Towards in silico design of epitope-based vaccines

Background: Epitope-based vaccines (EVs) make use of immunogenic peptides (epitopes) to trigger an immune response. Due to their manifold advantages, EVs have recently been attracting growing interest. The success of an EV is determined by the choice of epitopes used as a basis. However, the experimental discovery of candidate epitopes is expensive in terms of time and money. Furthermore, for the final choice of epitopes various immunological requirements have to be considered. Methods: Numerous in silico approaches exist that can guide the design of EVs. In particular, computational methods for MHC binding prediction have already become standard tools in immunology. Apart from binding prediction and prediction of antigen processing, methods for epitope design and selection have been suggested. We review these in silico approaches for epitope discovery and selection along with their strengths and weaknesses. Finally, we discuss some of the obvious problems in the design of EVs. Conclusion: State-of-the-art in silico approaches to MHC binding prediction yield high accuracies. However, a more thorough understanding of the underlying biological processes and significant amounts of experimental data will be required for the validation and improvement of in silico approaches to the remaining aspects of EV design.

[1]  M. Lefranc IMGT, the International ImMunoGeneTics Information System. , 2011, Cold Spring Harbor protocols.

[2]  James Robinson,et al.  IPD—the Immuno Polymorphism Database , 2004, Nucleic acids research.

[3]  Oliver Kohlbacher,et al.  OptiTope—a web server for the selection of an optimal set of peptides for epitope-based vaccines , 2009, Nucleic Acids Res..

[4]  Morten Nielsen,et al.  The PickPocket method for predicting binding specificities for receptors based on receptor pocket similarities: application to MHC-peptide binding , 2009, Bioinform..

[5]  Morten Nielsen,et al.  Pan-specific MHC class I predictors: a benchmark of HLA class I pan-specific prediction methods , 2009, Bioinform..

[6]  B. Korber,et al.  Expanded Breadth of the T-Cell Response to Mosaic Human Immunodeficiency Virus Type 1 Envelope DNA Vaccination , 2008, Journal of Virology.

[7]  Vladimir Brusic,et al.  Evaluation of MHC-II peptide binding prediction servers: applications for vaccine research , 2008, BMC Bioinformatics.

[8]  Oliver Kohlbacher,et al.  A Mathematical Framework for the Selection of an Optimal Set of Peptides for Epitope-Based Vaccines , 2008, PLoS Comput. Biol..

[9]  Gunnar Rätsch,et al.  Support Vector Machines and Kernels for Computational Biology , 2008, PLoS Comput. Biol..

[10]  Nebojsa Jojic,et al.  Shift-Invariant Adaptive Double Threading: Learning MHC II - Peptide Binding , 2007, RECOMB.

[11]  Morten Nielsen,et al.  Quantitative Predictions of Peptide Binding to Any HLA-DR Molecule of Known Sequence: NetMHCIIpan , 2008, PLoS Comput. Biol..

[12]  Morten Nielsen,et al.  Accurate approximation method for prediction of class I MHC affinities for peptides of length 8, 10 and 11 using prediction tools trained on 9mers , 2008, Bioinform..

[13]  C. Slingluff,et al.  A Multipeptide Vaccine is Safe and Elicits T-cell Responses in Participants With Advanced Stage Ovarian Cancer , 2008, Journal of immunotherapy.

[14]  Oliver Kohlbacher,et al.  EpiToolKit—a web server for computational immunomics , 2008, Nucleic Acids Res..

[15]  Hermann-Georg Holzhütter,et al.  Modeling the in vitro 20S proteasome activity: the effect of PA28-alphabeta and of the sequence and length of polypeptides on the degradation kinetics. , 2008, Journal of molecular biology.

[16]  John Sidney,et al.  A Systematic Assessment of MHC Class II Peptide Binding Predictions and Evaluation of a Consensus Approach , 2008, PLoS Comput. Biol..

[17]  Yoram Louzoun,et al.  Precise score for the prediction of peptides cleaved by the proteasome , 2008, Bioinform..

[18]  Jean-Philippe Vert,et al.  Efficient peptide-MHC-I binding prediction for alleles with few known binders , 2008, Bioinform..

