies to the vaccinations ending at 6 months of age was higher one month compared to seven months after vaccination. The strongest correlations at both time points were observed between antibody responses to different polio serotypes, certain pneumococcal serotypes and between responses to diphtheria and pneumococcal (conjugated to a diphtheria toxoid) vaccine antigens. Correlation between responses to tetanus, Hib, pertussis, polio and other vaccine antigens were weak. The correlation between antibody responses to the 12-month vaccine antigens was weaker than to the 6-month vaccine antigens and there was a negative correlation between responses to measles, mumps, rubella vaccine and non-live vaccine antigens (meningococcus C, tetanus and Hib). There was only weak correlation between antibody responses to vaccines of the same type (e.g. conjugated polysaccharide or toxoid vaccines)., Conclusion: Correlation between antibody responses to similar antigens in the same vaccine (such as different serotypes of a bacteria or virus), as well as responses to antigens conjugated to similar carrier proteins, are strong. In contrast, correlation between responses to other vaccines are weak. Measuring antibody responses to one or a few vaccine antigens therefore does not offer a reliable surrogate marker of responses to unrelated vaccines., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zimmermann, Ritz, Perrett, Messina, van der Klis and Curtis.)

Background: Heplisav-B, a hepatitis B virus (HBV) vaccine with an immunostimulatory adjuvant, was FDA approved in 2017 for adults ≥18 years. In randomized controlled trials, Heplisav-B demonstrated seroprotection rates (SPR) of 90%-95% versus 65%-80% for Engerix-B. No studies have included people with HIV (PWH), and the SPR and its predictors in this population are unknown., Setting: Quaternary care center HIV clinic., Methods: This retrospective cohort study evaluated PWH aged ≥18 years without current HBV seroprotection (anti-HBV surface antibody level [anti-HBs] <10 mIU/mL) who were administered Heplisav-B. Patients without post-immunization titers were excluded. The primary outcome was the SPR, the proportion of participants with HBV seroprotection at any point after the first vaccination., Results: Among 64 PWH included, median time to anti-HBs measurement after vaccination was 13 weeks. The median age was 58 years, 81% were men, and 95% had a viral load <200. The SPR was 81% in the entire cohort (and 86% in those without significant non-HIV immunosuppression), 79% in those with no prior HBV vaccination and no anti-HBc positivity, and 84% in those with prior vaccine nonresponse. Lower current and nadir CD4+ counts were associated with progressively lower seroprotection., Conclusion: In the first single-center retrospective study of Heplisav-B in PWH, the SPR compared favorably with the SPR seen among PWH from prior HBV vaccines across key subgroups. Given these findings, Heplisav-B should be considered for expanded use for HBV vaccination in PWH. Further research on the effectiveness of a repeat vaccination series or higher dosing in nonresponders is needed., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Idiopathic nephrotic syndrome is a childhood renal disease characterized by a damage of the glomerular filtration barrier leading to an intense leakage of proteins into the urine. This severe proteinuria causes a transient but strong reduction of serum IgG. Therefore, evaluation of vaccine competence by measuring serum levels of protective antibodies can be misleading in nephrotic syndrome, especially during the active phase of disease. To overcome this issue, in parallel to measuring serum antigen-specific IgG, we quantified by ELISPOT the number of antigen-specific memory B cells induced by previous immunization with tetanus and hepatitis B virus (HBV) in 11 steroid-sensitive nephrotic syndrome (SSNS) pediatric patients at onset before any immunosuppressive treatment (mean age 5.1±0.9 years). Five age-matched children with non-immunomediated nephro-urologic disorders were also enrolled as controls (mean age 6.9±2.3 years). Low total serum IgG levels (<520 mg/dl) were found in all the analyzed SSNS patients. In parallel, median levels of anti-tetanus and anti-HBV IgG were significantly reduced compared to controls [0.05 (0.03-0.16) vs. 0.45 (0.29-3.10) IU/ml and 0.0 (0.0-0.5) vs. 30.3 (5.5-400.8) mIU/ml, respectively; p = 0.02 for both], with serum IgG titers below protective threshold in 7/11 SSNS patients for tetanus and in 9/11 SSNS patients for HBV. In contrast, all SSNS patients had a competent B-cell response, showing an amount of total IgG-secreting B cells >1,000 counts/10 6 stimulated cells. The amount of anti-tetanus and anti-HBV IgG-secreting B cells was also comparable to that of controls ( p = 0.24, p = 0.32, respectively), with a frequency of memory anti-tetanus and anti-HBV IgG secreting B cells >0.1% of total IgG secreting B cells. In conclusion, SSNS children at disease onset pre-immunosuppressive therapy showed a competent immune and vaccine response against tetanus and HBV, which can be correctly evaluated by quantification of antigen-specific memory B cells rather than by measuring serum IgG levels. This approach allows early identification of the impairment of immune and vaccine competence, which may derive from protracted use of different immunosuppressive drugs during disease course., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Colucci, Piano Mortari, Zotta, Corrente, Concato, Carsetti, Emma and Vivarelli.)

