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The composition of glycan in immunoglobulin G (IgG) has shown to affect various diseases and can be regulated by drugs and preventive vaccination. A hepatitis B surface antigen (HBsAg)-hepatitis B immunoglobulin (HBIG) immune complex (YIC) therapeutic vaccine for chronic hepatitis B (CHB) patients has undergone clinical trials. To explore for markers of CHB, which could be associated with responsiveness to YIC therapeutic vaccine, serum IgG glycosylation in CHB patients was analyzed.Kinetic changes of serum galactosylated IgG in 53 hepatitis Be antigen (HBeAg)-positive CHB patients treated with YIC were monitored by matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) analysis. Whole blood cytokines were assayed by cytokine binding assay kits. All samples were back assayed before treatment, during therapy and follow-up for 6 months from a previous completed clinical trial.During YIC treatment, 26 patients with lower IgG galactosylation level at baseline [galactosylation level (Gal-ratio) = -0.29, 0.18 (mean, SD)] showed sustained increase of serum galactosylated IgG, and responded to YIC treatment by HBeAg seroconversion. While those who did not respond to YIC treatment [Gal-ratio = -0.40, 0.15 (mean, SD)] failed to show similar changes. Furthermore, this kinetic increase of galactosylated IgG correlated with marked up-regulated IL-2 level, confirming that effective cellular immune responses have participated in responsiveness.For HBeAg-positive CHB patients lower serum IgG galactosylation level may serve as an indicator for selecting a suitable subpopulation of candidates for YIC therapeutic vaccination.

An HBsAg-HBIG therapeutic vaccine (Yeast-derived Immune Complexes, YIC) for chronic hepatitis B (CHB) patients has undergone a series of clinical trials. The HBeAg sero-conversion rate of YIC varied from 21.9% to 14% depending on the immunization protocols from 6 to 12 injections. To analyze the immunological mechanisms exerted by 6 injections of YIC, 44 CHB patients were separately immunized with YIC, alum as adjuvant control or normal saline as blank control, with add on of antiviral drug Adefovir in all groups. Kinetic increase in Th1 and Th2 cells CD4 + T cell sub-populations with association in decrease in Treg cells and increase of Tc1 and Tc17 cells in CD8 + T cells were observed in YIC immunized group. No such changes were found in the other groups. By multifunctional analysis of cytokine profiles, significant increase of IL-2 levels was observed, both in CD4 + and CD8 + T cells in the YIC immunized group, accompanied by increase in IFN-gamma and decrease of inhibitory factors (IL-10, TGF-β and Foxp3) in CD4 + T cells. In the alum immunized group, slight increase of IL-10, TGF-β and Foxp3 in CD4 + T cells was found after the second injection, but decreased after more injections, suggesting that alum induced early inflammatory responses to a certain extent. Similar patterns of responses of IL-17A and TNF-α in CD8 + T cells were shown between YIC and the saline group. Results indicate that add on of Adefovir, did not affect host specific immune responses.

Chronic hepatitis B (CHB) remains a global health problem. Therapeutic vaccination has been successfully employed to treat a subpopulation of CHB patients. Personalized treatment can not only improve therapeutic efficacy, but also decrease the cost of medical care. Since microRNAs (miRNAs) are highly conserved and are involved in many cellular processes, exploring their expression profiles in CHB patients in association with responsiveness to therapeutic vaccination may be an approach for personalized treatment. In this study, we examined the kinetic expression profiles of 13 miRNAs in sera and serum-derived hepatitis surface antigen (HBsAg) particles in 10 CHB patients including 5 responders and 5 nonresponders selected from a large cohort of 136 patients enroled in a phase III clinical trial using antigen-antibody immunogenic complex based therapeutic vaccine (YIC). Eight miRNAs were detected in both sera and HBsAg particles. Among them, the levels of serum miRNAs and serum-derived HBsAg-carried miRNAs (let-7f, miR-22, miR-30a, and miR-122) were significantly lower in the responders group compared to those in the nonresponders group at baseline and throughout the course of treatment. The lower baseline levels of serum miRNAs and HBsAg-carried miRNAs were also associated with hepatitis e antigen clearance at week 76 and hepatitis e antigen seroconversion during the study period. In summary, our study suggests that lower baseline levels of serum miRNAs and HBsAg-carried miRNAs (let-7f, miR-22, miR-30a, and miR-122) associated with YIC treatment response and the variation trend of these 4 miRNAs could have a prognostic value for responsiveness to YIC treatment.

