Prediction of Prophylactic Peptide Vaccine Candidates for Human Papillomavirus (HPV): Immunoinformatics and Reverse Vaccinology Approaches

Mehreen       Ismail; Zureesha       Sajid; Amjad       Ali; Xiaogang       Wu; Syed    Aun    Muhammad; Rehan    Sadiq    Shaikh

doi:10.2174/1570164617999200505095802

Abstract

Background: Human Papillomavirus (HPV) is responsible for substantial morbidity and mortality worldwide. We predicted immunogenic promiscuous monovalent and polyvalent T-cell epitopes from the polyprotein of the Human Papillomavirus (HPV) using a range of bioinformatics tools and servers.

Methods: We used immunoinformatics and reverse vaccinology-based approaches to design prophylactic peptides by antigenicity analysis, T-cell epitopes prediction, proteasomal and conservancy evaluation, host-pathogen protein interactions, and in silico binding affinity analysis.

Results: We found two early proteins (E2 and E6) and two late proteins (L1 and L2) of HPV as potential vaccine candidates. Of these proteins (E2, E6, L1 & L2), 2-epitopes of each candidate protein for multiple alleles of MHC class I and II were found, bearing significant binding affinity (>-6.0 kcal/mole). These potential epitopes for CD4+ and CD8+ T-cells were also linked to design polyvalent construct using GPGPG linkers. Cholera toxin B and mycobacterial heparin-binding hemagglutinin adjuvant with a molecular weight of 12.5 and 18.5 kDa were used for epitopes of CD4+ and CD8+ T-cells, respectively. The molecular docking indicated the optimum binding affinity of HPV peptides with MHC molecules. This interaction showed that our predicted vaccine candidates are suitable to trigger the host immune system to prevent HPV infections.

Conclusion: The predicted conserved T-cell epitopes would contribute to the imminent design of HPV vaccine candidates, which will be able to induce a broad range of immune-responses in a heterogeneous HLA population.

Keywords: HPV, T-cells, epitopic peptides, immunoinformatics, binding affinity, HPV.

« Previous Next »