[19]  S. H. van der Burg,et al.  Phase I Immunotherapeutic Trial with Long Peptides Spanning the E6 and E7 Sequences of High-Risk Human Papillomavirus 16 in End-Stage Cervical Cancer Patients Shows Low Toxicity and Robust Immunogenicity , 2008, Clinical Cancer Research.

[20]  O. Lund,et al.  NetMHCpan, a method for MHC class I binding prediction beyond humans , 2008, Immunogenetics.

[21]  V. Brusic,et al.  Evaluation of MHC class I peptide binding prediction servers: Applications for vaccine research , 2008, BMC Immunology.

[22]  Morten Nielsen,et al.  Modeling the adaptive immune system: predictions and simulations , 2007, Bioinform..

[23]  C. Slingluff,et al.  Immunologic and Clinical Outcomes of a Randomized Phase II Trial of Two Multipeptide Vaccines for Melanoma in the Adjuvant Setting , 2007, Clinical Cancer Research.

[24]  Morten Nielsen,et al.  Large-scale validation of methods for cytotoxic T-lymphocyte epitope prediction , 2007, BMC Bioinformatics.

[25]  O. Lund,et al.  NetMHCpan, a Method for Quantitative Predictions of Peptide Binding to Any HLA-A and -B Locus Protein of Known Sequence , 2007, PloS one.

[26]  J. Wolchok,et al.  Immunological validation of the EpitOptimizer program for streamlined design of heteroclitic epitopes. , 2007, Vaccine.

[27]  Morten Nielsen,et al.  Prediction of MHC class II binding affinity using SMM-align, a novel stabilization matrix alignment method , 2007, BMC Bioinformatics.

[28]  Gary Dubin,et al.  Phase I/II studies to evaluate safety and immunogenicity of a recombinant gp350 Epstein-Barr virus vaccine in healthy adults. , 2007, Vaccine.

[29]  James McCluskey,et al.  More than one reason to rethink the use of peptides in vaccine design , 2007, Nature Reviews Drug Discovery.

[30]  Shinn-Ying Ho,et al.  POPI: predicting immunogenicity of MHC class I binding peptides by mining informative physicochemical properties , 2007, Bioinform..

[31]  Gajendra P.S. Raghava,et al.  A hybrid approach for predicting promiscuous MHC class I restricted T cell epitopes , 2007, Journal of Biosciences.

[32]  David Heckerman,et al.  Coping with Viral Diversity in HIV Vaccine Design , 2007, PLoS Comput. Biol..

[33]  Anthony Kusalik,et al.  Strength in numbers: achieving greater accuracy in MHC-I binding prediction by combining the results from multiple prediction tools , 2007, Immunome research.

[34]  N. Marchand-Geneste,et al.  Synthetic anticancer vaccine candidates: rational design of antigenic peptide mimetics that activate tumor-specific T-cells. , 2007, Journal of medicinal chemistry.

[35]  Avner Schlessinger,et al.  Towards a consensus on datasets and evaluation metrics for developing B‐cell epitope prediction tools , 2007, Journal of molecular recognition : JMR.

[36]  Y. Z. Chen,et al.  Prediction of MHC-binding peptides of flexible lengths from sequence-derived structural and physicochemical properties. , 2007, Molecular immunology.

[37]  Yoram Louzoun,et al.  Virus-epitope vaccine design: informatic matching the HLA-I polymorphism to the virus genome. , 2007, Molecular immunology.

[38]  Guido Ferrari,et al.  Durable HIV-1 antibody and T-cell responses elicited by an adjuvanted multi-protein recombinant vaccine in uninfected human volunteers. , 2007, Vaccine.

[39]  James Theiler,et al.  Polyvalent vaccines for optimal coverage of potential T-cell epitopes in global HIV-1 variants , 2007, Nature Medicine.

[40]  D. DeLuca,et al.  A modular concept of HLA for comprehensive peptide binding prediction , 2006, Immunogenetics.

[41]  Ji Wan,et al.  SVRMHC prediction server for MHC-binding peptides , 2006, BMC Bioinformatics.

[42]  Z. Cao,et al.  MHC-BPS: MHC-binder prediction server for identifying peptides of flexible lengths from sequence-derived physicochemical properties , 2006, Immunogenetics.

