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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.

SUBMITTER: Tscharke DC

PROVIDER: S-EPMC2212779 | biostudies-literature | 2005 Jan

REPOSITORIES: biostudies-literature

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Identification of poxvirus CD8+ T cell determinants to enable rational design and characterization of smallpox vaccines.

Tscharke David C DC Karupiah Gunasegaran G Zhou Jie J Palmore Tara T Irvine Kari R KR Haeryfar S M Mansour SM Williams Shanicka S Sidney John J Sette Alessandro A Bennink Jack R JR Yewdell Jonathan W JW

The Journal of experimental medicine 20041228 1

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 th ...[more]

PMID: 15623576

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Project description:BackgroundSmallpox was eradicated by 1980, but its possible use as a bioweapon has rekindled interest in the development of protective vaccines. Therefore, stockpiled calf lymph-derived vaccines and recently developed cell-cultured vaccines have been investigated to contribute information to smallpox emergency response plans, while newer (non-replication competent) vaccines are developed.ObjectivesTo assess the effects of smallpox vaccines in preventing the disease, in inducing immunity, and in regard to adverse events.Search strategyIn December 2006, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2006, Issue 4), MEDLINE, EMBASE, LILACS, and Current Controlled Trials, and handsearched Index Medicus. We also searched three databases of vaccine safety in December 2005.Selection criteriaRandomized controlled trials of smallpox vaccines versus placebo, other smallpox or non-smallpox vaccine, no intervention, or different dose of the same vaccine in people receiving smallpox vaccination irrespective of age.Data collection and analysisBoth authors independently assessed trial quality and extracted data. We combined dichotomous data using relative risk with a random-effects model.Main resultsTen trials involving 2412 participants were included. The vaccines investigated were calf-lymph derived first-generation vaccines (Dryvax, APVS, Lancy-vaxina, Lister), and cell-cultured second-generation vaccines (ACAM, CCSV). Vaccines were investigated in different dilutions. All undiluted vaccines induced a reaction in 95% of people vaccinated in terms of pustule and immunogenicity. Also 1:10 dilutions were fully efficient when the starting concentration was defined. Serious adverse events were reported in 1% to 2% of the volunteers. Fever was observed in 11% to 22% of participants, and headache in roughly half of the participants. Fever was less frequent when new vaccines were administered, but rates of headache were similar in new and old vaccines.Authors' conclusionsThe evidence shows that stockpiled vaccines have maintained their immunogenicity and new cell-cultured vaccines are similar to stockpiled vaccines in terms of vaccination success rate and immunogenicity. First- and second-generation vaccines diluted to at least 1:10 are as effective as undiluted vaccine in terms of clinical success rate and immunogenicity. Dilution did not reduce the frequency of adverse events. Success rate and immunogenicity were similar in naive and previously vaccinated persons, but there were fewer adverse events in previously vaccinated persons. The rate of adverse events found in this review reveals the need for further development and improvement of smallpox vaccines.

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Identification of poxvirus CD8+ T cell determinants to enable rational design and characterization of smallpox vaccines.

Publications

Identification of poxvirus CD8+ T cell determinants to enable rational design and characterization of smallpox vaccines.

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