title: Identification of protective Lassa virus epitopes that are restricted by HLA-A2.
abstract: Recovery from Lassa virus (LASV) infection usually precedes the appearance of neutralizing antibodies, indicating that cellular immunity plays a primary role in viral clearance. To date, the role of LASV-specific CD8(+) T cells has not been evaluated in humans. To facilitate such studies, we utilized a predictive algorithm to identify candidate HLA-A2 supertype epitopes from the LASV nucleoprotein and glycoprotein precursor (GPC) genes. We identified three peptides (GPC(42-50), GLVGLVTFL; GPC(60-68), SLYKGVYEL; and GPC(441-449), YLISIFLHL) that displayed high-affinity binding (< or =98 nM) to HLA-A*0201, induced CD8(+) T-cell responses of high functional avidity in HLA-A*0201 transgenic mice, and were naturally processed from native LASV GPC in human HLA-A*0201-positive target cells. HLA-A*0201 mice immunized with either GPC(42-50) or GPC(60-68) were protected against challenge with a recombinant vaccinia virus that expressed LASV GPC. The epitopes identified in this study represent potential diagnostic reagents and candidates for inclusion in epitope-based vaccine constructs. Our approach is applicable to any pathogen with existing sequence data, does not require manipulation of the actual pathogen or access to immune human donors, and should therefore be generally applicable to category A through C agents and other emerging pathogens.
authors.affiliation: Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, CA 92037, USA. jbotten@scripps.edu
authors.forename: Jason
authors.initials: J
authors.lastname: Botten
authors.forename: Jeff
authors.initials: J
authors.lastname: Alexander
authors.forename: Valerie
authors.initials: V
authors.lastname: Pasquetto
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.forename: Polly
authors.initials: P
authors.lastname: Barrowman
authors.forename: Joey
authors.initials: J
authors.lastname: Ting
authors.forename: Bjoern
authors.initials: B
authors.lastname: Peters
authors.forename: Scott
authors.initials: S
authors.lastname: Southwood
authors.forename: Barbara
authors.initials: B
authors.lastname: Stewart
authors.forename: Maria P
authors.initials: MP
authors.lastname: Rodriguez-Carreno
authors.forename: Bianca
authors.initials: B
authors.lastname: Mothe
authors.forename: J Lindsay
authors.initials: JL
authors.lastname: Whitton
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Buchmeier
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry* / Q000276:immunology; D015789:HLA-A2 Antigen / Q000378:metabolism*; D006801:Humans; D007114:Immunization; D007835:Lassa Fever / Q000276:immunology / Q000517:prevention & control; D007836:Lassa virus / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D019590:Nucleocapsid Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology; D014759:Viral Envelope Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D014765:Viral Vaccines / Q000008:administration & dosage / Q000276:immunology
chemical_list: D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D019590:Nucleocapsid Proteins; D010455:Peptides; D014759:Viral Envelope Proteins; D014765:Viral Vaccines