[43]  Ora Schueler-Furman,et al.  Learning MHC I - peptide binding , 2006, ISMB.

[44]  Oliver Kohlbacher,et al.  SVMHC: a server for prediction of MHC-binding peptides , 2006, Nucleic Acids Res..

[45]  N. Senzer,et al.  Phase I Trial of sequential administration of recombinant DNA and adenovirus expressing L523S protein in early stage non-small-cell lung cancer. , 2006, Molecular therapy : the journal of the American Society of Gene Therapy.

[46]  Chee Keong Kwoh,et al.  PREDTAP: a system for prediction of peptide binding to the human transporter associated with antigen processing , 2006, Immunome research.

[47]  Christian Bréchot,et al.  Immunogenicity of a hepatitis B DNA vaccine administered to chronic HBV carriers. , 2006, Vaccine.

[48]  Morten Nielsen,et al.  A Community Resource Benchmarking Predictions of Peptide Binding to MHC-I Molecules , 2006, PLoS Comput. Biol..

[49]  John Sidney,et al.  Improving MHC binding peptide prediction by incorporating binding data of auxiliary MHC molecules , 2006, Bioinform..

[50]  David Heckerman,et al.  Leveraging Information Across HLA Alleles/Supertypes Improves Epitope Prediction , 2006, RECOMB.

[51]  Tomer Hertz,et al.  PepDist: A New Framework for Protein-Peptide Binding Prediction based on Learning Peptide Distance Functions , 2006, BMC Bioinformatics.

[52]  Channa K. Hattotuwagama,et al.  MHCPred 2.0 , 2006 .

[53]  Channa K. Hattotuwagama,et al.  MHCPred 2.0: an updated quantitative T-cell epitope prediction server. , 2006, Applied bioinformatics.

[54]  Pingping Guan,et al.  EpiJen: a server for multistep T cell epitope prediction , 2006, BMC Bioinformatics.

[55]  Yang Dai,et al.  Prediction of MHC class II binding peptides based on an iterative learning model , 2005, Immunome research.

[56]  Oliver Kohlbacher,et al.  SNEP: SNP-derived Epitope Prediction program for minor H antigens , 2005, Immunogenetics.

[57]  Channa K. Hattotuwagama,et al.  AntiJen: a quantitative immunology database integrating functional, thermodynamic, kinetic, biophysical, and cellular data , 2005, Immunome research.

[58]  P. Dönnes,et al.  Integrated modeling of the major events in the MHC class I antigen processing pathway , 2005, Protein science : a publication of the Protein Society.

[59]  O. Lund,et al.  An integrative approach to CTL epitope prediction: A combined algorithm integrating MHC class I binding, TAP transport efficiency, and proteasomal cleavage predictions , 2005, European journal of immunology.

[60]  Gajendra P. S. Raghava,et al.  Pcleavage: an SVM based method for prediction of constitutive proteasome and immunoproteasome cleavage sites in antigenic sequences , 2005, Nucleic Acids Res..

[61]  Tomer Hertz,et al.  Predicting Protein-Peptide Binding Affinity by Learning Peptide-Peptide Distance Functions , 2005, RECOMB.

[62]  Bjoern Peters,et al.  Automated generation and evaluation of specific MHC binding predictive tools: ARB matrix applications , 2005, Immunogenetics.

[63]  P. Kloetzel,et al.  Modeling the MHC class I pathway by combining predictions of proteasomal cleavage,TAP transport and MHC class I binding , 2005, Cellular and Molecular Life Sciences CMLS.

[64]  Anne S De Groot,et al.  HIV vaccine development by computer assisted design: the GAIA vaccine. , 2005, Vaccine.

[65]  O. Lund,et al.  The role of the proteasome in generating cytotoxic T-cell epitopes: insights obtained from improved predictions of proteasomal cleavage , 2005, Immunogenetics.

[66]  Jérôme Lane,et al.  IMGT®, the international ImMunoGeneTics information system® , 2004, Nucleic Acids Res..

[67]  Steve Wilson,et al.  The Immune Epitope Database and Analysis Resource: From Vision to Blueprint , 2005, PLoS biology.

