Protection against lethal vaccinia virus challenge in HLA-A2 transgenic mice by immunization with a single CD8+ T-cell peptide epitope of vaccinia and variola viruses.
CD8(+) T lymphocytes have been shown to be involved in controlling poxvirus infection, but no protective cytotoxic T-lymphocyte (CTL) epitopes are defined for variola virus, the causative agent of smallpox, or for vaccinia virus. Of several peptides in vaccinia virus predicted to bind HLA-A2.1, three, VETFsm(498-506), A26L(6-14), and HRP2(74-82), were found to bind HLA-A2.1. Splenocytes from HLA-A2.1 transgenic mice immunized with vaccinia virus responded only to HRP2(74-82) at 1 week and to all three epitopes by ex vivo enzyme-linked immunosorbent spot (ELISPOT) assay at 4 weeks postimmunization. To determine if these epitopes could elicit a protective CD8(+) T-cell response, we challenged peptide-immunized HLA-A2.1 transgenic mice intranasally with a lethal dose of the WR strain of vaccinia virus. HRP2(74-82) peptide-immunized mice recovered from infection, while naïve mice died. Depletion of CD8(+) T cells eliminated protection. Protection of HHD-2 mice, lacking mouse class I major histocompatibility complex molecules, implicates CTLs restricted by human HLA-A2.1 as mediators of protection. These results suggest that HRP2(74-82), which is shared between vaccinia and variola viruses, may be a CD8(+) T-cell epitope of vaccinia virus that will provide cross-protection against smallpox in HLA-A2.1-positive individuals, representing almost half the population.
Snyder
James T
JT
Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1578, USA.
Belyakov
Igor M
IM
Dzutsev
Amiran
A
Lemonnier
François
F
Berzofsky
Jay A
JA
D000595:Amino Acid Sequence; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000235:genetics; D006801:Humans; D016056:Immunodominant Epitopes; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010455:Peptides / Q000737:chemistry / Q000276:immunology*; D012899:Smallpox / Q000276:immunology / Q000517:prevention & control*; D012900:Smallpox Vaccine / Q000008:administration & dosage / Q000276:immunology; D014611:Vaccination; D014616:Vaccinia virus / Q000276:immunology* / Q000472:pathogenicity; D012901:Variola virus / Q000276:immunology*
D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D016056:Immunodominant Epitopes; D010455:Peptides; D012900:Smallpox Vaccine