Hepatitis B virus infection and vaccination among people who use drugs in Xi'an, China.

BACKGROUND: While hepatitis B virus (HBV) infection in children has declined dramatically in China due to the vaccination strategy for newborns, HBV infection in high-risk adults is receiving an increasing attention. The number of people who use drugs (PWUD) in China is huge, but their status of HBV infection and vaccination is less reported, especially from large samples. The related knowledge can help decision makers develop the further strategy of HBV prevention and control. METHODS: A seroepidemiological survey was conducted in all four compulsory isolated detoxification centers (CIDCs) and all eight methadone maintenance treatment (MMT) clinics located in Xi'an, China. All PWUD who were undergoing detoxification or treatment in these settings were included. A questionnaire was designed to obtain the information of HBV vaccination history of participants, and sociodemographic and behavioral data of participants were obtained from the registration records of their respective CIDCs or MMT clinics. RESULTS: A total of 4705 PWUD participated in the survey. Positive rates of HBsAg (current infection) and HBsAg or anti-HBc (current/past infection) were 5.50% and 58.02%, notably higher than those reported for the general adult population in the same province during the same period. As age increased, the anti-HBc positive rate increased with statistically significant trend. The all-negative for HBsAg, anti-HBc, and anti-HBs accounted for 28.82%. Only 18.49% were identified by the questionnaire as having received HBV vaccine. The logistic regression found that compared with identified vaccinated PWUD, those unsure if having been vaccinated and those identified non-vaccinated had a significantly higher HBV current/past infection rate, with an increasing trend. CONCLUSION: PWUD are a high-risk adult group of HBV infection in China. Of them, more than half have not received HBV vaccine, and a significant portion are susceptible to HBV. Catch-up vaccination is need for this population to prevent and control HBV transmission.

Association of HLA-DRB1 alleles with status of antibodies to hepatitis B surface and e antigen.

Antigen presentation by HLA class II molecules to CD4+ T cells is an essential step for generating antibodies to hepatitis B antigens. In this study, we investigated the association between the HLA-DRB1 gene and the status of antibodies to hepatitis B surface and e antigens. Our results revealed a significant association between the status of anti-HBsAg and HLA-DRB1*04:03 (OR = 4.11, 95% CI = 1.50-10.84, p = 0.005, Padj. = 0.05) as well as HLA-DRB1*15:01 (OR = 1.74, 95% CI = 1.20-2.50, p = 0.002, Padj. = 0.045). MHC II binding predictions and in silico docking demonstrated strong binding affinity of HBsAg peptides to these two HLA-DRB1 molecules. Conversely, the status of anti-HBeAg was inversely associated with HLA-DRB1*14:54 (OR = 0.34, 95% CI = 0.18-0.64, p = 0.001, Padj. = 0.011), and in silico analysis revealed weak binding affinity of HBeAg peptides to HLA-DRB1*14:54. In conclusion, these findings support the involvement of HLA-DRB1 in humoral immunity against HBV infection.

Exchanges in the 'a' determinant of the hepatitis B virus surface antigen revisited.

The hepatitis B virus surface antigen's (HBsAg) 'a' determinant comprises a sequence of amino acid residues located in the major hydrophilic region of the S protein, whose exchanges are closely associated with compromising the antigenicity and immunogenicity of that antigen. The HBsAg is generally present in the bloodstream of individuals with acute or chronic hepatitis B virus (HBV) infection. It is classically known as the HBV infection marker, and is therefore the first marker to be investigated in the laboratory in the clinical hypothesis of infection by this agent. One of the factors that compromises the HBsAg detection in the bloodstream by the assays adopted in serological screening in both clinical contexts is the loss of S protein antigenicity. This can occur due to mutations that emerge in the HBV genome regions that encode the S protein, especially for its immunodominant region - the 'a' determinant. These mutations can induce exchanges of amino acid residues in the S protein's primary structure, altering its tertiary structure and the antigenic conformation, which may not be recognized by anti-HBs antibodies, compromising the infection diagnosis. In addition, these exchanges can render ineffective the anti-HBs antibodies action acquired by vaccination, compromise the effectiveness of the chronically HBV infected patient's treatment, and also the HBsAg immunogenicity, by promoting its retention within the cell. In this review, the residues exchange that alter the S protein's structure is revisited, as well as the mechanisms that lead to the HBsAg antigenicity loss, and the clinical, laboratory and epidemiological consequences of this phenomenon.