[68]  O. Lund,et al.  The Immune Epitope Database and Analysis Resource: From Vision to Blueprint , 2005, PLoS biology.

[69]  S. Holmes,et al.  Diversity and Recognition Efficiency of T Cell Responses to Cancer , 2004, PLoS medicine.

[70]  Ellis L. Reinherz,et al.  Enhancement to the RANKPEP resource for the prediction of peptide binding to MHC molecules using profiles , 2004, Immunogenetics.

[71]  Gajendra P.S. Raghava,et al.  Prediction of CTL epitopes using QM, SVM and ANN techniques. , 2004, Vaccine.

[72]  Richard Simon,et al.  Genomewide Conserved Epitope Profiles of HIV-1 Predicted by Biophysical Properties of MHC Binding Peptides , 2004, J. Comput. Biol..

[73]  H. Rammensee,et al.  The Tübingen approach: identification, selection and validation of tumor-associated HLA peptides for cancer therapy , 2004, Cancer Cell International.

[74]  Darren R Flower,et al.  Coupling In Silico and In Vitro Analysis of Peptide-MHC Binding: A Bioinformatic Approach Enabling Prediction of Superbinding Peptides and Anchorless Epitopes , 2004, The Journal of Immunology.

[75]  Søren Brunak,et al.  Improved prediction of MHC class I and class II epitopes using a novel Gibbs sampling approach , 2004, Bioinform..

[76]  J. Sidney,et al.  Improved Immunogenicity of an Immunodominant Epitope of the Her-2/neu Protooncogene by Alterations of MHC Contact Residues1 , 2004, The Journal of Immunology.

[77]  Manoj Bhasin,et al.  Analysis and prediction of affinity of TAP binding peptides using cascade SVM , 2004, Protein science : a publication of the Protein Society.

[78]  O. Lund,et al.  Definition of supertypes for HLA molecules using clustering of specificity matrices , 2004, Immunogenetics.

[79]  Gajendra P. S. Raghava,et al.  SVM based method for predicting HLA-DRB1*0401 binding peptides in an antigen sequence , 2004, Bioinform..

[80]  P. Opolon,et al.  High vaccination efficiency of low-affinity epitopes in antitumor immunotherapy. , 2004, The Journal of clinical investigation.

[81]  Marie-Paule Lefranc,et al.  IMGT/3Dstructure-DB and IMGT/StructuralQuery, a database and a tool for immunoglobulin, T cell receptor and MHC structural data , 2004, Nucleic Acids Res..

[82]  Irini A. Doytchinova,et al.  Towards the in silico identification of class II restricted T-cell epitopes: a partial least squares iterative self-consistent algorithm for affinity prediction , 2003, Bioinform..

[83]  S Brunak,et al.  Sensitive quantitative predictions of peptide-MHC binding by a 'Query by Committee' artificial neural network approach. , 2003, Tissue antigens.

[84]  John Sidney,et al.  Examining the independent binding assumption for binding of peptide epitopes to MHC-I molecules , 2003, Bioinform..

[85]  Ryuji Kato,et al.  Hidden Markov model-based approach as the first screening of binding peptides that interact with MHC class II molecules , 2003 .

[86]  Claude Beazley,et al.  A Novel Predictive Technique for the MHC Class II Peptide-Binding Interaction , 2003, Molecular medicine.

[87]  Bjoern Peters,et al.  Identifying MHC Class I Epitopes by Predicting the TAP Transport Efficiency of Epitope Precursors , 2003, The Journal of Immunology.

[88]  A. Sette,et al.  Epitope-based vaccines: an update on epitope identification, vaccine design and delivery. , 2003, Current opinion in immunology.

[89]  Manoj Bhasin,et al.  Prediction of promiscuous and high-affinity mutated MHC binders. , 2003, Hybridoma and hybridomics.

[90]  Pingping Guan,et al.  MHCPred: a server for quantitative prediction of peptide-MHC binding , 2003, Nucleic Acids Res..

[91]  Gajendra P. S. Raghava,et al.  ProPred1: Prediction of Promiscuous MHC Class-I Binding Sites , 2003, Bioinform..