New effects and mechanisms of alum on innate immunity have emerged in recent years. A number of cellular and molecular mechanisms induced by aluminum adjuvant have been reported, while the role of NALP3 and inflammasome in the cellular pathway induced by alum is still controversial. The effect of injection of alum alone without vaccine antigen into human has not been reported so far. Recently, in a phase IIIa double-blinded placebo controlled clinical trial testing the therapeutic HBsAg-anti-HBs vaccine formulated with alum against chronic viral hepatitis B patients, the placebo group receiving alum only showed substantial therapeutic effects. To explore possible underlying therapeutic mechanisms, mice were treated either with multiple injections of alum alone or with alum adsorbed to proteins (HBsAg-anti-HBs). After 4 injections Gr1(+)/CD11b(+) cells in the spleen were increased in both alum alone and alum adsorbed in proteins groups. Increased Gr1(+)/CD11b(+) cells in spleens remained consistently high in the alum alone treated group, while Gr1(+)/CD11b(+)cells decreased in the alum adsorbed to proteins group after 6 injections. Both treatments triggered increased levels of TNF-alpha measured in the plasma, but only the alum alone treated mice showed increased levels of IL-10. Histology of the liver tissues revealed a higher number of spotty necrotic foci in the alum alone immunized group. Taken together, potent inflammatory responses were induced in the alum alone immunized mice, which suggests that the substantial therapeutic effects observed in chronic hepatitis B patients immunized with alum alone might be attributed to inflammatory responses., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Objective: To observe the long-term effect of plasma-derived HBV vaccine., Methods: The effect of a plasma-derived HBV vaccine which was given to children born in 1986 in Huangpu district in Shanghai were followed up once every two years and testing for HBsAg, anti-HBs and anti-HBc was carried out. Compared to background results from cross-sectional survey of hepatitis B virus in 1984 and 1985 (as internal control) as well as finding of survey targeted in non-plasma-derived HBV vaccine of children born in the same time in the nearby area from results investigated in 1991 (as external control), positive rate was calculated to assess the effect of protection., Results: The population immunized was followed up for 23 years and 5993 blood samples were collected. During the period of follow-up, the positive rate of anti-HBs decreased from 89.01% to 18.77% and the average level was 40.39%. The average positive rate of anti-HBc was 1.87%. The annual positive rate fluctuated around the average level. HBsAg positive rate remained less than 1.00% (0.46% - 0.98%), with an average of 0.62% (37/5993). Ranges of positive efficacy were from 81.37% to 95.78% against background control and 72.76% against external control., Conclusion: The plasma-derived HBV vaccine showed a good long-term protective effect and there was no need for boosting the immunization 23 years later.

Currently, there are various approaches for developing therapeutic vaccines for chronic hepatitis B patients. Previously, an antigen-antibody-based therapeutic vaccine (YIC) has been conducted in a double-blind placebo controlled phase IIb clinical trial in 242 chronic hepatitis B patients. At the end of follow-up for 24 weeks, HBeAg sero-conversion rate was 21.6% in the 60 μg immunized group, compared to 9% in the alum immunized control group (p=0.03). To analyze the correlation between HBeAg-seroconversion, and decrease of serum HBsAg and HBV DNA, serum samples were back quantified for serum HBsAg and HBV DNA collected at baseline, end of treatment, and end of follow-up from patients who were treated either with 60 μg of YIC, or with placebo. Patients were dichotomized to HBeAg sero-converted and non-converted groups in comparison with patients in the placebo group. The correlations between HBeAg seroconversion and the decrease of HBsAg, HBV DNA and ALT levels during study period were analyzed using a logistic regression model. Results showed marked and sustained reduction of HBsAg, HBV DNA and ALT level in HBeAg sero-converted patients compared to those in patients of HBeAg non-converted and placebo groups. Reduction of HBV DNA and elevation of ALT was markedly associated with HBeAg seroconversion with an adjusted OR of 0.09 (95%CI: 0.01-0.62) and 0.08 (95%CI: 0.02-0.37) respectively after adjusted by age and sex, while reduction of HBsAg level was close to of significance (p=0.054). Analysis indicated that HBeAg sero-conversion was a reasonable endpoint for therapeutic vaccination., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: The safety of the immune complexes composed of yeast-derived hepatitis B surface antigen (HBsAg) and antibodies (abbreviated as YIC) among healthy adults and chronic hepatitis B patients has been proved in phase I and phase IIa trial. A larger number of patients for study of dosage and efficacy are therefore needed., Methods and Principal Findings: Two hundred forty two HBeAg-positive chronic hepatitis B patients were immunized with six injections of either 30 microg YIC, 60 microg of YIC or alum adjuvant as placebo at four-week intervals under code. HBV markers and HBV DNA were monitored during immunization and 24 weeks after the completion of immunization. The primary endpoint was defined as loss of HBeAg, or presence of anti-HBe antibody or suppression of HBV DNA, while the secondary endpoint was both HBeAg seroconversion and suppression of HBV DNA. Statistical significance was not reached in primary endpoints four weeks after the end of treatment among three groups, however, at the end of follow-up, HBeAg sero-conversion rate was 21.8% (17/78) and 9% (7/78) in the 60 microg YIC and placebo groups respectively (p = 0.03), with 95% confidence intervals at 1.5% to 24.1%. Using generalized estimating equations (GEEs) model, a significant difference of group effects was found between 60 microg YIC and the placebo groups in terms of the primary endpoint. Eleven serious adverse events occurred, which were 5.1%, 3.6%, and 5.0% in the placebo, 30 microg YIC and 60 microg YIC groups respectively (p>0.05)., Conclusions: Though statistical differences in the preset primary and secondary endpoints among the three groups were not reached, a late and promising HBeAg seroconversion effect was shown in the 60 microg YIC immunized regimen. By increasing the number of patients and injections, the therapeutic efficacy of YIC in chronic hepatitis B patients will be further evaluated., Trial Registration: ChiCTR.org ChiCTR-TRC-00000022.

Background & Aims: Even though various experimental therapeutic approaches for chronic hepatitis B infection have been reported, few of them have been verified by clinical trials. We have developed an antigen-antibody (HBsAg-HBIG) immunogenic complex therapeutic vaccine candidate with alum as adjuvant (YIC), aimed at breaking immune tolerance to HBV by modulating viral antigen processing and presentation. A double-blind, placebo-controlled, phase II B clinical trial of YIC has been reported previously, and herein we present the results of the phase III clinical trial of 450 patients. Methods: Twelve doses of either YIC or alum alone as placebo were administered randomly to 450 CHB patients and they were followed for 24weeks after the completion of immunization. The primary end point was HBeAg seroconversion, and the secondary end points were decrease in viral load, improvement of liver function, and histology. Results: In contrast to the previous phase II B trial using six doses of YIC and alum as placebo, six more injections of YIC or alum resulted in a decrease of the HBeAg seroconversion rate from 21.8% to 14.0% in the YIC group, but an increase from 9% to 21.9% in the alum group. Decrease in serum HBV DNA and normalization of liver function were similar in both groups (p >0.05). Conclusions: Overstimulation with YIC did not increase but decreased its efficacy due to immune fatigue in hosts. An appropriate immunization protocol should be explored and is crucial for therapeutic vaccination. Multiple injections of alum alone could have stimulated potent inflammatory and innate immune responses contributing to its therapeutic efficacy, and needs further investigation. [Copyright &y& Elsevier]