Analysis of Inflammatory and Thyroid Hormone Levels Based on Hepatitis A and B Virus Immunity Status: Age and Sex Stratification.

This study investigated the potential associations between hepatitis virus antibody status and thyroid and inflammatory function. The C-reactive protein (CRP), thyroid-stimulating hormone (TSH), and free thyroxine (FT4) levels were measured in individuals with and without antibodies to the hepatitis A virus (HAV) and hepatitis B virus (HBV). Participants were stratified by age, sex, and HAV/HBV antibody status. Participants with and without antibodies to HAV and HBV had normal CRP, TSH, and FT4 levels. However, notable discrepancies were observed in FT4 levels among participants with HAV antibodies and in CRP and FT4 levels among those with both HAV and HBV antibodies, suggesting potential associations between viral immunity and thyroid function, especially in younger participants. Significant variations in thyroid hormone levels were noted when the sample was stratified by sex and HAV and HBV antibody status, indicating that the association between antibody status and thyroid hormone levels varied by sex. This study underscores the need for further research on the effect of viral immunity on inflammatory parameters and thyroid hormone levels.

An innate immune signature induced by AS01- or AS03-adjuvanted vaccines predicts the antibody response magnitude and quality consistently over time.

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 (AS01B, AS01E, 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 AS01B, AS01E 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.

Anti-HBc mirrors the activation of HBV-specific CD8+ T cell immune response and exhibits a direct effect on HBV control.

BACKGROUND: Hepatitis B core antibody (anti-HBc) is commonly present in patients with chronic hepatitis B virus (HBV) infection and serves as a marker of humoral immunity. Herein, we aim to investigate the correlation between anti-HBc and antiviral immune response and its putative role in HBV control. METHODS: Quantitative anti-HBc and levels of anti-HBc subtypes were measured in chronic hepatitis B (CHB) patients. The effects of anti-HBc on immune cells and HBV replication were evaluated using the HBV mouse models and human hepatoma cell lines. RESULTS: Baseline levels of IgG1 and IgG3 anti-HBc were elevated in CHB patients with favorable treatment response, and correlated with the virological response observed at week 52. Additionally, increased levels of IgM and IgG1 anti-HBc were observed exclusively in CHB patients with liver inflammation. Notably, significant correlations were identified between quantitative levels of anti-HBc and the frequencies of HBcAg-specific CD8+ T cells. Intriguingly, HBcAg efficiently activates T cells aided by B cells in vitro experiments. Moreover, anti-HBc inhibits HBV replication either by a direct effect or through complement-mediated cytotoxicity in HBV-producing cell lines. CONCLUSIONS: Anti-HBc reflects the activation of an HBV-specific CD8+ T cell immune response and may have anti-HBV activity.

Both middle and large envelope proteins can mediate neutralization of hepatitis B virus infectivity by anti-preS2 antibodies: escape by naturally occurring preS2 deletions.