[92]  O. Lund,et al.  novel sequence representations Reliable prediction of T-cell epitopes using neural networks with , 2003 .

[93]  Gajendra P. S. Raghava,et al.  MHCBN: a comprehensive database of MHC binding and non-binding peptides , 2003, Bioinform..

[94]  P. Kloetzel,et al.  MAPPP: MHC class I antigenic peptide processing prediction. , 2003, Applied bioinformatics.

[95]  Naoki Abe,et al.  Empirical Evaluation of a Dynamic Experiment Design Method for Prediction of MHC Class I-Binding Peptides1 , 2002, The Journal of Immunology.

[96]  Arne Elofsson,et al.  Prediction of MHC class I binding peptides, using SVMHC , 2002, BMC Bioinformatics.

[97]  E. Reinherz,et al.  Prediction of MHC class I binding peptides using profile motifs. , 2002, Human immunology.

[98]  T. Hanai,et al.  Hidden Markov model-based prediction of antigenic peptides that interact with MHC class II molecules. , 2002, Journal of bioscience and bioengineering.

[99]  Yao-Tseng Chen,et al.  CD8+ T cell responses against a dominant cryptic HLA-A2 epitope after NY-ESO-1 peptide immunization of cancer patients , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[100]  Vladimir Brusic,et al.  Prediction of promiscuous peptides that bind HLA class I molecules , 2002, Immunology and cell biology.

[101]  D. Flower,et al.  Additive method for the prediction of protein-peptide binding affinity. Application to the MHC class I molecule HLA-A*0201. , 2002, Journal of proteome research.

[102]  S. Brunak,et al.  Prediction of proteasome cleavage motifs by neural networks. , 2002, Protein engineering.

[103]  Pierre Baldi,et al.  Bioinformatics - the machine learning approach (2. ed.) , 2000 .

[104]  Trevor Hastie,et al.  The Elements of Statistical Learning , 2001 .

[105]  Gajendra P. S. Raghava,et al.  ProPred: prediction of HLA-DR binding sites , 2001, Bioinform..

[106]  R. R. Mallios,et al.  Predicting class II MHC/peptide multi-level binding with an iterative stepwise discriminant analysis meta-algorithm , 2001, Bioinform..

[107]  John Sidney,et al.  Structural Features of Peptide Analogs of Human Histocompatibility Leukocyte Antigen Class I Epitopes That Are More Potent and Immunogenic than Wild-Type Peptide , 2001, The Journal of experimental medicine.

[108]  G. Jung,et al.  From combinatorial libraries to MHC ligand motifs, T-cell superagonists and antagonists. , 2001, Biologicals : journal of the International Association of Biological Standardization.

[109]  Maria V. Tejada-Simon,et al.  Naturally Processed HLA Class II Peptides Reveal Highly Conserved Immunogenic Flanking Region Sequence Preferences That Reflect Antigen Processing Rather Than Peptide-MHC Interactions1 , 2001, The Journal of Immunology.

[110]  K. Hadeler,et al.  PAProC: a prediction algorithm for proteasomal cleavages available on the WWW , 2001, Immunogenetics.

[111]  Ferry Ossendorp,et al.  Efficient Identification of Novel Hla-A*0201–Presented Cytotoxic T Lymphocyte Epitopes in the Widely Expressed Tumor Antigen Prame by Proteasome-Mediated Digestion Analysis , 2001, The Journal of experimental medicine.

[112]  P. Kloetzel,et al.  A kinetic model of vertebrate 20S proteasome accounting for the generation of major proteolytic fragments from oligomeric peptide substrates. , 2000, Biophysical journal.

[113]  Hans-Georg Rammensee,et al.  Erratum: An algorithm for the prediction of proteasomal cleavages (Journal of Molecular Biology (2000) 298 (417-427)) , 2000 .

[114]  Cécile Gouttefangeas,et al.  Identification of tumor‐associated MHC class I ligands by a novel T cell‐independent approach , 2000, European journal of immunology.

[115]  O. Schueler‐Furman,et al.  Structure‐based prediction of binding peptides to MHC class I molecules: Application to a broad range of MHC alleles , 2000, Protein science : a publication of the Protein Society.

[116]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..

