title: Identification of poxvirus CD8+ T cell determinants to enable rational design and characterization of smallpox vaccines.
abstract: The large size of poxvirus genomes has stymied attempts to identify determinants recognized by CD8+ T cells and greatly impeded development of mouse smallpox vaccination models. Here, we use a vaccinia virus (VACV) expression library containing each of the predicted 258 open reading frames to identify five peptide determinants that account for approximately half of the VACV-specific CD8+ T cell response in C57BL/6 mice. We show that the primary immunodominance hierarchy is greatly affected by the route of VACV infection and the poxvirus strain used. Modified vaccinia virus ankara (MVA), a candidate replacement smallpox vaccine, failed to induce responses to two of the defined determinants. This could not be predicted by genomic comparison of viruses and is not due strictly to limited MVA replication in mice. Several determinants are immunogenic in cowpox and ectromelia (mousepox) virus infections, and immunization with the immunodominant determinant provided significant protection against lethal mousepox. These findings have important implications for understanding poxvirus immunity in animal models and bench-marking immune responses to poxvirus vaccines in humans.
authors.affiliation: Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. davidT@qimr.edu.au
authors.forename: David C
authors.initials: DC
authors.lastname: Tscharke
authors.forename: Gunasegaran
authors.initials: G
authors.lastname: Karupiah
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.forename: Tara
authors.initials: T
authors.lastname: Palmore
authors.forename: Kari R
authors.initials: KR
authors.lastname: Irvine
authors.forename: S M Mansour
authors.initials: SM
authors.lastname: Haeryfar
authors.forename: Shanicka
authors.initials: S
authors.lastname: Williams
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.forename: Jack R
authors.initials: JR
authors.lastname: Bennink
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Yewdell
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D003001:Cloning, Molecular; D017931:DNA Primers; D003713:Dendritic Cells / Q000378:metabolism; D000939:Epitopes / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015723:Gene Library; D005805:Genes, MHC Class I / Q000235:genetics; D007114:Immunization; D051379:Mice; D008810:Mice, Inbred C57BL; D016366:Open Reading Frames / Q000235:genetics; D010455:Peptides / Q000378:metabolism; D017422:Sequence Analysis, DNA; D012900:Smallpox Vaccine / Q000235:genetics / Q000276:immunology*; D013045:Species Specificity; D013154:Spleen / Q000166:cytology; D014162:Transfection; D014616:Vaccinia virus / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D000939:Epitopes; D010455:Peptides; D012900:Smallpox Vaccine