Hepatitis B virus (HBV) expresses co-terminal large (L), middle (M), and small (S) envelope proteins containing preS1/preS2/S, preS2/S, and S domain alone, respectively. S and preS1 domains mediate sequential virion attachment to heparan sulfate proteoglycans and sodium taurocholate cotransporting polypeptide (NTCP), respectively, which can be blocked by anti-S and anti-preS1 antibodies. How anti-preS2 antibodies neutralize HBV infectivity remains enigmatic. The late stage of chronic HBV infection often selects for mutated preS2 translation initiation codon to prevent M protein expression, or in-frame preS2 deletions to shorten both L and M proteins. When introduced to infectious clone of genotype C or D, both M-minus mutations and most 5' preS2 deletions sustained virion production. Such mutant progeny viral particles were infectious in NTCP-reconstituted HepG2 cells. Neutralization experiments were performed on the genotype D clone. Although remaining susceptible to anti-preS1 and anti-S neutralizing antibodies, M-minus mutants were only partially neutralized by two anti-preS2 antibodies tested while preS2 deletion mutants were resistant. By infection experiments using viral particles with lost versus increased M protein expression, or a neutralization escaping preS2 deletion only present on L or M protein, we found that both full-length L and M proteins contributed to virus neutralization by the two anti-preS2 antibodies. Thus, immune escape could be a driving force for the selection of M-minus mutations, and especially preS2 deletions. The fact that both L and M proteins could mediate neutralization by anti-preS2 antibodies may shed light on the underlying molecular mechanism.IMPORTANCEThe large (L), middle (M), and small (S) envelope proteins of hepatitis B virus (HBV) contain preS1/preS2/S, preS2/S, and S domain alone, respectively. The discovery of heparan sulfate proteoglycans and sodium taurocholate cotransporting polypeptide (NTCP) as the low- and high-affinity HBV receptors could explain neutralizing potential of anti-S and anti-preS1 antibodies, respectively, but how anti-preS2 neutralizing antibodies work remains enigmatic. In this study, we found two M-minus mutants in the context of genotype D partially escaped two anti-preS2 neutralizing antibodies in NTCP-reconstituted HepG2 cells, while several naturally occurring preS2 deletion mutants escaped both antibodies. By point mutations to eliminate or enhance M protein expression, and by introducing preS2 deletion selectively to L or M protein, we found binding of anti-preS2 antibodies to both L and M proteins contributed to neutralization of wild-type HBV infectivity. Our finding may shed light on the possible mechanism(s) whereby anti-preS2 antibodies neutralize HBV infectivity.

Hepatitis B Virus Reactivation after Switch to Cabotegravir/Rilpivirine in Patient with Low Hepatitis B Surface Antibody.

A patient in Japan with HIV began antiretroviral therapy because of acute hepatitis B virus (HBV) 15 years ago, with low hepatitis B surface antibody, and experienced breakthrough HBV reactivation 4 months after switching from bictegravir/emtricitabine/tenofovir alafenamide to cabotegravir/rilpivirine. An immune escape mutation, E164V, was identified in the isolated HBV DNA.

Quantitative HBV Core Antibodies as a Prognostic Marker for HBeAg Seroclearance: A Systematic Review with Meta-Analysis.

During chronic hepatitis B virus (HBV) infection, the seroclearance of hepatitis B e antigen (HBeAg) is an important event and a significant surrogate endpoint of all current therapeutic strategies. The prediction of HBeAg seroclearance can help assess the benefits of therapy in patients during or before therapy initiation. The quantitation of HBV core antibodies (qAnti-HBc) is a new non-invasive biomarker for solving multiple diagnostic dilemmas. A systematic review and meta-analysis of studies that measured qAnti-HBc in patients who achieved HBeAg seroclearance were performed through PubMed, Web of Science (WoS) and SCOPUS electronic database searches. Nineteen articles were included in the systematic review, comprising 3434 chronically infected patients (1014 with and 2420 without HBeAg seroclearance). Sixteen publications with data regarding qAnti-HBc levels were included in the meta-analysis. The baseline level of qAnti-HBc antibodies was significantly higher in patients with than without HBeAg seroclearance (SMD = 0.88, 95%CI SMD = 0.56-1.2, p < 0.001). The same conclusion was reached for patients originating from Asia (SMD = 0.94, 95%CI SMD = 0.55-1.33) and for the qAnti-HBc antibodies among adult HBV patients with therapy-induced HBeAg seroclearance (SMD = 0.90, 95%CI SMD = 0.54-1.25, p < 0.001). The systematic review and meta-analysis provide evidence of the role of qAnti-HBc as a promising biomarker for predicting HBeAg seroclearance in chronically infected patients.

The Impact of Smoking on Long-Term Protection Following Hepatitis B Vaccination: A 24-Year Cohort Study.

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.

Risk of hepatic decompensation from hepatitis B virus reactivation in hematological malignancy treatments.

In this editorial, we discussed the apparent discrepancy between the findings described by Colapietro et al, in their case report and data found in the literature. Colapietro et al reported a case of hepatitis B virus (HBV)-related hepatic decompensation in a patient with chronic myeloid leukemia and a previously resolved HBV infection who was receiving Bruton's tyrosine kinase (BTK) inhibitor therapy. First of all, we recapitulated the main aspects of the immune system involved in the response to HBV infection in order to underline the role of the innate and adaptive response, focusing our attention on the protective role of anti-HBs. We then carefully analyzed literature data on the risk of HBV reactivation (HBVr) in patients with previous HBV infection who were treated with either tyrosine kinase inhibitors or BTK inhibitors for their hematologic malignancies. Based on literature data, we suggested that several factors may contribute to the different risks of HBVr: The type of hematologic malignancy; the type of therapy (BTK inhibitors, especially second-generation, seem to be at a higher risk of HBVr than those with tyrosine kinase inhibitors); previous exposure to an anti-CD20 as first-line therapy; and ethnicity and HBV genotype. Therefore, the warning regarding HBVr in the specific setting of patients with hematologic malignancies requires further investigation.

