Generic placeholder image

Current Computer-Aided Drug Design


ISSN (Print): 1573-4099
ISSN (Online): 1875-6697

Research Article

Broad Spectrum Peptide Vaccine Design Against Hepatitis C Virus

Author(s): Sherly Kurnia Dewi, Soegianto Ali and Vivitri Dewi Prasasty*

Volume 15 , Issue 2 , 2019

Page: [120 - 135] Pages: 16

DOI: 10.2174/1573409914666181003151222

Price: $65


Background: Hepatitis C virus (HCV) infection is a global burden. There is no peptide vaccine found as modality to cure the disease is available due to the weak cellular immune response and the limitation to induce humoral immune response.

Methods: Five predominated HCV subtypes in Indonesia (1a, 1b, 1c, 3a, and 3k) were aligned and the conserved regions were selected. Twenty alleles of class I MHC including HLA-A, HLA-B, and HLAC types were used to predict the potential epitopes by using NetMHCPan and IEDB. Eight alleles of HLA-DRB1, together with a combination of 3 alleles of HLA-DQA1 and 5 alleles of HLA-DQB1 were utilized for Class II MHC epitopes prediction using NetMHCIIPan and IEDB. LBtope and Ig- Pred were used to predict B cells epitopes. Moreover, proteasome analysis was performed by NetCTL and the stability of the epitopes in HLA was calculated using NetMHCStabPan for Class I. All predicted epitopes were analyzed for its antigenicity, toxicity, and stability. Population coverage, molecular docking and molecular dynamics were performed for several best epitopes.

Results: The results showed that two best epitopes from envelop protein, GHRMAWDMMMNWSP (E1) and PALSTGLIHLHQN (E2) were selected as promising B cell and CD8+ T cell inducers. Other two peptides, LGIGTVLDQAETAG and VLVLNPSVAATLGF, taken from NS3 protein were selected as CD4+ T cell inducer.

Conclusion: This study suggested the utilization of all four peptides to make a combinational peptide vaccine for in vivo study to prove its ability in inducing secondary response toward HCV.

Keywords: HCV vaccine design, epitope prediction, in silico, Indonesia, cellular immune responses, humoral immune response.

