title: Development and preliminary clinical evaluation of a peptide immunotherapy vaccine for cat allergy.
abstract: BACKGROUND
  Allergic sensitization to cat allergens is common and represents a major risk factor for asthma. Specific immunotherapy (SIT) is effective but cumbersome and associated with IgE-dependent adverse events. Immunotherapy targeting allergen-specific T cells, with synthetic peptides representing T-cell epitopes, might improve safety and reduce the duration of treatment.
  
  
  OBJECTIVE
  We sought to define major T-cell epitopes of Fel d 1 for peptide immunotherapy, generate a peptide vaccine, and evaluate its safety and tolerability in subjects with cat allergy.
  
  
  METHODS
  We determined the binding affinities of Fel d 1 peptides for 10 commonly expressed HLA-DR molecules. Functionally immunodominant peptides were identified by means of proliferation and cytokine secretion. Histamine-releasing activity was assessed, and a peptide vaccine was formulated. Safety and tolerability were evaluated in a dose-ranging phase IIa clinical trial.
  
  
  RESULTS
  MHC-binding sequences were identified throughout Fel d 1. Some regions contained multiple overlapping T-cell epitopes that bound multiple MHC molecules. Immunodominant sequences were identified on the basis of proliferative and cytokine (IFN-γ, IL-10, and IL-13) responses. Cat allergen extract, but not peptides, induced histamine release in blood basophils. A single administration of peptide vaccine was safe and well tolerated. The dose of vaccine resulting in the greatest inhibition of the late-phase skin response to intradermal whole allergen challenge was 3 nmol.
  
  
  CONCLUSIONS
  Fel d 1 contains multiple overlapping MHC-binding motifs. A peptide vaccine comprising the immunodominant regions of the allergen was safe and well tolerated when given to subjects with cat allergy as a single dose. The dose of vaccine resulting in the greatest reduction in late-phase skin response was defined for future clinical development.
authors.affiliation: Department of Dermatology, Venerology and Allergology, Charité Universitätsmedizin, Berlin, Germany.
authors.forename: Margitta
authors.initials: M
authors.lastname: Worm
authors.forename: Hae-Hyuk
authors.initials: HH
authors.lastname: Lee
authors.forename: Jörg
authors.initials: J
authors.lastname: Kleine-Tebbe
authors.forename: Roderick P
authors.initials: RP
authors.lastname: Hafner
authors.forename: Paul
authors.initials: P
authors.lastname: Laidler
authors.forename: David
authors.initials: D
authors.lastname: Healey
authors.forename: Cecile
authors.initials: C
authors.lastname: Buhot
authors.forename: Adrienne
authors.initials: A
authors.lastname: Verhoef
authors.forename: Bernard
authors.initials: B
authors.lastname: Maillère
authors.forename: A Barry
authors.initials: AB
authors.lastname: Kay
authors.forename: Mark
authors.initials: M
authors.lastname: Larché
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002415:Cats; D004311:Double-Blind Method; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006023:Glycoproteins / Q000276:immunology / Q000627:therapeutic use; D006684:HLA-DR Antigens; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology / Q000517:prevention & control*; D016056:Immunodominant Epitopes; D007167:Immunotherapy / Q000379:methods*; D008969:Molecular Sequence Data; D022223:Vaccines, Subunit / Q000276:immunology* / Q000627:therapeutic use
chemical_list: D018984:Epitopes, T-Lymphocyte; D006023:Glycoproteins; D006684:HLA-DR Antigens; D016056:Immunodominant Epitopes; D022223:Vaccines, Subunit; C059296:Fel d 1 protein, Felis domesticus