High Rates of Seroprotection to Hepatitis B After a Hepatitis B Challenge Dose in Previously Vaccinated Patients with Inflammatory Bowel Disease on Immunosuppressive Therapy.

BACKGROUND: Healthy populations have high rates of sustained vaccine-induced seroprotection to hepatitis B virus, but previous studies in immunosuppressed patients with inflammatory bowel disease (IBD) have shown suboptimal seroprotection rates. A challenge dose of hepatitis B vaccine (HepB) is recommended in previously vaccinated individuals who are seronegative to elicit an anamnestic response and determine if they are seroprotected. The aim of our study was to determine sustained seroprotection rates to hepatitis B vaccine (HepB) in patients with IBD. METHODS: This was a single-center prospective study of patients with IBD previously vaccinated with a three dose HepB series. Patients had a hepatitis B surface antibody (anti-HBs) drawn; if it was below 10 mIU/mL, they received a challenge dose of the HepB vaccine to assess for anamnestic response and sustained seroprotection. The primary outcome was to determine the rate of sustained seroprotection (anti-HBs ≥ 10). RESULTS: A total of 168 patients met inclusion criteria, mean age 35.7 years ± 13.6 standard deviation (SD). Initially 120 (71.4%) had anti-HBs ≥ 10 mIU/mL, with median anti-HBs of 37 mIU/mL (interquartile range 0-234); 48 (28.6%) needed a challenge dose, of which 34 responded with anti-HBs ≥ 10 mIU/mL. In total, 154 (91.7%) demonstrated sustained seroprotection to HepB. Those not seroprotected were more likely to have been vaccinated on immunosuppressive therapy or after their diagnosis of IBD. CONCLUSIONS: Most vaccinated patients with IBD maintain sustained seroprotection to HepB despite prolonged exposure to immunosuppression. This contradicts prior studies and shows that immunosuppression does not lead to loss of seroprotection.

Immune-Escape Mutations Are Prevalent among Patients with a Coexistence of HBsAg and Anti-HBs in a Tertiary Liver Center in the United States.

The concurrent seropositivity of HBsAg and anti-HBs has been described among patients with chronic hepatitis B (CHB), but its prevalence is variable. HBV S-gene mutations can affect the antigenicity of HBsAg. Patients with mutations in the 'α' determinant region of the S gene can develop severe HBV reactivation under immunosuppression. In this study at a tertiary liver center in the United States, we evaluated the frequency and virological characteristics of the HBsAg mutations among CHB patients with the presence of both HBsAg and anti-HBs. In this cohort, 45 (2.1%) of 2178 patients were identified to have a coexistence of HBsAg and anti-HBs, and 24 had available sera for the genome analysis of the Pre-S1, Pre-S2, and S regions. The frequency of mutations in the S gene was significantly higher among those older than 50 years (mean 8.5 vs. 5.4 mutations per subject, p = 0.03). Twelve patients (50%) had mutations in the 'α' determinant region of the S gene. Mutations at amino acid position 126 were most common in eight subjects. Three had a mutation at position 133. Only one patient had a mutation at position 145-the classic vaccine-escape mutation. Despite the universal HBV vaccination program, the vaccine-escape mutant is rare in our cohort of predominantly Asian patients.

Serological profile of hepatitis B virus infection among traditional birth attendants and the attending pregnant women in Ibadan, Nigeria.

Although a sizable number of pregnant women patronize Traditional Birth Attendants (TBAs) for deliveries in Nigeria, efforts to prevent or reduce the risk of HBV transmission are not targeted at the TBAs and the pregnant women patronizing them. This may be linked to the dearth of information on the serological profiles of HBV among this cohort. We, therefore, show the serological profiles of HBV among the cohort. One hundred and seventy pregnant women and 91 TBAs participated in this study between May and July 2019. Serological markers of HBV infection were assayed using ELISA. A prevalence of, 8.0% (95% CI: 5.0% - 11.5%) for HBsAg, 0.8% (95% CI: 0.0% - 1.9%) for HBeAg, 2.7% (95% CI: 0.8% - 5.0%) for HBcIgM, 26.1% (95% CI: 20.7% - 31.4%) for anti-HBs, 21.5% (95% CI: 16.5% - 25.4%) for anti-HBe and 67.0% (95% CI: 60.9% - 72.8%) for anti-HBc was found indicating a high percentage of carriers. Although 32 (12.3%) of the entire participants claimed to be fully vaccinated, serological evidence was only detected in 4 (12.5%). The high percentage of carriers and low evidence of vaccination necessitate intensified efforts to ensure that adequate interventions are made available and accessible to the TBAs and the pregnant women patronizing them (including newborn babies).

Impact of Hepatitis B Surface and Core Antibody Levels on Hepatitis B Virus Reactivation.

Hepatitis B virus reactivation (HBV-R) is a serious complication that can occur in patients with resolved HBV infection during cancer chemotherapy. We examined the levels of HBV surface antibody (HBsAb) and HBV core antibody (HBcAb) to assess the incidence of HBV-R in cancer patients including hematopoietic stem cell transplantation (HSCT) and rituximab administration. This retrospective cohort study included 590 patients with resolved HBV infection. The incidence of HBV-R was evaluated 761.5 (range, 90-3898) days after the inititiation of chemotherapy. Of the patients, 13 (2.2%) developed HBV-R after the start of chemotherapy. All 13 patients exhibited lower HBsAb (<100 mIU/mL) levels at baseline. A higher level of HBcAb (≥100 cut off index (C.O.I.)) was a possible risk factor for HBV-R as well as HSCT and rituximab administration. The simultaneous presence of HBsAb <100 mIU/mL and HBcAb ≥100 C.O.I. increased the risk of HBV-R by 18.5%. Patients treated with rituximab were at a higher risk of HBV-R (18.4%) despite having HBcAb <100 C.O.I. Our results suggest that assessment of HBsAb and HBcAb levels prior to the chemotherapy is important for identifying patients at high risk of HBV-R, especially in solid cancers without HSCT and rituximab administration.

Comparison of the effectiveness four years after Homo/Hetero prime-boost with 10 µg HP and 20 µg CHO recombinant hepatitis B vaccine at 1 and 6 months in maternal HBsAg-negative children.

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.

The lack of HBsAg secretion does neither facilitate induction of antiviral T cell responses nor Hepatitis B Virus clearance in mice.

Immune tolerance to the hepatitis B virus (HBV) is crucial for developing chronic hepatitis B, and the HBV surface antigen (HBsAg) produced and secreted in high amounts is regarded as a key contributor. HBsAg is expressed in HBV-infected hepatocytes and those carrying an HBV integration. Whether either HBsAg secretion or the high antigen amount expressed in the liver determines its immunomodulatory properties, however, remains unclear. We, therefore, developed a novel HBV animal model that allowed us to study the role of secreted HBsAg. We introduced a previously described HBs mutation, C65S, abolishing HBsAg secretion into a replication-competent 1.3-overlength HBV genome and used adeno-associated virus vectors to deliver it to the mouse liver. The AAV-HBV established a carrier state of wildtype and C65S mutant HBV, respectively. We investigated antiviral B- and T-cell immunity in the HBV-carrier mice after therapeutic vaccination. Moreover, we compared the effect of a lacking HBsAg secretion with that of an antiviral siRNA. While missing HBsAg secretion allowed for higher levels of detectable anti-HBs antibodies after therapeutic vaccination, it did neither affect antiviral T-cell responses nor intrahepatic HBV gene expression, irrespective of the starting level. A treatment with HBV siRNA restricting viral antigen expression within hepatocytes, however, improved the antiviral efficacy of therapeutic vaccination, irrespective of the ability of HBV to secrete HBsAg. Our data indicate that clearing HBsAg from blood cannot significantly impact HBV persistence or T-cell immunity. This indicates that a restriction of hepatic viral antigen expression will be required to break HBV immunotolerance.

