A dendritic cell-targeted chimeric hepatitis B virus immunotherapeutic vaccine induces both cellular and humoral immune responsesin vivo

Abstract

Chimigen® HBV Immunotherapeutic Vaccine (C-HBV), a recombinant chimeric fusion protein comprising hepatitis B virus (HBV) S1 and S2 surface antigen fragments, Core antigen and a murine monoclonal antibody heavy chain fragment (Fc), was designed and produced in Sf9 insect cells. C-HBV targets the host immune system through specific receptors present on dendritic cells (DCs) which facilitates antigen internalization, processing, and presentation on MHC class I and II to induce both cellular and humoral immune responses against HBV antigens. T cell responses, previously assessed by ex vivo antigen presentation assays using human peripheral blood mononuclear cell (PBMC)-derived DCs and T cells from uninfected and HBV chronicinfected donors, demonstrated that C-HBV was highly immunogenic. A vaccine dose response study was performed in sheep to analyze the immunogenicity of C-HBV in vivo. Sheep (n = 8/group) received three consecutive subcutaneous injections of each dose of C-HBV at four-week intervals. Analysis of serum antibody levels confirmed C-HBV induced a dose-dependent antibody response to C-HBV and S1/S2-Core. Kinetics of the S1/S2-Core specific antibody response was similar to hepatitis B surface antigen (HBsAg)specific antibody responses induced by ENGERIX-B. Analysis of cell-mediated immune responses (CMI) confirmed C-HBV induced both dose-dependent S1/S2-Core-specific lymphocyte proliferative responses and IFN-γ secretion. These responses were stronger with blood lymphocytes than with cells isolated from the lymph node draining the vaccination site. No correlation was seen between antibody titers and CMI. The results confirm C-HBV is an effective delivery vehicle for the induction of T cell responses and may be an appropriate candidate for immunotherapy for chronic HBV infections.

A dendritic cell receptor-targeted chimeric immunotherapeutic protein (C-HBV) for the treatment of chronic hepatitis B

“…The protein showed no toxic effect either in ex vivo studies using human PBMCs, or in vivo studies using sheep. 59 Furthermore, the antibody responses observed against the 6xHis were of much lower magnitude than any of the HBV antigens. The presence of the tag could be an issue if used in clinical trials but there are products with His tag that have reached Phase 2, including one for HBV, 92,93 with no safety issue identified and none has reached Phase 3 so far.…”

“…cytokines might have revealed further aspects of the immune response, even if such data do not fit the hypothesis that Th1 response is more relevant to the clearance of chronic hepatitis B. Both Th1 and Th2 responses to C-HBV were evaluated in sheep, 59 by measuring lymphocyte proliferation and IFN-γ secretion, as well as the production of HBV antigen-specific antibodies. The results in sheep show a mixed Th1/Th2 response, but nature of the involvement of Th2 cytokines could not be predicted, as this data is not available.…”

Designing the next‐generation therapeutic vaccines to cure chronic hepatitis B: focus on antigen presentation, vaccine properties and effect measures

“…In addition, several other protein‐based forms of antigen delivery are currently assessed in pre‐clinical studies: modified cell‐permeable HBV capsids are tested to deliver HBV antigens to the DCs cytoplasm to favor HLA I presentation 85,86 . Furthermore, a chimeric fusion protein consisting of the Fc fragment of a murine antibody and HBV antigens is tested targeting HBV antigens to DCs via Fcɣ and mannose receptors 87 …”

“…85,86 Furthermore, a chimeric fusion protein consisting of the Fc fragment of a murine antibody and HBV antigens is tested targeting HBV antigens to DCs via Fcɣ and mannose receptors. 87 Possibly, one platform alone may not do the job. As such heterologous prime-boost vaccine regimens have proven to be an effective strategy to induce both humoral and cellular immune responses.…”

Dendritic cell‐based immunotherapy: A potential therapeutic option for chronic Hepatitis B virus infection

“…However, further studies are needed to optimize this approach to gain a better chance of a functional cure for HBV infection. Recently, DC‐targeted DNA vaccine and chimeric HBV immunotherapeutic vaccine have shown promising results in the induction of HBV‐specific immune responses 69–71 . In the future, optimized DC‐based immunotherapy is used either alone or more likely in combination with current antiviral agents may be a promising strategy for eradicating persistent HBV infection.…”