New Applications On Hepatitis C Vaccine Biology Essay

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Hepatitis C virus (HCV) is a dangerous pathogen that most of its infections becoming chronic one, beside they cause clear damage to liver (cirrhosis) requiring liver transplantation, and sometimes progress to hepato cellular carcinoma. This type of infections is blood born disease, so spread widely between patients with blood transfusion,hemodyalysis, and health care workers. Now ,there is 170 million infected. There is antiviral therapy(combined of interferon with ribavirine) but that is long,toxic,expensive and effective in only 50% of patients[1]. Also, there is passive immunization by different types of antibodies as Civacir and Bavituximab[2] but that is not effective in chronic infections and can not prevent reinfection. So, development of HCV vaccine is essential. Although that would be difficult (because of high variability of its genome and its high mutant capacity), there is several theories and trials working on it. Some of them work on developing peptide vaccine which activate T-cells, others work on developing of neutralizing antibodies(Abs) against envelop vaccine. third work on DNA vaccine and viral vector vaccine. Each one has its own advantages and disadvantages.


Recently, there is much talking about T cell epitope based vaccine which depend on use of variety of conserved T cell epitopes to activate both CD4+ and CD8+ T cell response. Apropriate epitopes selected by using Rapid Epitope Identification system(EIS)[3].One of trials work on this by a group of scientists and virologists aimed to assess the major role of cellular immune response to different types of HCV epitopes in HCV infections( chronic or spontaneously resolved )by using 750 overlapping peptides (to include complete amino acid sequence of HCV poly-protein encoding from genotype a1,and they were divided in peptide pools. These peptide amino acid sequence were known by using mass spectrometry. Then these were introduced to isolated leukocytes from blood units of 3 groups(infection resolved participants who have Abs in their serum but not HCV RNA,healthy with -ive HCV RNA and -ive serotyping and chronic infected participant).Also they used

ELIS spot essay to measure CD8+T cell activity(according to interferon g production)after culturing these cells with viral peptide-presenting dendritic cells, and found that CD4+T cell response is major player in spontaneously resolved infections, it respond to NS33H and NS35H which are conserved epitopes associated with recovery and can express on 7 types of MHC molecules. But in chronic infections ,CD4Tcell response doesn't exist ,there was only CD8Tcell response, these CD8T cells don't play role in virus clearance(there is no 2nd signal) but can slightly control viremia (may be by primed CD8Tcell).Also these scientists think neutralizing Abs against viral envelop peptide may be applicable but not adequate to activate CD4,8Tcells that control HCV infection[4].

Other type is DNA HCV vaccine(CIGB230)which aimed to deliver RNA into a target cell where HCV peptide can be expressed through MHC1 molecules to stimulate cytotoxicT lymphocytes(CTL)that has great effect in HCV elimination following infection. This trial developed new DNA for HCV which is CIGB230 plasmid for HCV antigens, and HCV recombinant capsid protein that raise immunity response(both humeral and cellular).That by intra muscular injection of mice. After 3 months, the plasmid disappeared from tissues. There was no observed toxicity or damage[5].Thus it can be safe and specific vaccine. Also,there is no viral agents used (as viral peptides).

Other type is viral vector vaccine ,chosen that doesn't integrate its genome into host cell genes,instead,its RNA is confined to cytoplasm. such (immuno potentiating reconstituted influenza virosome (IRIV)),this vaccine aims to generate cytotoxic immunity by delivery IRIV a carrier to give HCV derived peptides(especially core peptides35,131-140 which are conserved in most HCV genotypes)to cytoplasm of 3 different target cells from -ive HCV blood serum invitro(which are T1cells,EBV infected B cells,and transporter associated with antigen processing(TAP)deficient T2cells)and found this virosome use endogenous, TAP independent, and BrefeldinA sensitive pathway to express HCV antigens through MHC1 molecules. IRIV is fusogenic because of influenza derived hemagglutinin surround HCV antigens. Hemagglutinin facilitate attachment and fusion, even more importantly ,it act as recognition antigen because most of people has some immunity response to hemagglutinin due to previous exposure to influenza. Virosome has important function,it protects its contents of immunogenic peptides from degradation by proteases invivo. The result of this vaccine trial was amazing, there was high cytotoxicity response(large target cells lyses assessed by cr-release)[6].this is so important for future studies including in vivo mouse models with optimistic expectations.

Also, there is some people worked to develop Abs against HCV envelope glycoproteinsE1,E2.these glycoproteins extracted from infected Hela cells, then combined to adjuvant (MF59) and administered in 3 booster shots to chimpanzees. when challenged with low dose of identical HCV strain, 5 of 7 chimpanzees were completely resistant to HCV infection. These 5 chimpanzees had high titer of neutralizing Abs to this strain. the remaining 2 got acute infection but were able to resolve it before converting to chronic[3].Also there is other type of Abs specific to NS3 HCV protein[2].but humeral immune response for HCV seem largely specific for small groups, and the model used(chimpanzees)although may be the closest one to HCV infections in human. but there is a difference, that chronic infected chimpanzees show no effect or damage in their hepatocytes.

According to WHO, there is no HCV vaccine available until now, and that will be difficult because HCV genome is highly heterogeneous with a lots of mutations. but approximately one third of HCV infected patients recover spontaneously by their specific immunity against the virus. So developing a vaccine mimicking this response will be effective[7].


Various immunological hypotheses and trials had been identified, together for clearance HCV infection. but there is many questions on some of them with no answer till now. For example, in T-cell epitopes vaccine, peptide must be selected and testing for each HLA type, requiring larger database on MHC reactivity. In DNA vaccine, exactly how many cells express foreign DNA and for how long is still unknown. Also, there is some concern about its safety.Viral vector vaccine(IRIV) seem to be a powerful tool for design of an effective vaccine because it is safe (no DNA mutations)with high experimental efficacy.