Objectives: Overt and occult hepatitis B infection (HBI) among mothers and infants were investigated, and the effectiveness of vaccination against HBI was evaluated based on transmission types., Methods: A hospital-based cohort was built with 2,734 mothers and 330 mother-infant pairs. Their demographic data were collected. Serological HBV markers, nested-PCR for HBV genes, viral load detection, and phylogenetic analysis were done., Results: The overall prevalence of HBI among mothers was 12.1% (330/2,734), with 10.4% for the overt type and 1.8% for the occult type. In 330 out of 1,650 (20%) mother-infant pairs, the overall, type-I (from overt mother to overt infant), type-II (from overt mother to occult infant), and type-Ⅲ (from occult mother to occult infant) transmissions were 1.9% (1/54), 5.6% (3/54) and 0.0% (0/7). The refinement of HBI classification improved the estimate of vaccine effectiveness against HBI from 74.4%-80.9% to 94.4%, which was more prominent for type-II. One mother-infant pair with type-II transmission shared nearly identical complete sequences. However, the high rate of lost-to-follow-up could not be ignored., Conclusions: During the transition period, HBV is mainly transmitted from the overt type of HBI mother to infant. Intensive prenatal screening for mothers is vital., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Hepatitis B is a major global health challenge. In the absence of an effective treatment for the disease, hepatitis B vaccines provide protection against the viral infection. However, some individuals do not have positive immune responses after being vaccinated with the hepatitis B vaccines available in the market. Thus, it is important to develop a more protective vaccine. Previously, we showed that hepatitis B virus (HBV) 'a' determinant (aD) displayed on the prawn nodavirus capsid (Nc) and expressed in Spodoptera frugiperda (Sf9) cells (namely, Nc-aD-Sf9) self-assembled into virus-like particles (VLPs). Immunisation of BALB/c mice with the Nc-aD-Sf9 VLPs showed significant induction of humoral, cellular and memory B-cell immunity. In the present study, the biophysical properties of the Nc-aD-Sf9 VLPs were studied using dynamic light scattering (DLS) and circular dichroism (CD) spectroscopy. Enzyme-linked immunosorbent assay (ELISA) was used to determine the antigenicity of the Nc-aD-Sf9 VLPs, and multiplex ELISA was employed to quantify the cytokine response induced by the VLPs administered intramuscularly into BALB/c mice ( n = 8). CD spectroscopy of Nc-aD-Sf9 VLPs showed that the secondary structure of the VLPs predominantly consisted of beta (β)-sheets (44.8%), and they were thermally stable up to ~52 °C. ELISA revealed that the aD epitope of the VLPs was significantly antigenic to anti-HBV surface antigen (HBsAg) antibodies. In addition, multiplex ELISA of serum samples from the vaccinated mice showed a significant induction ( p < 0.001) of IFN-γ, IL-4, IL-5, IL-6, IL-10, and IL-12p70. This cytokine profile is indicative of natural killer cell, macrophage, dendritic cell and cytotoxic T-lymphocyte activities, which suggests a prophylactic innate and adaptive cellular immune response mediated by Nc-aD-Sf9 VLPs. Interestingly, Nc-aD-Sf9 induced a more robust release of the aforementioned cytokines than that of Nc-aD VLPs produced in Escherichia coli and a commercially used hepatitis B vaccine. Overall, Nc-aD-Sf9 VLPs are thermally stable and significantly antigenic, demonstrating their potential as an HBV vaccine candidate.