Graphical Abstract
Polaris Observatory HCV Collaborators. Global prevalence and genotype distribution of hepatitis C virus infection in 2015: A modelling study. Lancet Gastroenterol. Hepatol., 2017, 2(3), 161-176.
Sibley, A.; Han, K.H.; Abourached, A.; Lesmana, L.A.; Makara, M.; Jafri, W.; Salupere, R.; Assiri, A.M.; Goldis, A.; Abaalkhail, F.; Abbas, Z.; Abdou, A.; Al Braiki, F.; Al Hosani, F.; Al Jaberi, K.; Al Khatry, M.; Al Mulla, M.A.; Al Quraishi, H.; Al Rifai, A.; Al Serkal, Y.; Alam, A.; Alavian, S.M.; Alashgar, H.I.; Alawadhi, S.; Al-Dabal, L.; Aldins, P.; Alfaleh, F.Z.; Alghamdi, A.S.; Al-Hakeem, R.; Aljumah, A.A.; Almessabi, A.; Alqutub, A.N.; Alswat, K.A.; Altraif, I.; Alzaabi, M.; Andrea, N.; Babatin, M.A.; Baqir, A.; Barakat, M.T.; Bergmann, O.M.; Bizri, A.R.; Blach, S.; Chaudhry, A.; Choi, M.S.; Diab, T.; Djauzi, S.; El Hassan, E.S.; El Khoury, S.; Estes, C.; Fakhry, S.; Farooqi, J.I.; Fridjonsdottir, H.; Gani, R.A.; Ghafoor, K.A.; Gheorghe, L.; Gottfredsson, M.; Gregorcic, S.; Gunter, J.; Hajarizadeh, B.; Hamid, S.; Hasan, I.; Hashim, A.; Horvath, G.; Hunyady, B.; Husni, R.; Jeruma, A.; Jonasson, J.G.; Karlsdottir, B.; Kim, D.Y.; Kim, Y.S.; Koutoubi, Z.; Liakina, V.; Lim, Y.S.; Löve, A.; Maimets, M.; Malekzadeh, R.; Matičič, M.; Memon, M.S.; Merat, S.; Mokhbat, J.E.; Mourad, F.H.; Muljono, D.H.; Nawaz, A.; Nugrahini, N.; Olafsson, S.; Priohutomo, S.; Qureshi, H.; Rassam, P.; Razavi, H.; Razavi-Shearer, D.; Razavi-Shearer, K.; Rozentale, B.; Sadik, M.; Saeed, K.; Salamat, A.; Sanai, F.M.; Sanityoso, S.A.; Sayegh, R.A.; Sharara, A.I.; Siddiq, M.; Siddiqui, A.M.; Sigmundsdottir, G.; Sigurdardottir, B.; Speiciene, D.; Sulaiman, A.; Sultan, M.A.; Taha, M.; Tanaka, J.; Tarifi, H.; Tayyab, G.; Tolmane, I.; Udin, M.; Umar, M.; Valantinas, J.; Videčnik-Zorman, J.; Yaghi, C.; Yunihastuti, E.; Yusuf, M.A.; Zuberi, B.F.; Schmelzer, J.D. The present and future disease burden of hepatitis C virus infections with today’s treatment paradigm-volume 3. J. Viral Hepat., 2015, 22, 21-41.
Utsumi, T.; Pranawa, L.M.I.; Yano, Y.; Wahyuni, R.M.; Istimagfiroh, A.; Amin, M.; Rinonce, H.T.; Juniastuti, W.A.; Tjempakasari, A.; Basuki, W.; Soetjipto, H.H.; Hayashi, Y. Prevalence and risk factors of hepatitis B and C infections among hemodialysis patients from private hemodialysis unit in Surabaya, Indonesia. Southeast Asian J. Trop. Med. Public Health, 2016, 47(5), 927-934.
Wait, S.; Kell, E.; Hamid, S.; Muljono, D.H.; Sollano, J.; Mohamed, R.; Shah, S. Al-Mahtab, Mamun.; Abbas, Z.; Johnston, J.; Tanwandee, T.; Wallace, J. Hepatitis B and hepatitis C in southeast and southern Asia: Challenges for governments. Lancet Gastroenterol. Hepatol., 2016, 1, 248-255.
Nurtjahyani, S.P.; Handajani, R.; Amin, M.; Hidayati, D.; Jadid, N. Validation of anti HCV-hepatitis C identification in blood donors using PCR: Case study at Tuban East Java district, Indonesia. Biomed. Res., 2018, 29(8), 1672-1674.
Manns, M.P.; Buti, M.; Gane, E.; Pawlotsky, J.M.; Razavi, H.; Terrault, N.; Younossi, Z. Hepatitis C virus infection. Nat. Rev. Dis. Primers, 2017, 3, 17006.
Baumert, T.F.; Fauvelle, C.; Chen, D.Y.; Lauer, G.M. A prophylactic hepatitis C virus vaccine: A distant peak still worth climbing. J. Hepatol., 2014, 61, S34-S44.
Ikram, A.; Anjum, S.; Tahir, M. In Silico identification and conservation analysis of B-cell and T-cell epitopes of hepatitis C virus 3a genotype enveloped glycoprotein 2 from Pakistan: A step towards heterologous vaccine design. Hepat. Mon., 2014, 14(6), e9832.
Li, W.; Joshi, M.D.; Singhania, S.; Ramsey, K.H.; Murthy, A.K. Peptide vaccine: Progress and challenges. Vaccines, 2014, 2, 515-536.
Toussaint, N.C.; Maman, Y.; Kohlbacher, O.; Louzoun, Y. Universal peptide vaccines – Optimal peptide vaccine design based on viral sequence conservation. Vaccine, 2011, 29, 8745-8753.
Ashraf, N.M.; Bilal, M.; Mahmood, M.S.; Hussain, A.; Mehboob, M.Z. In-silico analysis of putative HCV epitopes against Pakistani human leukocyte antigen "background An approach towards development of future vaccines for Pakistani population. Infect. Genet. Evol., 2016, 43, 58-66.
