Firbas, C, Jilma, B, Tauber, E, Buerger, V, Jelovcan, S, Lingnau, K et al.. Immunogenicity and safety of a novel therapeutic hepatitis C virus (HCV) peptide vaccine: a randomized, placebo controlled trial for dose optimization in 128 healthy subjects. Vaccine 24: 4343-4353
ABSTRACT As interferon/ribavirin-based standard therapy is curative in only about half of HCV patients, there remains an important need for alternatives including vaccines. The novel peptide vaccine IC41 consists of five synthetic peptides harboring HCV T cell epitopes and poly-L-arginine as synthetic adjuvant. In this randomized, placebo-controlled trial, 128 HLA-A2 positive healthy volunteers received four s.c. vaccinations of seven different doses IC41, HCV peptides alone, poly-l-arginine alone or saline solution, every 4 weeks. IC41 was safe and well tolerated. Mild to moderate local reactions were transient. Immunogenicity was assessed using T cell epitope specific [3H]-thymidine proliferation, IFN-gamma ELIspot and HLA-tetramer assays. IC41 induced responses in all dose groups. Higher responder rates were recorded in higher dose groups and increasing number of vaccinations were associated with higher responder rates and more robust responses. Poly-L-arginine was required for the aimed-for Th1/Tc1-type immunity (IFN-gamma secreting T cells).
- SourceAvailable from: Alexander Moysa
[Show abstract] [Hide abstract]
- "The fragments 23—44, 132—140, 1248— 1261, 1764—1772 are conservative in various HCV genotypes (the identify of their sequences in the subtypes 1a, 1b, and 2 is not less than 87%) (Lauer et al., 2004). The NS3 fragment 1073—1081 differs in various HCV genotypes (the identity did not exceed 15%); however, vaccine developers used this peptide as one of effective T-epitopes typical for the HCV genotype 1a frequently detected in Europe (Firbas et al., 2006). Phase I clinical trials have shown that the IC41 vaccine induces formation of HCV-specific CD8+ Tlymphocytes in healthy patients and is well-tolerated in patients (Klade et al., 2008). "
ABSTRACT: In order to surpass the problem of genetic variability of hepatitis C virus envelope proteins during vaccine development, we used the so-called "reverse vaccinology"approach - "from genome to vaccine". Database of HCV protein sequences was designed, viral genome analysis was performed, and several highly conserved sites were revealed in HCV envelope proteins in the framework of this approach. These sites demonstrated low antigenic activity in full-size proteins and HCV virions: antibodies against these sites were not found in all hepatitis C patients. However, two sites, which contained a wide set of potential T-helper epitope motifs, were revealed among these highly conserved ones. We constructed and prepared by solid-phase peptide synthesis several artificial peptide constructs composed of two linker-connected highly conserved HCV envelope E2 protein sites; one of these sites contained a set of T-helper epitope motifs. Experiments on laboratory animals demonstrated that the developed peptide constructs manifested immunogenicity compared with one of protein molecules and were able to raise antibodies, which specifically bound HCV envelope proteins. We succeeded in obtaining antibodies reactive with HCV from hepatitis C patient plasma upon the immunization with some constructs. An original preparation of a peptide vaccine against hepatitis C is under development on the basis of these peptide constructs.03/2015; 61(2):254-264. DOI:10.18097/pbmc20156102254
[Show abstract] [Hide abstract]
- "IC41 is a peptide vaccine, containing five synthetic peptides from core, NS3 and NS4 proteins that correspond to conserved HLA-A2 restricted CD8 and promiscuous CD4 epitopes, together with poly-L arginine as an adjuvant. Phase I and phase II clinical trials demonstrated that the approach is safe and well-tolerated, though the induced T cell responses were relatively modest,   , especially when compared to responses, induced by the viral vectors described above. No significant changes in HCV RNA were observed when patients with chronic HCV infection were vaccinated . "
ABSTRACT: Hepatitis C virus (HCV) infects an estimated more than 150 million people and is a leading cause of liver disease worldwide. The development of direct-acting antivirals (DAAs) will markedly improve the outcome of antiviral treatment with cure of the majority of treated patients. However, several hurdles remain before HCV infection can be considered a menace of the past: High treatment costs will most likely result in absent or limited access in middle and low resource countries and will lead to selective use even in wealthier countries. The limited efficacy of current HCV screening programs leads to a majority of cases being undiagnosed or diagnosed at a late stage and DAAs will not cure virus-induced end-stage liver disease such as hepatocellular carcinoma. Certain patient subgroups may not respond or not be eligible for DAA-based treatment strategies. Finally, reinfection remains possible, making control of HCV infection in people with ongoing infection risk difficult. The unmet medical needs justify continued efforts to develop an effective vaccine, protecting from chronic HCV infection as a mean to impact the epidemic on a global scale. Recent progress in the understanding of virus–host interactions provides new perspectives for vaccine development, but many critical questions remain unanswered. In this review, we focus on what is known about the immune correlates of HCV control, highlight key mechanisms of viral evasion that pose challenges for vaccine development and suggest areas of further investigation that could enable a rational approach to vaccine design. Within this context we also discuss insights from recent HCV vaccination studies and what they suggest about the best way to go forward.Journal of Hepatology 11/2014; 61(1). DOI:10.1016/j.jhep.2014.09.009 · 11.34 Impact Factor
[Show abstract] [Hide abstract]
- "Since molecular cloning of HCV in 1989, a variety of vaccines have been generated for preclinical trials, including subunit protein or peptide vaccines –, recombinant DNA vaccines –, recombinant HCV-like particle vaccines –, microbial vector vaccines –, and more recently, DC-targeting vaccines –. Despite decades of intense research, there is no HCV vaccine available to date and several major obstacles have been identified . "
ABSTRACT: In this study, we engineered Listeria monocytogens (Lm) by deleting the LmΔactA/ΔinlB virulence determinants and inserting HCV-NS5B consensus antigens to develop a therapeutic vaccine against hepatitis C virus (HCV) infection. We tested this recombinant Lm-HCV vaccine in triggering of innate and adaptive immune responses in vitro using immune cells from HCV-infected and uninfected individuals. This live-attenuated Lm-HCV vaccine could naturally infect human dendritic cells (DC), thereby driving DC maturation and antigen presentation, producing Th1 cytokines, and triggering CTL responses in uninfected individuals. However, vaccine responses were diminished when using DC and T cells derived from chronically HCV-infected individuals, who express higher levels of inhibitory molecule Tim-3 on immune cells. Notably, blocking Tim-3 signaling significantly improved the innate and adaptive immune responses in chronically HCV-infected patients, indicating that novel strategies to enhance the potential of antigen presentation and cellular responses are essential for developing an effective therapeutic vaccine against HCV infection.PLoS ONE 01/2014; 9(1):e87821. DOI:10.1371/journal.pone.0087821 · 3.23 Impact Factor