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  • 1. Immunological databases on the web Ole Lund Center for Biological Sequence Analysis BioCentrum-DTU Technical University of Denmark [email_address]
  • 2. Vaccines have been made for 36 of >400 human pathogens Immunological Bioinformatics , The MIT press . +HPV & Rotavirus
  • 3. Deaths from infectious diseases in the world in 2002 www.who.int/entity/whr/2004/annex/topic/en/annex_2_en.pdf
  • 4. Pathogenic Viruses Data derived from /www.cbs.dtu.dk/databases/Dodo. 1st column: log10 of the number of deaths caused by the pathogen per year 2nd column: DNA Advisory Committee (RAC) classification DNA Advisory Committee guidelines [RAC, 2002] which includes those biological agents known to infect humans, as well as selected animal agents that may pose theoretical risks if inoculated into humans. RAC divides pathogens into four classes. Risk group 1 (RG1). Agents that are not associated with disease in healthy adult humans Risk group 2 (RG2). Agents that are associated with human disease which is rarely serious and for which preventive or therapeutic interventions are often available Risk group 3 (RG3). Agents that are associated with serious or lethal human disease for which preventive or therapeutic interventions may be available (high individual risk but low community risk) Risk group 4 (RG4). Agents that are likely to cause serious or lethal human disease for which preventive or therapeutic interventions are not usually available (high individual risk and high community risk) 3rd column: CDC/NIAID bioterror classification classification of the pathogens according to the Centers for Disease Control and Prevention (CDC) bioterror categories A–C, where category A pathogens are considered the worst bioterror threats 4th column: Vaccines available A letter indicating the type of vaccine if one is available (A: acellular/adsorbet; C: conjugate; I: inactivated; L: live; P: polysaccharide; R: recombinant; S staphage lysate; T: toxoid). Lower case indicates that the vaccine is released as an investigational new drug (IND)). 5th column: G: Complete genome is sequenced
  • 5. Need for new vaccine technologies
    • The classical way of making vaccines have in many cases been tried for the pathogens for which no vaccines exist
    • Need for new ways for making vaccines
  • 6. Databases Used for Vaccine Design
    • Sequence databases
      • General
      • Sequences of proteins of the immune system
    • Epitope databases
    • Pathogen centered databases
      • HIV
      • mTB
      • Malaria
  • 7. Sequence Databases
    • Used to study sequence variability of microbes
      • Sequence conservation
      • Positive/negative selection
    • Examples
      • Swissprot http://expasy.org/sprot/
      • GenBank http://www.ncbi.nlm.nih.gov/Genbank/
  • 8. MHC Class I pathway Figure by Eric A.J. Reits
  • 9. The binding of an immunodominant 9-mer Vaccinia CTL epitope, HRP2 (KVDDTFYYV) to HLA-A*0201. Position 2 and 9 of the epitopes are buried deeply in the HLA class I molecule. Figure by Anne Mølgaard, peptide (KVDDTFYYV) used as vaccine by Snyder et al. J Virol 78, 7052-60 (2004).
  • 10. Expression of HLA is codominant
  • 11. Polymorphism and polygeny
  • 12. The MHC gene region http://www.ncbi.nlm.nih.gov/mhc/MHC.fcgi?cmd=init&user_id=0&probe_id=0&source_id=0&locus_id=0&locus_group=0&proto_id=0&banner=1&kit_id=0&graphview=0
  • 13. Human Leukocyte antigen (HLA=MHC in humans) polymorphism - alleles http://www.anthonynolan.com/HIG/index.html
  • 14. Logos of HLA-A alleles   O Lund et al., Immunogenetics. 2004 55:797-810
  • 15. Clustering of HLA alleles   O Lund et al., Immunogenetics. 2004 55:797-810
  • 16. Databases of Sequences of Proteins of Immune system
    • Used to study variability of the human genome
    • Anthony Nolan Database (IMGT/HLA sequences)
      • http:// www.anthonynolan.com/HIG/
    • IMmunoGeneTics HLA (IMGT/HLA) database
      • Sequences of HLA, antibody and other molecules
      • http://imgt.cines.fr/
    • dbMHC
      • Clinical data and sequences related to the immune system
      • http:// www.ncbi.nlm.nih.gov/gv/mhc/main.cgi?cmd =init
  • 17.  2 m Heavy chain peptide Determination of peptide-HLA binding Step I: Folding of MHC class I molecules in solution Step II: Detection of de novo folded MHC class I molecules by ELISA C Sylvester-Hvid et al., Tissue Antigens. 2002 59:251-8 Development Incubation Peptide-MHC complex
  • 18. HLA Binding Results
    • 1215 peptides received
    • 1114 tested for binding
    • 827 (74%) bind with K D better than 500nM
    • 484 (43%) bind with K D better han 50 nM
    KDPathogen Influenza Marburg Pox F. tularensis Dengue Hantaan Lassa West Nile Yellow Fever K D <50 42 45 97 45 67 59 27 52 50 50<K D <500 63 39 42 21 44 20 21 41 52 K D >500 87 29 38 6 30 11 22 29 35 in progress 9 1 1 4 6 4 12 31 33 Total 201 114 178 76 147 94 82 153 170 Søren Buus Lab
  • 19. ELISPOT assay
    • Measure number of white blood cells that in vitro produce interferon-  in response to a peptide
    • A positive result means that the immune system has earlier reacted to the peptide (during a response to a vaccine/natural infection)
    SLFNTVATL SLFNTVATL SLFNTVATL SLFNTVATL SLFNTVATL SLFNTVATL Two spots
  • 20. Influenza Peptides positive in ELISPOT Mingjun Wang et al., submitted
  • 21. Peters B, et al. Immunogenetics. 2005 57:326-36, PLoS Biol. 2005 3:e91.
