title: Development and validation of an epitope prediction tool for swine (PigMatrix) based on the pocket profile method.
abstract: BACKGROUND
  T cell epitope prediction tools and associated vaccine design algorithms have accelerated the development of vaccines for humans. Predictive tools for swine and other food animals are not as well developed, primarily because the data required to develop the tools are lacking. Here, we overcome a lack of T cell epitope data to construct swine epitope predictors by systematically leveraging available human information. Applying the "pocket profile method", we use sequence and structural similarities in the binding pockets of human and swine major histocompatibility complex proteins to infer Swine Leukocyte Antigen (SLA) peptide binding preferences. We developed epitope-prediction matrices (PigMatrices), for three SLA class I alleles (SLA-1*0401, 2*0401 and 3*0401) and one class II allele (SLA-DRB1*0201), based on the binding preferences of the best-matched Human Leukocyte Antigen (HLA) pocket for each SLA pocket. The contact residues involved in the binding pockets were defined for class I based on crystal structures of either SLA (SLA-specific contacts, Ssc) or HLA supertype alleles (HLA contacts, Hc); for class II, only Hc was possible. Different substitution matrices were evaluated (PAM and BLOSUM) for scoring pocket similarity and identifying the best human match. The accuracy of the PigMatrices was compared to available online swine epitope prediction tools such as PickPocket and NetMHCpan.
  
  
  RESULTS
  PigMatrices that used Ssc to define the pocket sequences and PAM30 to score pocket similarity demonstrated the best predictive performance and were able to accurately separate binders from random peptides. For SLA-1*0401 and 2*0401, PigMatrix achieved area under the receiver operating characteristic curves (AUC) of 0.78 and 0.73, respectively, which were equivalent or better than PickPocket (0.76 and 0.54) and NetMHCpan version 2.4 (0.41 and 0.51) and version 2.8 (0.72 and 0.71). In addition, we developed the first predictive SLA class II matrix, obtaining an AUC of 0.73 for existing SLA-DRB1*0201 epitopes. Notably, PigMatrix achieved this level of predictive power without training on SLA binding data.
  
  
  CONCLUSIONS
  Overall, the pocket profile method combined with binding preferences from HLA binding data shows significant promise for developing T cell epitope prediction tools for pigs. When combined with existing vaccine design algorithms, PigMatrix will be useful for developing genome-derived vaccines for a range of pig pathogens for which no effective vaccines currently exist (e.g. porcine reproductive and respiratory syndrome, influenza and porcine epidemic diarrhea).
authors.affiliation: Institute for Immunology and Informatics, CMB/CELS, University of Rhode Island, Providence, RI, 02903, USA. anunez.uri@gmail.com.
authors.forename: Andres H
authors.initials: AH
authors.lastname: Gutiérrez
authors.affiliation: EpiVax, Inc., Providence, RI, 02860, USA. martinb@epivax.com.
authors.forename: William D
authors.initials: WD
authors.lastname: Martin
authors.affiliation: Department of Computer Science, Dartmouth College, Hanover, NH, 03755, USA. cbk@cs.dartmouth.edu.
authors.forename: Chris
authors.initials: C
authors.lastname: Bailey-Kellogg
authors.affiliation: EpiVax, Inc., Providence, RI, 02860, USA. fterry@epivax.com.
authors.forename: Frances
authors.initials: F
authors.lastname: Terry
authors.affiliation: Institute for Immunology and Informatics, CMB/CELS, University of Rhode Island, Providence, RI, 02903, USA. lmoise@epivax.com.|EpiVax, Inc., Providence, RI, 02860, USA. lmoise@epivax.com.
authors.forename: Leonard
authors.initials: L
authors.lastname: Moise
authors.affiliation: Institute for Immunology and Informatics, CMB/CELS, University of Rhode Island, Providence, RI, 02903, USA. dr.annie.degroot@gmail.com.|EpiVax, Inc., Providence, RI, 02860, USA. dr.annie.degroot@gmail.com.
authors.forename: Anne S
authors.initials: AS
authors.lastname: De Groot
mesh_terms: D000465:Algorithms; D000483:Alleles; D000818:Animals; D020134:Catalytic Domain; D019295:Computational Biology / Q000379:methods*; D018604:Epitope Mapping / Q000379:methods*; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D008962:Models, Theoretical; D062105:Molecular Docking Simulation; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D012372:ROC Curve; D013552:Swine; D014612:Vaccines / Q000276:immunology
chemical_list: D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D010446:Peptide Fragments; D014612:Vaccines; C438668:swine leukocyte antigen