Introduction. The widespread of hepatitis B virus is a severe global public problem, and the infant hepatitis B vaccine has been proved effective. But the failure of the immune response was reported in studies, and boosters were recommended. There were few studies about the effect of hepatitis B vaccine boosters in different levels of the epidemic area. Hypothesis. Booster immunization is recommended because there may be a lack of immunization in infants vaccinated with the hepatitis B vaccine. In order to verify the effectiveness of booster immunization, this study hypothesized that it worked well in different levels of endemic areas. Aim. To evaluate the effects of hepatitis B vaccine boosters on children from the areas with different prevalence of hepatitis B whose hepatitis B surface antibody (anti-HBs) were negative (<10 mIU ml -1 ). Methodology. A total of 940 children were initially enrolled in screening; however, 421 were excluded. The participants were divided into three groups according to the different areas they come from: group I, low epidemic area; group II, middle epidemic area; and group III, high epidemic area. In total, 519 subjects were administered three doses of booster hepatitis B vaccine (0-1-6 months, 10 µg). The antibody titre changes were examined at four time points: 1 month after dose 1, 1 month, 1 year and 5 years after dose 3. Results. The protective seroconversion rates in three groups were 96.30, 97.16, 96.63% at 1 month after dose 1, and 100.00, 100.00, 100.00% at 1 month after dose 3, and 97.79, 100.00, 98.50% at 1 year after dose 3, and 90.77, 93.67, 93.59% at 5 years after dose 3 ( P >0.05). Conclusions. This study demonstrates that three doses of booster vaccination have a longtime effect, no matter whether it is in low, middle or high prevalence areas in which subjects live.

Vaccinations are effective in preventing infections; however, it is unknown if patients with chronic lymphocytic leukemia (CLL) who are treatment naïve (TN) or receiving Bruton tyrosine kinase inhibitors (BTKi's) respond to novel adjuvanted vaccines. Understanding the effect of BTKi's on humoral immunity is timely because BTKi's are widely used and vaccination against coronavirus disease 2019 is urgently needed. In 2 open-label, single-arm clinical trials, we measured the effect of BTKi's on de novo immune response against recombinant hepatitis B vaccine (HepB-CpG) and recall response against recombinant zoster vaccine (RZV) in CLL patients who were TN or on BTKi. The primary end point was serologic response to HepB-CpG (anti-hepatitis B surface antibodies ≥10 mIU/mL) and RZV (≥fourfold increase in anti-glycoprotein E). The response rate to HepB-CpG was lower in patients on BTKi (3.8%; 95% confidence interval [CI], 0.7-18.9) than patients who were TN (28.1%; 95% CI, 15.6-45.4; P = .017). In contrast, the response rate to RZV did not differ significantly between the BTKi (41.5%; 95% CI, 27.8-56.6) and TN cohorts (59.1%; 95% CI, 38.7-76.7; P = .2). BTKi's were associated with a decreased de novo immune response following HepB-CpG, whereas recall immune response following RZV was not significantly affected by BTKi therapy. These trials were registered at www.clinicaltrials.gov as #NCT03685708 (Hep-CpG) and #NCT03702231 (RZV).