Graphical Abstract

[1] 
Muñoz, N.; Bosch, F.X.; de Sanjosé, S.; Herrero, R.; Castellsagué, X.; Shah, K.V.; Snijders, P.J.; Meijer, C.J. International Agency for Research on Cancer Multicenter Cervical Cancer Study Group. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N. Engl. J. Med.,  2003, 348(6), 518-527.
[http://dx.doi.org/10.1056/NEJMoa021641] [PMID: 12571259] 
[2] 
McLellan, J.S.; Chen, M.; Joyce, M.G.; Sastry, M.; Stewart-Jones, G.B.; Yang, Y.; Zhang, B.; Chen, L.; Srivatsan, S.; Zheng, A.; Zhou, T.; Graepel, K.W.; Kumar, A.; Moin, S.; Boyington, J.C.; Chuang, G.Y.; Soto, C.; Baxa, U.; Bakker, A.Q.; Spits, H.; Beaumont, T.; Zheng, Z.; Xia, N.; Ko, S.Y.; Todd, J.P.; Rao, S.; Graham, B.S.; Kwong, P.D. Structure-based design of a fusion glycoprotein vaccine for respiratory syncytial virus. Science,  2013, 342(6158), 592-598.
[http://dx.doi.org/10.1126/science.1243283] [PMID: 24179220] 
[3] 
Handforth, J.; Friedland, J.S.; Sharland, M. Basic epidemiology and immunopathology of RSV in children. Paediatr. Respir. Rev.,  2000, 1(3), 210-214.
[http://dx.doi.org/10.1053/prrv.2000.0050] [PMID: 12531081] 
[4] 
Griffiths, C.; Drews, S.J.; Marchant, D.J. Respiratory Syncytial Virus: Infection, Detection, and New Options for Prevention and Treatment. Clin. Microbiol. Rev.,  2017, 30(1), 277-319.
[http://dx.doi.org/10.1128/CMR.00010-16] [PMID: 27903593] 
[5] 
de Villiers, E.M.; Fauquet, C.; Broker, T.R.; Bernard, H.U.; zur Hausen, H. Classification of papillomaviruses. Virology,  2004, 324(1), 17-27.
[http://dx.doi.org/10.1016/j.virol.2004.03.033] [PMID: 15183049] 
[6] 
Chouhy, D.; Bolatti, E.M.; Pérez, G.R.; Giri, A.A. Analysis of the genetic diversity and phylogenetic relationships of putative human papillomavirus types. J. Gen. Virol.,  2013, 94(Pt 11), 2480-2488.
[http://dx.doi.org/10.1099/vir.0.055137-0] [PMID: 23997181] 
[7] 
Zheng, Z.M.; Baker, C.C. Papillomavirus genome structure, expression, and post-transcriptional regulation. Front. Biosci.,  2006, 11, 2286-2302.
[http://dx.doi.org/10.2741/1971] [PMID: 16720315] 
[8] 
Kelly, D.F.; Rappuoli, R. Hot Topics in Infection and Immunity in Children II; Springer, 2005, pp. 217-223.
[http://dx.doi.org/10.1007/0-387-25342-4_151] 
[9] 
White, M.D. Pros, cons, and ethics of HPV vaccine in teens-Why such controversy? Transl. Androl. Urol.,  2014, 3(4), 429-434.
[PMID: 26816799] 
[10] 
Dar, H.A.; Zaheer, T.; Shehroz, M.; Ullah, N.; Naz, K.; Muhammad, S.A.; Zhang, T.; Ali, A. 
                        Immunoinformatics-aided design and evaluation of a potential multi-epitope vaccine against 
                        Klebsiella Pneumoniae. Vaccines (Basel),  2019, 7(3), 88.
[http://dx.doi.org/10.3390/vaccines7030088] [PMID: 31409021] 
[11] 
Sette, A.; Fikes, J. Epitope-based vaccines: an update on epitope identification, vaccine design and delivery. Curr. Opin. Immunol.,  2003, 15(4), 461-470.
[http://dx.doi.org/10.1016/S0952-7915(03)00083-9] [PMID: 12900280] 
[12] 
Patronov, A.; Doytchinova, I. T-cell epitope vaccine design by immunoinformatics. Open Biol.,  2013, 3(1), 120139.
[http://dx.doi.org/10.1098/rsob.120139] [PMID: 23303307] 
[13] 