[117]  D. Rognan,et al.  Predicting binding affinities of protein ligands from three-dimensional models: application to peptide binding to class I major histocompatibility proteins. , 1999, Journal of medicinal chemistry.

[118]  J. Sidney,et al.  Nine major HLA class I supertypes account for the vast preponderance of HLA-A and -B polymorphism , 1999, Immunogenetics.

[119]  H. Rammensee,et al.  SYFPEITHI: database for MHC ligands and peptide motifs , 1999, Immunogenetics.

[120]  R. Orlando,et al.  A new liquid chromatography/tandem mass spectrometric approach for the identification of class I major histocompatibility complex associated peptides that eliminates the need for bioassays. , 1999, Rapid communications in mass spectrometry : RCM.

[121]  U. Şahin,et al.  Generation of tissue-specific and promiscuous HLA ligand databases using DNA microarrays and virtual HLA class II matrices , 1999, Nature Biotechnology.

[122]  P. Kloetzel,et al.  A theoretical approach towards the identification of cleavage-determining amino acid motifs of the 20 S proteasome. , 1999, Journal of molecular biology.

[123]  H Mamitsuka,et al.  Predicting peptides that bind to MHC molecules using supervised learning of hidden markov models , 1998, Proteins.

[124]  Jonathan J. Lewis,et al.  Heteroclitic Immunization Induces Tumor Immunity , 1998, The Journal of experimental medicine.

[125]  A. D. De Groot,et al.  Prediction of well-conserved HIV-1 ligands using a matrix-based algorithm, EpiMatrix. , 1998, Vaccine.

[126]  V Brusic,et al.  Relationship between peptide selectivities of human transporters associated with antigen processing and HLA class I molecules. , 1998, Journal of immunology.

[127]  M F del Guercio,et al.  Several common HLA-DR types share largely overlapping peptide binding repertoires. , 1998, Journal of immunology.

[128]  Vladimir Brusic,et al.  Prediction of MHC class II-binding peptides using an evolutionary algorithm and artificial neural network , 1998, Bioinform..

[129]  Vladimir Brusic,et al.  A neural network model approach to the study of human TAP transporter , 1998, Silico Biol..

[130]  Vladimir Brusic,et al.  MHCPEP, a database of MHC-binding peptides: update 1996 , 1997, Nucleic Acids Res..

[131]  Søren Buus,et al.  Peptide binding specificity of major histocompatibility complex class I resolved into an array of apparently independent subspecificities: quantitation by peptide libraries and improved prediction of binding , 1996, European journal of immunology.

[132]  M. V. Regenmortel,et al.  Mapping Epitope Structure and Activity: From One-Dimensional Prediction to Four-Dimensional Description of Antigenic Specificity , 1996 .

[133]  A Sette,et al.  The peptide-binding motif for the human transporter associated with antigen processing , 1995, The Journal of experimental medicine.

[134]  P. Kloetzel,et al.  The cleavage preference of the proteasome governs the yield of antigenic peptides , 1995, The Journal of experimental medicine.

[135]  J. Berzofsky,et al.  Two novel T cell epitope prediction algorithms based on MHC-binding motifs; comparison of predicted and published epitopes from Mycobacterium tuberculosis and HIV protein sequences. , 1995, Vaccine.

[136]  J A Koziol,et al.  Prediction of binding to MHC class I molecules. , 1995, Journal of immunological methods.

[137]  A. Vitiello,et al.  The relationship between class I binding affinity and immunogenicity of potential cytotoxic T cell epitopes. , 1994, Journal of immunology.

[138]  Z. Nagy,et al.  Precise prediction of major histocompatibility complex class II-peptide interaction based on peptide side chain scanning , 1994, The Journal of experimental medicine.

[139]  D. Zaller,et al.  Prediction of peptide affinity to HLA DRB1*0401. , 1994, International archives of allergy and immunology.

[140]  K. Parker,et al.  Scheme for ranking potential HLA-A2 binding peptides based on independent binding of individual peptide side-chains. , 1994, Journal of immunology.

[141]  Peter Walden,et al.  Exact prediction of a natural T cell epitope , 1991, European journal of immunology.

[142]  H. Rammensee,et al.  Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules , 1991, Nature.