  • 22. Epitope Databases
    • Used to find regions that can be recognized by the immune system
    • General Epitope Databases
      • IEDB General epitope database
        • http://immuneepitope.org/home.do
      • AntiJen (MHC Ligand, TCR-MHC Complexes, T Cell Epitope, TAP , B Cell Epitope molecules and immunological Protein-Protein interactions)
        • http://www.jenner.ac.uk/AntiJen/
      • FIMM (MHC, antigens, epitopes, and diseases)
        • http://research.i2r.a-star.edu.sg/fimm/
  • 23. More Epitope Databases
    • SYFPEITHI
      • Natural ligands: sequences of peptides eluded from MHC molecules on the surface of cells
      • http://www.syfpeithi.de/
    • MHCBN: Immune related databases and predictors
      • http:// www.imtech.res.in/raghava/mhcbn /
      • http:// bioinformatics.uams.edu/mirror/mhcbn /
    • HLA Ligand/Motif Database: Discontinued
    • MHCPep: Static since 1998, replaced by FIMM
  • 24. Prediction of HLA binding
    • Many methods available, including:
      • bimas, syfpeithi, Hlaligand, libscore, mapppB, mapppS,mhcpred, netmhc, pepdist, predbalbc, predep, rankpep, svmhc
    • See links at:
      • http://immuneepitope.org/hyperlinks.do?dispatch=loadLinks
    • Recent benchmark:
      • http://mhcbindingpredictions.immuneepitope.org/internal_allele.html
  • 25. B cell Epitope Databases
    • Linear
      • IEDB, Bcipep, Jenner, FIMM, BepiPred
      • HIV specific database
        • http:// www.hiv.lanl.gov/content/immunology/ab_search
    • Conformational
      • CED: Conformational B cell epitopes
        • http://web.kuicr.kyoto-u.ac.jp/~ced/
  • 26. MHC class II pathway Figure by Eric A.J. Reits
  • 27. Pathogen Centered Databases
    • HIV
      • http://www.hiv.lanl.gov/content/index
    • Influenza
      • http://www.flu.lanl.gov/
    • Tuberculosis
      • http://www.sanger.ac.uk/Projects/M_tuberculosis/
    • POX
      • http://www.poxvirus.org/
  • 28. Reviews
      • Tong JC, Tan TW, Ranganathan S. Methods and protocols for prediction of immunogenic epitopes. Brief Bioinform. 2006 Oct 31
      • Web based Tools for Vaccine Design (Lund et al, 2002)
        • http://www.cbs.dtu.dk/researchgroups/immunology/webreview.html
  • 29. Other Resources
    • Gene expression data
    • Localization prediction
      • SignalP
  • 30. Immunological resources at CBS
    • Web servers
    • CTL epitopes
    • http://www.cbs.dtu.dk/services/NetCTL/
      • MHC binding
        • http://www.cbs.dtu.dk/services/NetMHC/
        • http://www.cbs.dtu.dk/services/NetMHCII/
        • http://www.cbs.dtu.dk/services/NetMHCpan/
        • Proteasome processing
        • http://www.cbs.dtu.dk/services/NetChop-3.0/
        • B-cell epitopes
        • http://www.cbs.dtu.dk/services/BepiPred/
        • http://www.cbs.dtu.dk/services/DiscoTope/
        • Plotting of epitopes relative to reference sequence
        • http://www.cbs.dtu.dk/services/EpiPlot-1.0/
    • Analysis of human immunoglobulin VDJ recombination
    • http://www.cbs.dtu.dk/services/VDJsolver/
    • Geno-pheno type association based mapping of binding sites
    • http://www.cbs.dtu.dk/services/SigniSite/
    • PhD/master course in Immunological Bioinformatics, June, 2008
      • http://www.cbs.dtu.dk/courses/27685.imm/
  • 31. Other Predictions at CBS
    • Training matrix and neural network methods
    • Training of Gibbs sampler
  • 32. Links to links
    • IEDB’s Links
      • http://immuneepitope.org/hyperlinks.do?dispatch=loadLinks