Ali, M.; Pandey, R.K.; Khatoon, N.; Narula, A.; Mishra, A.; Prajapati, V.K. Exploring dengue genome to construct a multi-epitope based subunit vaccine by utilizing immunoinformatics approach to battle against dengue infection. Sci. Rep.,  2017, 7(1), 9232.
[http://dx.doi.org/10.1038/s41598-017-09199-w] [PMID: 28835708] 
[14] 
Van Doorslaer, K.; Li, Z.; Xirasagar, S.; Maes, P.; Kaminsky, D.; Liou, D.; Sun, Q.; Kaur, R.; Huyen, Y.; McBride, A.A. The Papillomavirus Episteme: a major update to the papillomavirus sequence database. Nucleic Acids Res.,  2017, 45(D1), D499-D506.
[http://dx.doi.org/10.1093/nar/gkw879] [PMID: 28053164] 
[15] 
Shen, H.B.; Chou, K.C. Virus-mPLoc: a fusion classifier for viral protein subcellular location prediction by incorporating multiple sites. J. Biomol. Struct. Dyn.,  2010, 28(2), 175-186.
[http://dx.doi.org/10.1080/07391102.2010.10507351] [PMID: 20645651] 
[16] 
Shen, H.B.; Chou, K.C. Virus-PLoc: a fusion classifier for predicting the subcellular localization of viral proteins within host and virus-infected cells. Biopolymers,  2007, 85(3), 233-240.
[http://dx.doi.org/10.1002/bip.20640] [PMID: 17120237] 
[17] 
Doytchinova, I.A.; Flower, D.R. VaxiJen: a server for prediction of protective antigens, tumour antigens and subunit vaccines. BMC Bioinformatics,  2007, 8(1), 4.
[http://dx.doi.org/10.1186/1471-2105-8-4] [PMID: 17207271] 
[18] 
Wakeman, C.A.; Hammer, N.D.; Stauff, D.L.; Attia, A.S.; Anzaldi, L.L.; Dikalov, S.I.; Calcutt, M.W.; Skaar, E.P. Menaquinone biosynthesis potentiates haem toxicity in Staphylococcus aureus. Mol. Microbiol.,  2012, 86(6), 1376-1392.
[http://dx.doi.org/10.1111/mmi.12063] [PMID: 23043465] 
[19] 
Naz, A.; Awan, F.M.; Obaid, A.; Muhammad, S.A.; Paracha, R.Z.; Ahmad, J.; Ali, A. Identification of putative vaccine candidates against Helicobacter pylori exploiting exoproteome and secretome: a reverse vaccinology based approach. Infect. Genet. Evol.,  2015, 32, 280-291.
[http://dx.doi.org/10.1016/j.meegid.2015.03.027] [PMID: 25818402] 
[20] 
Singh, H.; Raghava, G.P. ProPred1: prediction of promiscuous MHC Class-I binding sites. Bioinformatics,  2003, 19(8), 1009-1014.
[http://dx.doi.org/10.1093/bioinformatics/btg108] [PMID: 12761064] 
[21] 
Bui, H.H.; Sidney, J.; Li, W.; Fusseder, N.; Sette, A. Development of an epitope conservancy analysis tool to facilitate the design of epitope-based diagnostics and vaccines. BMC Bioinform.,  2007, 8(1), 361.
[http://dx.doi.org/10.1186/1471-2105-8-361] [PMID: 17897458] 
[22] 
Camproux, A.C.; Gautier, R.; Tufféry, P. A hidden markov model derived structural alphabet for proteins. J. Mol. Biol.,  2004, 339(3), 591-605.
[http://dx.doi.org/10.1016/j.jmb.2004.04.005] [PMID: 15147844] 
[23] 
Zhang, Y.; Liu, T.; Meyer, C.A.; Eeckhoute, J.; Johnson, D.S.; Bernstein, B.E.; Nusbaum, C.; Myers, R.M.; Brown, M.; Li, W.; Liu, X.S. Model-based analysis of ChIP-Seq (MACS). Genome Biol.,  2008, 9(9), R137.
[http://dx.doi.org/10.1186/gb-2008-9-9-r137] [PMID: 18798982] 
[24] 
Pettersen, E.F.; Goddard, T.D.; Huang, C.C.; Couch, G.S.; Greenblatt, D.M.; Meng, E.C.; Ferrin, T.E. UCSF Chimera--a visualization system for exploratory research and analysis. J. Comput. Chem.,  2004, 25(13), 1605-1612.
[http://dx.doi.org/10.1002/jcc.20084] [PMID: 15264254] 
[25] 