Fibras, C.; Jilma, B.; Tauber, E.; Buerger, V.; Jelovcan, S.; Lingnau, K.; Buschle, M.; Frisch, J.; Klade, C.S. 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, 2006, 24, 4343-4353.
Yutani, S.; Ueshima, K.; Abe, K.; Ishiguro, A.; Eguchi, J.; Matsueda, S.; Komatsu, N.; Shichijo, S.; Yamada, A.; Itoh, K.; Sasada, T.; Kudo, M.; Noguchi, M. Phase II study of personalized peptide vaccination with both a hepatitis C virus-Derived peptide and peptides from tumor-associated antigens for the treatment of HCV-Positive advanced hepatocellular carcinoma patients. J. Immunol. Res., 2015, 2015, 473909.
Xue, J.; Zhu, H.; Chen, Z. Therapeutic vaccines against hepatitis C virus. Infect. Genet. Evol., 2014, 22, 120-129.
Bartenschlager, R.; Baumert, T.F.; Bukh, J.; Houghton, M.; Lemon, S.M.; Lindenbach, B.D.; Lohmann, V.; Moradpour, D.; Pietschmann, T.; Rice, C.M.; Thimme, R.; Wakita, T. Critical challenges and emerging opportunities in hepatitis C virus research in an era of potent antiviral therapy: Considerations for scientists and funding agencies. Virus Res., 2018, 248, 53-62.
Feinstone, S.M.; Hu, D.J.; Major, M.E. Prospects for prophylactic and therapeutic vaccines against hepatitis C virus. Clin. Infect. Dis., 2012, 55, S25-S32.
Kuniholm, M.H.; Anastos, K.; Kovacs, A.; Gao, X.; Marti, D.; Sette, A.; Greenblatt, R.M.; Peters, M.; Cohen, M.H.; Minkoff, H.; Gange, S.J.; Thio, C.L.; Young, M.A.; Xue, X.; Carrington, M.; Strickler, H.D. Relation of HLA class I and II supertypes with spontaneous clearance of hepatitis C virus. Genes Immun., 2013, 14(5), 330-335.
Hickey, M.J.; Valenzuela, N.M.; Reed, E.F. Alloantibody generation and effector function following sensitization to Human Leukocyte Antigen. Front. Immunol., 2016, 7, 30.
Shehzadi, A.; Ur-Rehman, S.; Husnain, T. Selection of epitope-based vaccine targets of HCV genotype 1 of Asian origin: A systematic in silico approach. Bioinformation, 2012, 8(20), 957-962.
Nielsen, M.; Andreatta, M. NetMHCpan-3.0; improved prediction of binding to MHC class I molecules integrating information from multiple receptor and peptide length datasets. Genome Med., 2016, 8, 33.
Kolaskar, A.S.; Tongaonkar, P.C. A semi-empirical method for prediction of antigenic determinants on protein antigens. FEBS Lett., 1990, 276(1-2), 172-174.
Huang, W.L.; Tsai, M.J.; Hsu, K.T.; Wang, J.R.; Chen, Y.H.; Ho, S.Y. Prediction of linear B-cell epitopes of hepatitis C virus for vaccine development. BMC Med. Genomics, 2015, 8, S3.
Peters, B.; Bulik, S.; Tampe, R.; Van-Endert, P.M.; Holzhütter, H.G. Identifying MHC class I epitopes by predicting the TAP transport efficiency of epitope precursors. J. Immunol., 2003, 171(4), 1741-1749.
Lundegaard, C.; Lund, O.; Buus, S.; Nielsen, M. Major histocompatibility complex class I binding predictions as a tool in epitope discovery. Immunology, 2010, 130(3), 309-318.
Trott, O.; Olson, A.J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J. Comput. Chem., 2010, 31(2), 455-461.
Abraham, M.J.; Teemu, M.; Roland, S.; Szilárd, P.; Jeremy, C.; Berk, H.; Erik, L. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX, 2004, 1(2), 19-25.
Marwan, M.B.; Afra, A.F.; Salma, S.; Wafa, A.M.; Duaa, A.N.; Samar, A.A.A.A.; Entissar, M.E.A.; Abdah, A.A.; Ranya, O.A.; Mohamed, A.S. Immunoinformatics predication and in silico modeling of epitope-based peptide vaccine against virulent newcastle disease viruses. Am. J. Infec. Dis. Microbiol., 2016, 4(3), 61-71.
Molero-Abraham, M.; Lafuente, E.M.; Flower, D.R.; Reche, P.A. Selection of conserved epitopes from hepatitis C virus for pan-populational stimulation of T-cell responses. Clin. Dev. Immunol., 2013, 2013
von Delft, A.; Donnison, T.A.; Lourenço, J.; Hutchings, C.; Mullarkey, C.E.; Brown, A.; Pybus, O.G.; Klenerman, P.; Chinnakannan, S.; Barnes, E. The generation of a simian adenoviral vectored HCV vaccine encoding genetically conserved gene segments to target multiple HCV genotypes. Vaccine, 2018, 36(2), 313-321.
