PreHevbrio (R) is a 3-antigen HBV vaccine (3-A-HBV) engineered to express the three HBV envelope proteins; the small 'S' hepatitis B surface antigen (SHBs or HBsAg), the middle pre-S2 + HBsAg (MHBs) and the large PreS1 + PreS2 + HBsAg (LHBs) antigens. 3-A-HBV has been shown to induce superior and more durable antibody responses relative to a 1-A-HBV despite containing half the 'S' antigen dose. To explain the mechanism(s) behind the high immunogenicity, the potential influence of mammalian glycosylation, HBs antigen conformation, antiHBs epitope binding profiles and T-cell responses to the PreS antigens were investigated. In this paper, we demonstrate that glycosylation status does not play a role in the increased immunogenicity of the 3-A-HBV, but that the 3-A-HBV particles are able to induce T cell responses to PreS1 and PreS2 antigens. Epitope mapping demonstrated that the 3-A-HBV particles are inherently more antigenic than 1-A-HBV particles, leading to quantitative differences in the anti-HBs antibody response. Further, we demonstrate that the T cell responses significantly correlate with the higher observed anti-HBs titers and may contribute to the higher and more durable anti-HBs titers. This trial is registered at Clinicaltrials.gov (NCT03393754) and EudraCT (2017-001819-36).

Supplementary Figure 2 from Periostin, a Cell Adhesion Molecule, Facilitates Invasion in the Tumor Microenvironment and Annotates a Novel Tumor-Invasive Signature in Esophageal Cancer

Supplementary Figure 3 from Periostin, a Cell Adhesion Molecule, Facilitates Invasion in the Tumor Microenvironment and Annotates a Novel Tumor-Invasive Signature in Esophageal Cancer

Virus-like particles (VLPs), composed of the small hepatitis B virus surface antigen (HBsAgS), are the antigenic components of the hepatitis B virus (HBV) vaccine and represent the backbones for a chimeric anti-malaria vaccine and various vaccine candidates. Biological vectors have to face pre-existing anti-vector immune responses due to previous immune exposure. Vector recognition after natural infections or vaccinations can result in unwarranted outcomes, with compromising effects on clinical outcomes. In order to evaluate the impact of a pre-existing anti-HBsAgS immune response, we developed mutant VLPs composed of subunits with reduced HBsAgS-specific antigenicity. The insertion of a Plasmodium falciparum circumsporozoite protein (CSP)-derived epitope as a read-out allowed the assessment of wild type (wt) and mutant VLPs in the context of a pre-existing immune response. Mutant and wt VLP platforms with a CSP-epitope insert are immunogenic and have the ability to generate anti-CSP antibody responses in both naïve BALB/c mice and mice with a pre-existing anti-HBsAgS immune response, but with superior anti-CSP responses in mice with a pre-existing immunity. The data indicate that previous HBsAgS exposure facilitates enhanced antibody responses against foreign epitopes delivered by the HBsAgS platform, and, in this context, the state of immune sensitization alters the outcome of subsequent vaccinations.

Supplementary Figure 1 A-C from Periostin, a Cell Adhesion Molecule, Facilitates Invasion in the Tumor Microenvironment and Annotates a Novel Tumor-Invasive Signature in Esophageal Cancer

Supplementary Figure 4 from Periostin, a Cell Adhesion Molecule, Facilitates Invasion in the Tumor Microenvironment and Annotates a Novel Tumor-Invasive Signature in Esophageal Cancer

Conclusion:In non-cirrhotic patients with HBeAg-positive CHB, decreased HBV DNA levels at baseline was associated with a significantly high risk of HCC during antiviral treatment.Early initiation of antiviral treatment with a high viral load (≥8.00 log 10 IU/ml) would retain a low on-treatment risk of HCC in HBeAgpositive CHB patients.

Hepatitis B Virus (HBV) is a hepadnavirus that is the principal pathogen underlying viral liver disease in human populations. In this study, we describe the isolation and characterization of a fully human monoclonal antibody for HBV. This HuMab was isolated by a combinatorial screen of the memory B-cell repertoire from an acute/recovered HBV-infected patient. Lead candidate selection was based upon strong binding and neutralizing activity for live HBV. We provide a detailed biochemical/biophysical, and subclass characterization of its specificity and affinity against all of the principal HBV genotypes combined with a functional analysis of its in vitro activity. We also demonstrate its potential as a prophylaxis/therapy in vivo using human liver chimeric mouse models for HBV infection. These data have important implications for our understanding of natural human immunity to HBV and suggest that this potentially represents a new antibody-based anti-viral candidate for prophylaxis and/or therapy for HBV infection.