Hepatitis B causes liver failure, cirrhosis and cancer. It has an estimated global prevalence of 6%, and 700,000 to 1 million persons die every year of hepatitis B-related causes. In 1989, hepatitis B incidence in Cuba was 14.9 per 100,000 population. To control infection, the Genetic Engineering and Biotechnology Center and the Ministry of Public Health, both in Havana, collaborated on a joint project that first produced natural interferon and recombinant interferon alpha-2b, and later a polyethylene glycolconjugated interferon. As part of the Cuban biotechnology development strategy, the project produced a vaccine against hepatitis B in 1985. At that time, hepatitis B vaccines available elsewhere in the world were costly and inaccessible to Cubans due to the US economic and trade embargo. The Heberbiovac HB preventive vaccine was approved by the Cuban regulatory authority and added to the Cuban newborn vaccination program in 1992 after phase 1-3 clinical trials demonstrated its safety and immunogenicity. From 2001 to 2003, PAHO/WHO qualified and requalified the vaccine four times. When associated with other antigens or molecules, Heberbiovac HB provides a common platform of virus-like particles that can be used in different ways, such as in the pentavalent vaccine containing Bordetella pertussis and Haemophilus infl uenzae type b antigens and tetanus and diptheria toxoids. Thanks to this vaccine, annual incidence of acute hepatitis in Cuba has dropped from more than 2000 cases to fewer than 100, and no infections in children aged 0-15 years have been reported since 2007. It is now used in more than 30 countries, providing protective, long-lasting antibody levels with no reports of serious adverse events. Yet, hepatitis B cannot be eliminated until there are no chronic patients. The comprehensive hepatitis B control project therefore included development of a therapeutic vaccine based on Heberbiovac HB. Using its platform, researchers designed an innovative version of the vaccine that was the precursor of a therapeutic nasal/subcutaneous vaccine for chronic hepatitis B, HeberNasvac. This precursor vaccine, which combines Heberbiovac HB with a recombinant antigen from the virus nucleocapsid (rHBcAg), was patented and licensed in 2015 by the Cuban regulatory authority. This article provides an overview of the progress-to-date on the development of this therapeutic vaccine, including clinical trials (some completed and others ongoing) to determine safety, efficacy and therapeutic benefits.

Occult hepatitis B virus (HBV) infection (OBI) has been observed among infants born to hepatitis B surface antigen (HBsAg)-positive mothers despite successful immunoprophylaxis. This study enrolled 549 infants [349 infants received a 10μg/dose of hepatitis B vaccine (HepB), and 200 infants received 20μg/dose HepB] born to HBsAg-positive mothers with HBV DNA load >6log 10 IU/mL. The anti-HBs levels in the 10μg group were significantly lower than that in the 20μg group both at 7 [652.48 (564.05-754.82) vs. 1541.72 (1268.69-1873.51) mIU/mL, P <0.001] and 12 months old [257.44 (220.29-300.88) vs. 1073.41 (839.27-1372.78) mIU/mL, P <0.001]. The OBI incidence in the 10μg group was significantly higher than that in the 20μg group at both 7 [21.55% (25/116) vs. 7.56% (9/119), P =0.002] and 12 months old [17.07% (14/82) vs. 6.90% (6/87), P =0.041]. OBI incidence in infants with anti-HBs levels <100mIU/mL was higher than that of those with anti-HBs ≥100mIU/mL [35.71% (5/14) vs. 13.12% (29/221), P =0.036]. This study showed that increasing the immunisation dose from 10μg to 20μg significantly improved anti-HBs levels and decreased OBI incidence in infants with a high maternal viral load. We recommend 20μg HepB to treat this high-risk population.

The programmed cell death 1 (PD-1) pathway represents a major immune checkpoint which may be engaged by cells in a tumor microenvironment to overcome active T-cell immune surveillance. Pembrolizumab (Keytruda ® ) is a potent and highly selective humanized monoclonal antibody (mAb) of the IgG 4 /κ isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. The current work was focused on developing a mouse T-Dependent Antibody Response (TDAR) model using a murinized rat anti-mouse PD-1 antibody (muDX400; a rodent surrogate for pembrolizumab) to evaluate the potential impact of treatment with a PD-1 inhibitor on immune responses to an antigen challenge (e.g. HBsAg in Hepatitis B vaccine). Despite the lower binding affinity and T 1/2 compared to pembrolizumab, ligand blocking data indicated muDX400 had appropriate pharmacological activity and demonstrated efficacy in mouse tumor models, thus was suitable for pharmacodynamic and vaccination studies in mice. In a vaccination study in which mice were concomitantly administered muDX400 and the Hepatitis B vaccine, muDX400 was well-tolerated and did not result in any immune-mediated adverse effects. The treatment with muDX400 was associated with a shift in the ratio between naive and memory cells in both CD4 + and CD8 + T-lymphocytes in the spleen but did not affect anti-HBsAg antibody response profile. The mouse TDAR model using the Hepatitis B vaccine and the surrogate anti-PD1 monoclonal antibody was a useful tool in the evaluation of the potential immune-mediated effects of pembrolizumab following vaccination and appears to be a suitable alternative for the nonhuman primate TDAR models utilized for other checkpoint inhibitors.