Ammari, M.G.; Gresham, C.R.; McCarthy, F.M.; Nanduri, B. HPIDB 2.0: a curated database for host–pathogen interactions. Database Oxford, 2016. [Epub ahead of print]
[http://dx.doi.org/10.1093/database/baw103] [PMID: 27374121] 
[26] 
Dominguez, C.; Boelens, R.; Bonvin, A.M. HADDOCK: a protein-protein docking approach based on biochemical or biophysical information. J. Am. Chem. Soc.,  2003, 125(7), 1731-1737.
[http://dx.doi.org/10.1021/ja026939x] [PMID: 12580598] 
[27] 
van Zundert, G.C.P.; Rodrigues, J.P.G.L.M.; Trellet, M.; Schmitz, C.; Kastritis, P.L.; Karaca, E.; Melquiond, A.S.J.; van Dijk, M.; de Vries, S.J.; Bonvin, A.M.J.J. The HADDOCK2.2 web server: User-friendly integrative modeling of biomolecular complexes. J. Mol. Biol.,  2016, 428(4), 720-725.
[http://dx.doi.org/10.1016/j.jmb.2015.09.014] [PMID: 26410586] 
[28] 
Nezafat, N.; Ghasemi, Y.; Javadi, G.; Khoshnoud, M.J.; Omidinia, E. A novel multi-epitope peptide vaccine against cancer: an in silico approach. J. Theor. Biol.,  2014, 349, 121-134.
[http://dx.doi.org/10.1016/j.jtbi.2014.01.018] [PMID: 24512916] 
[29] 
Tamura, S.; Funato, H.; Nagamine, T.; Aizawa, C.; Kurata, T. Effectiveness of cholera toxin B subunit as an adjuvant for nasal influenza vaccination despite pre-existing immunity to CTB. Vaccine,  1989, 7(6), 503-505.
[http://dx.doi.org/10.1016/0264-410X(89)90273-9] [PMID: 2609726] 
[30] 
Prabakaran, M.; Velumani, S.; He, F.; Karuppannan, A.K.; Geng, G.Y.; Yin, L.K.; Kwang, J. Protective immunity against influenza H5N1 virus challenge in mice by intranasal co-administration of baculovirus surface-displayed HA and recombinant CTB as an adjuvant. Virology,  2008, 380(2), 412-420.
[http://dx.doi.org/10.1016/j.virol.2008.08.002] [PMID: 18786689] 
[31] 
Bowen, J.C.; Nair, S.K.; Reddy, R.; Rouse, B.T. Cholera toxin acts as a potent adjuvant for the induction of cytotoxic T-lymphocyte responses with non-replicating antigens. Immunology,  1994, 81(3), 338-342.
[PMID: 8206507] 
[32] 
Zhang, Y. I-TASSER server for protein 3D structure prediction. BMC Bioinformatics,  2008, 9(1), 40.
[http://dx.doi.org/10.1186/1471-2105-9-40] [PMID: 18215316] 
[33] 
Zhang, Y. Template-based modeling and free modeling by I-TASSER in CASP7. Proteins,  2007, 69(S8), 108-117.
[http://dx.doi.org/10.1002/prot.21702] [PMID: 17894355] 
[34] 
Bhattacharya, D.; Cheng, J. i3Drefine software for protein 3D structure refinement and its assessment in CASP10. PLoS One,  2013, 8(7), e69648.
[http://dx.doi.org/10.1371/journal.pone.0069648] [PMID: 23894517] 
[35] 
Gopalakrishnan, K.; Sowmiya, G.; Sheik, S.S.; Sekar, K. Ramachandran plot on the web (2.0). Protein Pept. Lett.,  2007, 14(7), 669-671.
[http://dx.doi.org/10.2174/092986607781483912] [PMID: 17897092] 
[36] 
Benkert, P.; Tosatto, S.C.; Schomburg, D. QMEAN: A comprehensive scoring function for model quality assessment. Proteins,  2008, 71(1), 261-277.
[http://dx.doi.org/10.1002/prot.21715] [PMID: 17932912] 
[37] 
Muñoz, J.; Mirelis, B.; Aragón, L.M.; Gutiérrez, N.; Sánchez, F.; Español, M.; Esparcia, O.; Gurguí, M.; Domingo, P.; Coll, P. Clinical and microbiological features of nocardiosis 1997-2003. J. Med. Microbiol.,  2007, 56(Pt 4), 545-550.
[http://dx.doi.org/10.1099/jmm.0.46774-0] [PMID: 17374898] 
