Dendritic Cell-Mediated, DNA-Based Vaccination against Hepatitis C Induces the Multi-Epitope-Specific Response of Humanized, HLA Transgenic Mice

Abstract

Hepatitis C virus (HCV) is the etiologic agent of chronic liver disease, hepatitis C. Spontaneous resolution of viral infection is associated with vigorous HLA class I- and class II-restricted T cell responses to multiple viral epitopes. Unfortunately, only 20% of patients clear infection spontaneously, most develop chronic disease and require therapy. The response to chemotherapy varies, however; therapeutic vaccination offers an additional treatment strategy. To date, therapeutic vaccines have demonstrated only limited success. Vector-mediated vaccination with multi-epitope-expressing DNA constructs alone or in combination with chemotherapy offers an additional treatment approach. Gene sequences encoding validated HLA-A2- and HLA-DRB1-restricted epitopes were synthesized and cloned into an expression vector. Dendritic cells (DCs) derived from humanized, HLA-A2/DRB1 transgenic (donor) mice were transfected with these multi-epitope-expressing DNA constructs. Recipient HLA-A2/DRB1 mice were vaccinated s.c. with transfected DCs; control mice received non-transfected DCs. Peptide-specific IFN-γ production by splenic T cells obtained at 5 weeks post-immunization was quantified by ELISpot assay; additionally, the production of IL-4, IL-10 and TNF-α were quantified by cytokine bead array. Splenocytes derived from vaccinated HLA-A2/DRB1 transgenic mice exhibited peptide-specific cytokine production to the vast majority of the vaccine-encoded HLA class I- and class II-restricted T cell epitopes. A multi-epitope-based HCV vaccine that targets DCs offers an effective approach to inducing a broad immune response and viral clearance in chronic, HCV-infected patients.

Hepatitis C Virus Infection and Vaccine Development

“…99 A recent experimental study in mice also showed that multi-epitopebased HCV vaccine targeting DCs offers an effective approach to inducing a broad immune response and viral clearance in chronic, HCV-infected patients. 100 As for this type of vaccines, no active human clinical trial has been reported. 86…”

Evolution of efficacious pangenotypic hepatitis C virus therapies

“…Dendritic cell‐based vaccines are now being developed by transfecting dendritic cells with plasmids encoding HCV antigens. In 2014, a dendritic cell‐based vaccine study in mice has demonstrated an effective immune response and viral clearance . However, no human clinical trial is being conducted using dendritic cell‐based vaccine.…”

iVAX: An integrated toolkit for the selection and optimization of antigens and the design of epitope-driven vaccines

“…Significant advancements in immunome-derived, epitopedriven vaccines designed using the iVAX toolkit have been made in recent years; in particular, basic research studies have demonstrated the ability of the tools to select epitopes for Burkholderia species, 29 H. pylori 30 and HCV, [31][32][33] and validated the importance of the presence of T cell epitopes in subunit vaccines. Recently, the collaborating groups at EpiVax and iCubed discovered epitopes that activate T regulatory cells (Tregs) in viral pathogens using the JanusMatrix tool.…”