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Experimental Studies on Recombinant Hepatitis B Immunogenic Complex Therapeutic Vaccine (YIC)

Wen Yumei, He Lifang, QU Di, Ma Zhangmei, Yao Xin (Department of Molecular Virology, Shanghai Medical University, Shanghai 200032, China )  
A therapeutic vaccine composed of HBsAg complexed to anti-HBs (IC) has been developed for viral hepatitis B. Enhanced immune response was induced in hosts immunized with this complex, and the mechanisms of this vaccine was studied in mice. It was shown that the Fc fragment of anti-HBs in the complex was critical for induction of potent immune responses. The Fc fragment of the anti-HBs in the complex could attach to the Fc receptors on the antigen presenting cells (APC), increasing the uptake of HBsAg into these cells. After being ingested, the antigen complexed to antibody could be more effectively processed and presented to T cells. After incubation with macrophages previously treated with IC, T cells showed higher proliferation rate, and higher level of interferon-γ mRNA was detected. Enhanced immune response in host has also been shown by comparing anti-HBs titer in mice immunized with antigen-antibody complex versus the anti-HBs titer in mice immunized only with HBsAg. More than tenfold increase in anti-HBs was observed in the latter group. In addition, this complex was used to immunize an HBsAg low-responder mouse strain (B10. S). Compared to the normal responsive counterpart mouse strain (B10), immunization with HBsAg induced (cont. on. p. 57) (cont. from. p. 42) low titer of antibody, whereas, immunization using HBsAg-anti-HBs complex, B10.S mice responded by producing similar level of anti-HBs as that induced in the B10 mice. When the complex was used to immunize HBsAg positive transgenic mice (TgE), after four injections, in the female mice, 72% cleared HBsAg and developed anti-HBs (mean titer 1: 1070 by EIA); while in the male mice, 54% cleared HBsAg and developed anti-HBs (mean titer 1: 455 by EIA). Though some of non-immunized mice lost their HBsAg spontaneously during the experiment, none developed anti-HBs. Data showed that this immunogenic complex has promising potential to be used for the treatment of hepatitis B patients. For human use, a therapeutic vaccine composed of yeast-derived recombinant HBsAg complexed to human high-titer anti-HBs immunoglobulin (HBIG) has been developed. Standard procedure for manufacturing this complex, as well as in vitro assay for monitoring its effect were also established. This complex will be further optimized for mass production and application for clinical trial will be submitted.
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