Wentworth, P.A.; Sette, A.; Celis, E.; Sidney, J.; Southwood, S.; Crimi, C.; Stitely, S.; Keogh, E.; Wong, N.C.; Livingston, B.; Alazard, D.; Vitiello, A.; Grey, H.M.; Chisari, F.V.; Chesnut, R.W.; Fikes, J. Identification of A2-restricted hepatitis C virus-specific cytotoxic T lymphocyte epitopes from conserved regions of the viral genome. Int. Immunol., 1996, 8(5), 651-659.
Alexander, J.; Del Guercio, M.F.; Fikes, J.D.; Chesnut, R.W.; Chisari, F.V.; Chang, K.M.; Appella, E.; Sette, A. Recognition of a novel naturally processed, A2 restricted, HCV-NS4 epitope triggers IFN-gamma release in absence of detectable cytopathicity. Hum. Immunol., 1998, 59(12), 776-782.
Shawky, H. Expression, immunogenicity and diagnostic value of envelope proteins from an Egyptian hepatitis C virus isolate. Arch. Virol., 2015, 160, 945-958.
Urbaczek, A.C. Recombinant hepatitis C virus-envelope protein 2 interactions with low-density lipoprotein/CD81 receptors. Mem. Inst. Oswaldo Cruz, 2015, 110(4), 534-542.
Orlova, O.V. The role of HCV E2 protein glycosylation in functioning of virus envelope proteins in insect and mammalian cells. Acta Naturae, 2015, 7(1), 87-97.
Ziegler, S. Impact of sequence variation in a dominant HLA-A*02-restricted epitope in hepatitis C virus on priming and cross-reactivity of CD8+ T cells. J. Virol., 2014, 88(19), 11080-11090.
Nielsen, M.; Lund, O.; Buus, S.; Lundegaard, C. MHC Class II epitope predictive algorithms. Immunology, 2010, 130(3), 319-328.
Roche, P.A.; Kazuyuki, F. The ins and outs of MHC class II- mediated antigen processing and presentation. Nat. Rev. Immunol., 2015, 15(4), 203-216.
Gededzha, M.P.; Mphahlele, M.J.; Selabe, S.G. Prediction of T-cell epitopes of hepatitis C virus genotype 5a. Virol. J., 2014, 11, 187.
Kuniholm, M.H. Specific HLA class I and II alleles associated with hepatitis C virus viremia. Hepatology, 2010, 51(5), 1514-1522.
Samimi-Rad, K. Association of HLA class II alleles with hepatitis C virus clearance and persistence in thalassemia patients from Iran. J. Med. Virol., 2015, 87(9), 1565-1572.
El-Bendary, M. Associations of human leucocyte antigen class II-DQB1 alleles with hepatitis C virus infection in Egyptian population: A multicentre family-based study. J. Viral Hepat., 2016, 23(12), 961-970.
Lee, M.H. Human leukocyte antigen variants and risk of hepatocellular carcinoma modified by HCV genotypes: A genome-wide association study. Hepatology, 2017, 2017
Abdel-Hady, K.M. Identification and retrospective validation of T-cell epitopes in the hepatitis C virus genotype 4 proteome: An accelerated approach toward epitope-driven vaccine development. Hum. Vaccin. Immunother., 2014, 10(8), 2366-2377.
Naiyer, M.M. KIR2DS2 recognizes conserved peptides derived from viral helicases in the context of HLA-C. . Sci. Immunol, 2017, 2 (15) pii, eaal5296.
Buss, S. High-resolution mapping of linear antibody epitopes using ultrahigh-density peptide microarrays. Mol. Cell. Proteomics, 2012, 11(12), 1790-1800.
Deng, K. Antibodies targeting novel neutralizing epitopes of hepatitis C virus glycoprotein preclude genotype 2 virus infection. PLoS One, 2015, 10(9), e0138756.
Olenina, L.V. Mapping and characterization of B cell linear epitopes in the conservative regions of hepatitis C virus envelope glycoproteins. J. Viral Hepat., 2002, 9(3), 174-182.
Potter, J.A.; Owsianka, A.M.; Jeffery, N.; Matthews, D.J.; Keck, Z.Y.; Lau, P.; Foung, S.K.; Taylor, G.L.; Patel, A.H. Toward a hepatitis C virus vaccine: The structural basis of hepatitis C virus neutralization by AP33, a broadly neutralizing antibody. J. Virol., 2012, 86(23), 12923-12932.
Dunlop, J.I.; Owsianka, A.M.; Cowton, V.M.; Patel, A.H. Current and future prophylactic vaccines for hepatitis C virus. Vaccine Development and Therapy, 2015, 5, 31-44.
Ip, P.P.; Nijman, H.W.; Daemen, T. Epitope prediction assays combined with validation assays strongly narrows down putative cytotoxic t lymphocyte epitopes. Vaccines (Basel),, 2015, 3(2), 203-220.
Firbas, C. Immunogenicity and safety of different injection routes and schedules of IC41, a Hepatitis C virus (HCV) peptide vaccine. Vaccine, 2010, 28, 2397-2407.

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy