Analysis of immunological mechanisms exerted by HBsAg-HBIG therapeutic vaccine combined with Adefovir in chronic hepatitis B patients

Abstract

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 CD8T cells were shown between YIC and the saline group. Results indicate that add on of Adefovir, did not affect host specific immune responses.

Evaluation of antiviral - passive - active immunization (“sandwich”) therapeutic strategy for functional cure of chronic hepatitis B in mice

“…HBsAg-HBsAb immune complex therapeutic vaccine has been established in our laboratory [28] and in phase IIB clinical trials, six injections per month followed for six months have been shown to result in HBeAg seroconversion rates of around 20% [29] . In addition, this vaccine was shown to decrease the percentage of regulatory T cells and to increase T helper cells and cytotoxic CD8 + T cells [19] . Here, adding a mouse version of this therapeutic vaccine to the "sandwich" strategy efficiently induced both HBsAgspecific humoral and cellular immune responses.…”

“…The "sandwich" treatment regime was administered three times as indicated and mice were sacrificed three weeks after the third treatment ( n = 5/group) (a). The mice serum was collected at day 0, 2, 5,9,12,15,19,23,28,34,41,55 tably, after the three treatments, a significant reduction of HBeAg levels was only observed in the sandwich group compared to the control TDF group ( p = 0.01; Fig. 4 c).…”

“…In previous clinical studies using HBsAg-HBIG immune complex (YIC) as a therapeutic vaccine, decreases of HBV DNA and HBeAg seroconversion were found in around 21% of CHB patients [19] . Based on the "sandwich" strategy, we examined the combined effect of TDF, G12 and a mouse-derived YIC (mYIC) in the AAV/ HBVcarrier mice.…”

From therapeutic antibodies to immune complex vaccines

“…In the IC-immunized group of patients, increases in Th1 and Th2 cells among the CD 4 + T cells were associated with decrease in Treg cells and increase in Tc1 and Tc17 cells among the CD 8 + T cells. 86…”

HBV Immune-Therapy: From Molecular Mechanisms to Clinical Applications

“…Further novel protein-based vaccine candidates incorporating HBsAg and HBcAg and currently in clinical trials are Theravax (DV-601), combined with a saponin-based ISCOMATRIX adjuvant [79], and ABX203, administered by the intranasal route [80]. In addition, an innovative vaccination approach consists of the yeast-derived HBsAg and human anti-HBs immunoglobulin complex combined with alum adjuvant (HBsAg-HBIG) [81,82].…”