Background: About 10% of Hepatitis B vaccinated individuals mount no protective antibody levels against the hepatitis B surface antigen (HBs-Ag). Older age at primary immunization, obesity and smoking have previously been reported as risk factors associated with vaccine non-response. Here we tested whether these factors alone may allow selecting subjects that benefit from individualized immunization schedules., Methods: Retrospective database analysis screening > 15,000 individual anti-HBs-IgG measurements. Non-responders (NR; anti-HBs-IgG < 10 IU/L) and low-responders (LR; anti-HBs-IgG 10-100 IU/L) were identified. Vaccine type, demographics, lifestyle, and immunological factors (leucocyte subset counts) were compared between NR, LR, and responders (R)., Results: We identified 113 LR/NR and compared them to 134 vaccine responders. We confirmed higher median age at primary vaccination (24.0 (R) vs. 30.5 (NR) vs. 31 (LR) years, p = 0.001), higher median BMI (23.2 kg/m 2 (R) vs. 23.4 kg/m 2 (NR) vs. 25.1 kg/m 2 (LR), p = 0.001) and being a smoker (% smokers: 30.8% (R) vs. 57.1% (NR) vs. 52.5% (LR), p = 0.01) as factors negatively associated with anti-HBs-IgG levels. In a ROC analysis including these factors in a 6-point score, a high score predicted non-response with a specificity of 85% but at low sensitivity (47%)., Conclusion: A simple clinical risk score based on age, obesity, and smoking identifies individuals with a high likelihood of vaccine failure. Non-responders with a low score are candidates for in-depth analyses to better understand the immunological causes of HBV vaccine non-response.

The immunization of allogeneic hematopoietic cell transplantation (HCT) recipients against vaccine-preventable diseases is a part of posttransplantation guidelines. We conducted a prospective study to assess clinical and immunological parameters that would determine the response and long-term maintenance of protective antibody titers upon the hepatitis B virus (HBV) vaccination after HCT. The investigated variables included: vaccination of the HCT recipients and their donors prior to HCT, chronic graft versus host disease (cGVHD) and the timing of post-HCT vaccination, and B- and T-cell subtype status. Forty-two patients were immunized with three or more doses of recombinant hepatitis B surface antigen (rHBsAg) administered according to the individualized schedule of 0-1-2-6-(12) months. After vaccination, seroconversion was achieved in the whole group. The vaccines were categorized according to the antibody (Ab) titers as weak (WRs; 28.7%), good (GRs; 38%) or very good responders (VGRs; 3.3%). In multivariate logistic regression, severe cGVHD (OR= 15.5), and preceding donor immunization (OR= 0.13) were independent predictors of a weak response to vaccination. A prior belonging to the WR group impaired the durability of protection (OR= 0.17) at a median follow-up of 11.5 years. Patients with severe cGVHD showed a trend toward lower median Ab titers, although they required a higher rate of booster vaccine doses. All VGRs had CD4+ cells > 0.2 x 10 6 /L. There was a lower mean rate of CD4+IL2+ lymphocytes in WRs. Vaccination demonstrated the immunomodulatory effect on B-cell and T-cell subsets and a Th1/Th2 cytokine profile, while shifts depended on a history of severe cGVHD and the type of vaccine responder. To conclude, vaccination of HCT donors against HBV allows a better response to vaccination in the respective HCT recipients. Double doses of rHBsAg should be considered in patients with cGVHD and in those not immunized before HCT. A dedicated intensified vaccination schedule should be administered to WRs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Piekarska, Wisniewski, Lewandowski, Gil, Trzonkowski, Bieniaszewska and Zaucha.)