Immunogenicity of CIGB‐230, a therapeutic DNA vaccine preparation, in HCV‐chronically infected individuals in a Phase I clinical trial

Abstract

Hepatitis C virus (HCV) is a worldwide health problem. No vaccine is available against this pathogen and therapeutic treatments currently in use are of limited efficacy. In the present study, the immunogenicity of the therapeutic vaccine candidate CIGB-230, based on the mixture of pIDKE2, a plasmid expressing HCV structural antigens, with a recombinant HCV core protein, Co.120, was evaluated. CIGB-230 was administered by intramuscular injection on weeks 0, 4, 8, 12, 16 and 20 to 15 HCV-chronically infected individuals, non-responders to previous treatment with interferon (IFN) plus ribavirin. Interestingly, following the final immunization, neutralizing antibody responses against heterologous viral pseudoparticles were modified in eight individuals, including six de novo responders. In addition, 73% of vaccinees exhibited specific T cell proliferative response and T cell IFN-gamma secretory response 24 weeks after primary immunization with CIGB-230. Furthermore, 33.3% of individuals developed de novo cellular immune response against HCV core and the number of patients (46.7% at the end of treatment) with cellular immune response against more than one HCV structural antigen increased during vaccination (P = 0.046). In addition, despite persistent detection of HCV RNA, more than 40% percent of vaccinated individuals improved or stabilized liver histology, particularly reducing fibrosis, which correlated with cellular immune response against more than one HCV antigen (P = 0.0053). In conclusion, CIGB-230 is a promising candidate for effective therapeutic interventions based on its ability for enhancing the immune response in HCV chronically infected individuals.

Inhibition of Intrahepatic Gamma Interferon Production by Hepatitis C Virus Nonstructural Protein 5A in Transgenic Mice

“…Abundant evidence indicates that the immune system fails to eliminate virus from the liver in a large number of HCV-infected patients, and as a result, most acute infections lead to long-term viral persistence (12,36). The efficacies of therapeutic vaccination for chronic hepatitis C nonresponder patients are correlated with the inhibition of IFN-␥ secretion (3,18,34). Our results revealed that HCV NS5A affects Gata-3 and Tbx21 expression and impairs IFN-␥ production (Fig.…”

High, Broad, Polyfunctional, and Durable T Cell Immune Responses Induced in Mice by a Novel Hepatitis C Virus (HCV) Vaccine Candidate (MVA-HCV) Based on Modified Vaccinia Virus Ankara Expressing the Nearly Full-Length HCV Genome

“…This is the first time in which all of the HCV proteins are expressed in the same context by a single virus vector. Usually, the HCV vaccine candidates target the structural proteins (Core, E1, and E2) (42)(43)(44)(45), a combination of structural and nonstructural proteins (Core, NS3, and NS4) (46)(47)(48), or the nonstructural proteins (generally NS3, NS4, and NS5) (20,25). Undoubtedly, the most frequently used HCV antigen is NS3 since the majority of the viral epitopes recognized by cytotoxic T lymphocytes and CD4 ϩ T cells in patients with HCV infection are located in this protein (9,49).…”

Synthetic peptide vaccines

“…However, HCV envelope proteins demonstrate the highest sequence variability, with regard to HCV genetic variants, among all viral proteins (Sobolev et al, 2000). Though the immunization with the full-size HCV envelope proteins can elicit virus-neutralizing antibodies, these antibodies are specific to certain HCV genetic variants, relative to the one, from which the envelope proteins used for immunization, are taken (Elmowalid et al, 2007;Alvarez-Lajonchere et al, 2009). Several highly conserved sites were determined in HCV envelope proteins E1 and E2 (Sobolev et al, 2000); however, most these sites did not elicit specific antibodies because of insufficient Tlymphocyte help resulting from the absence of T-helper epitopes in the vicinity.…”