[38] 
Forslund, O.; Antonsson, A.; Higgins, G.; Ly, H.; Delius, H.; Hunziker, A.; de Villiers, E.M. Nucleotide sequence and phylogenetic classification of candidate human papilloma virus type 92. Virology,  2003, 312(2), 255-260.
[http://dx.doi.org/10.1016/S0042-6822(03)00391-X] [PMID: 12919731] 
[39] 
Garçon, N.; Chomez, P.; Van Mechelen, M. GlaxoSmithKline Adjuvant Systems in vaccines: concepts, achievements and perspectives. Expert Rev. Vaccines,  2007, 6(5), 723-739.
[http://dx.doi.org/10.1586/14760584.6.5.723] [PMID: 17931153] 
[40] 
Greer, C.E.; Wheeler, C.M.; Ladner, M.B.; Beutner, K.; Coyne, M.Y.; Liang, H.; Langenberg, A.; Yen, T.S.; Ralston, R. Human papillomavirus (HPV) type distribution and serological response to HPV type 6 virus-like particles in patients with genital warts. J. Clin. Microbiol.,  1995, 33(8), 2058-2063.
[http://dx.doi.org/10.1128/JCM.33.8.2058-2063.1995] [PMID: 7559948] 
[41] 
Arbyn, M.; Castellsagué, X.; de Sanjosé, S.; Bruni, L.; Saraiya, M.; Bray, F.; Ferlay, J. Worldwide burden of cervical cancer in 2008. Ann. Oncol.,  2011, 22(12), 2675-2686.
[http://dx.doi.org/10.1093/annonc/mdr015] [PMID: 21471563] 
[42] 
Madrid-Marina, V.; Torres-Poveda, K.; López-Toledo, G.; García-Carrancá, A. Advantages and disadvantages of current prophylactic vaccines against HPV. Arch. Med. Res.,  2009, 40(6), 471-477.
[http://dx.doi.org/10.1016/j.arcmed.2009.08.005] [PMID: 19853187] 
[43] 
Pizza, M.; Scarlato, V.; Masignani, V.; Giuliani, M.M.; Aricò, B.; Comanducci, M.; Jennings, G.T.; Baldi, L.; Bartolini, E.; Capecchi, B.; Galeotti, C.L.; Luzzi, E.; Manetti, R.; Marchetti, E.; Mora, M.; Nuti, S.; Ratti, G.; Santini, L.; Savino, S.; Scarselli, M.; Storni, E.; Zuo, P.; Broeker, M.; Hundt, E.; Knapp, B.; Blair, E.; Mason, T.; Tettelin, H.; Hood, D.W.; Jeffries, A.C.; Saunders, N.J.; Granoff, D.M.; Venter, J.C.; Moxon, E.R.; Grandi, G.; Rappuoli, R. Identification of vaccine candidates against serogroup B meningococcus by whole-genome sequencing. Science,  2000, 287(5459), 1816-1820.
[http://dx.doi.org/10.1126/science.287.5459.1816] [PMID: 10710308] 
[44] 
Petersen, E.; Wilson, M.E.; Touch, S.; McCloskey, B.; Mwaba, P.; Bates, M.; Dar, O.; Mattes, F.; Kidd, M.; Ippolito, G. Rapid spread of Zika virus in the Americas-implications for public health preparedness for mass gatherings at the 2016 Brazil Olympic Games. Int. J. Infect. Dis.,  2016, 44, 11-15.
[http://dx.doi.org/10.1016/j.ijid.2016.02.001] [PMID: 26854199] 
[45] 
Hou, J.; Liu, Y.; Hsi, J.; Wang, H.; Tao, R.; Shao, Y. Cholera toxin B subunit acts as a potent systemic adjuvant for HIV-1 DNA vaccination intramuscularly in mice. Hum. Vaccin. Immunother.,  2014, 10(5), 1274-1283.
[http://dx.doi.org/10.4161/hv.28371] [PMID: 24633335] 

Rights & Permissions Print Cite

Article Metrics

14

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/1570164617999200505095802	Print ISSN 1570-1646
Publisher Name Bentham Science Publisher	Online ISSN 1875-6247

Current Proteomics

Prediction of Prophylactic Peptide Vaccine Candidates for Human Papillomavirus (HPV): Immunoinformatics and Reverse Vaccinology Approaches

Abstract Play Pause

Graphical Abstract

Related Journals

Related Books

Abstract