BACKGROUND & AIMS:HBsAg-specific antibody responses are difficult to detect during chronic hepatitis B infection (CHB) and are often overlooked. The aim of this study was to examine whether anti-HBs may be involved in functional cure (FC) by profiling anti-HBs responses in patients with CHB using a panel of specific assays. METHODS:Longitudinal serum samples were obtained from 25 patients with CHB who were infected with HBV genotype A and were undergoing nucleos(t)ide analogue (NA) treatment: 14 achieved FC while 11 remained infected (non-FC). Anti-HBs immune complexes (HBsAg-IC), FcγRIIIa dimer binding, epitope specificity and neutralisation efficacy were measured. RESULTS:HBsAg-IC peaks were detected prior to HBsAg loss in 10/14 FC patients. These HBsAg-IC peaks overlapped with either an alanine aminotransferase (ALT) flare (8/10 patients), or a rise in ALT (2/10 patients). HBsAg-IC peaks were detected in 7/11 non-FC patients, but were not associated with an ALT flare. FCγRIIIa binding was detected in 9/14 FC patients, independent from detection of overlapping HBsAg-IC/ALT peaks. FC patients had stable HBsAg epitope occupancy across the study, whereas non-FC patients had a reduction in HBsAg epitope occupancy within the first 12-24 weeks of NA treatment. Convalescent sera from FC patients recognised more HBsAg epitopes and neutralised HBV infection more potently than anti-HBs derived from vaccinees. Neutralisation potency appeared to increase post-HBsAg loss in 4/5 FC patients examined. CONCLUSIONS:Using these assays, we confirm that anti-HBs responses are present and fluctuate over time in this cohort of patients with HBeAg+ CHB, who were infected with HBV genotype A and treated with NAs. Key anti-HBs profiles associated with either FC or failure to achieve FC were also identified, suggesting a role for anti-HBs responses in FC. LAY SUMMARY:Using a panel of assays to characterise hepatitis B surface antibody (anti-HBs) responses in a group of patients with chronic hepatitis B, we identified anti-HBs profiles associated with either functional cure, or failure to achieve functional cure. Functional cure was associated with immune complex peaks which overlapped with alanine aminotransferase flares. Conversely, in those who did not achieve functional cure, immune complex peaks were present, but were not associated with alanine aminotransferase flares, and a decline in anti-HBs diversity was observed early during treatment.

The authors regret there is an error in the reported study enrollment period and an inclusion criterion in the above paper. The reported study period is between January 2000 and February 2008. A recent reabstraction of the data demonstrated that the end date of the enrollment period was actually September 2009. Additionally, the Results section reports that the analysis was conducted on 9280 index cardiac arrest events; the set of 9280 events includes non-index events as well prior to their exclusion. The amended text is as follows: Data were analyzed from 242 hospitals during the study period from January 2000 to September 2009. All patients who were younger than 18 years and sustained a clinical event that required chest compressions for at least 2 min at a participating hospital were eligible for inclusion. According to GWTG-R operational definitions, a CPR event includes any event characterized by either pulselessness or critically compromised perfusion treated with chest compressions and/or defibrillation, when a unit-wide or hospital-wide emergency response was activated. Events that commence out-of-hospital are excluded. For our study, all patients meeting database operational definitions who had documented pVT/VF at some point during their event were included. Patients were excluded if they had no pVT/VF, if they were receiving lidocaine and/or amiodarone therapy prior to their event, or if their initial arrest rhythm was unknown. For the purpose of this study, the prospectively determined primary outcome variable was return of spontaneous circulation (ROSC). Secondary outcomes included 24-h survival and survival to hospital discharge. There were 9280 cardiac arrests events in children during the study period with pVT/VF documented in 1099 (12%) at some point during their resuscitation event. After excluding patients with lidocaine or amiodarone therapy in place prior to the event and patients with missing data, 889 patients were included in the final data set. The authors would like to apologize for any inconvenience caused. Outcomes associated with amiodarone and lidocaine in the treatment of in-hospital pediatric cardiac arrest with pulseless ventricular tachycardia or ventricular fibrillationResuscitationVol. 85Issue 3PreviewTo determine the association between amiodarone and lidocaine and outcomes in children with cardiac arrest with pulseless ventricular tachycardia (pVT) and ventricular fibrillation (VF). Full-Text PDF

Background and Aim Functional cure is the major goal of chronic hepatitis B (CHB) therapy though few biomarkers predict this outcome. HBsAg epitope occupancy can be influenced by therapeutic and immune pressure. The aim of this study was to map the HBsAg epitope profiles during long-term nucleos(t)ide analogue therapy in patients with genotype A CHB, in the context of HBsAg loss (SL)/seroconversion. Methods We evaluated 25 genotype A CHB patients in the GS-US-174-0103 trial of HBeAg-positive CHB patients treated with tenofovir or adefovir for 4 years, 14 who achieved SL whilst 11 had no change. We epitope mapped the major domains of HBsAg to identify those patients with HBsAg clearance profile (CP) (loss of binding at both loops 1 and 2 epitopes of the 'a' determinant) vs non-clearance profile (no change in epitope recognition, or loss of epitope binding at one loop only), correlating this to on-treatment HBsAg responses. Complexed anti-HBs was also measured. Results Analysis of the HBsAg epitope profiles of the 25 patients at baseline identified no predictive correlation with SL. In contrast, analysis at week 48 and end of study (week 192) or prior to SL identified significant predictive associations between development of HBsAg CPs and outcome of functional cure. The detection of a CP also correlated with the development of an alanine aminotransferase flare and detection of anti-HBs complexed with HBsAg. Conclusion The detection of HBsAg CPs by epitope mapping represents a novel viral biomarker, reflecting an emerging anti-HBs selection pressure prior to functional cure.