Current and future use of antibody-based passive immunity to prevent or control HBV/HDV infections.

With the increasing momentum and success of monoclonal antibody therapy in conventional medical practices, there is a revived emphasis on the development of monoclonal antibodies targeting the hepatitis B surface antigen (anti-HBs) for the treatment of chronic hepatitis B (HBV) and hepatitis D (HDV). Combination therapies of anti-HBs monoclonal antibodies, and novel anti-HBV compounds and immunomodulatory drugs presenting a promising avenue to enhanced therapeutic outcomes in HBV/HDV cure regimens. In this review, we will cover the role of antibodies in the protection and clearance of HBV infection, the association of anti-HBV surface antigen antibodies (anti-HBs) in protection against HBV and how antibody effector functions, beyond neutralization, are likely necessary. Lastly, we will review clinical data from previous and ongoing clinical trials of passive antibody therapy to provide a state-of-the-are perspective on passive antibody therapies in combinations with additional novel agents.

Re-examining Hepatitis B Postexposure Prophylaxis Following Pediatric Community-acquired Needle-stick Injury in an Era of a National Immunization Registry.

BACKGROUND: Long-term hepatitis B immunity has been demonstrated following the completion of the primary vaccination series in childhood. Some guidelines recommend a hepatitis B surface antibody (anti-HBs) directed approach following community-acquired needle-stick injury (CANSI) to inform hepatitis B postexposure prophylaxis (PEP) management. We assessed the utility of anti-HBs testing post-CANSI, as well as the costing of, and adherence to PEP at a pediatric hospital. METHODS: Children presenting to an Australian tertiary pediatric hospital post-CANSI (2014-2019) were identified retrospectively using medical and laboratory records. Immunization status was obtained from the Australian Immunisation Registry. RESULTS: Fifty-six children with CANSI were identified. Of those with immunization records, all had completed hepatitis B vaccinations (n = 52). At presentation, 44% (n = 23) had anti-HBs <10 IU/L, which was more likely in older (≥6 years, 68%) versus younger children (OR 4.59, P < 0.02). HBIG and hepatitis B vaccine adherence was 65% (15/23) and 78% (18/23), respectively. All children (n = 14) with anti-HBs ≥4 weeks postvaccination ±HBIG, demonstrated an anamnestic response. No hepatitis B infections were detected. Using completed immunizations versus anti-HBs levels as a marker of immunity to direct PEP resulted in a projected cost savings of AUD$ 4234. CONCLUSION: Anti-HBs levels <10 IU/L, despite previous vaccinations, were frequent in children post-CANSI, with many demonstrating an anamnestic response. Adherence to postexposure HBIG and hepatitis B vaccine was suboptimal using an anti-HBs directed approach. These data support re-evaluating PEP in an era of the national immunization registry; completion of hepatitis B vaccinations as a marker of immunity provides a practical approach, ensuring optimized care for pediatric CANSI.

Multiple epitopes of hepatitis B virus surface antigen targeted by human plasma-derived immunoglobulins coincide with clinically observed escape mutations.

Hepatitis B immune globulin (HBIG) is a human plasma-derived immunoglobulin G concentrate that contains a high titer of neutralizing antibodies (anti-HBs) to the hepatitis B virus (HBV) surface antigen (HBsAg). HBIG is known to be highly effective in treating HBV infections, however, a more systematic characterization of the antibody binding sites on HBsAg and their correlation with emerging "escape" mutations in HBsAg was lacking. By using anti-HBs antibodies from HBIG lots to screen random peptide phage display libraries, we identified five clusters of peptides that corresponded to five distinct anti-HBs binding sites on the HBsAg. Three sites, Site II (C121-C124), Site III (M133-P135), and Site IV (T140-G145), were mapped within the "a" determinant, while the two other sites, Site I (Q101-M103) and Site V (I152-S154), were outside the "a" determinant. We then tested in binding assays HBsAg peptides containing clinically relevant mutations previously reported within these sites, such as Y134S, P142S, and G145R, and observed a significant reduction in anti-HBs binding activity to the mutated sites, suggesting a mechanism the virus may use to avoid HBIG-mediated neutralization. The current HBIG treatment could be improved by supplementing it with site-specific neutralizing monoclonal antibodies that target these mutations for control of HBV infections.