The Journal of Experimental Medicine
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Published online 28 December 2004 doi:10.1084/jem.20041912
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 1, 95-104
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ARTICLE

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

David C. Tscharke1,2, Gunasegaran Karupiah3, Jie Zhou3, Tara Palmore1, Kari R. Irvine1, S.M. Mansour Haeryfar1, Shanicka Williams1, John Sidney4, Alessandro Sette4, Jack R. Bennink1, and Jonathan W. Yewdell1

1 Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
2 EBV Biology Laboratory, Division of Immunology and Infectious Diseases, Queensland Institute of Medical Research, Herston, QLD 4006, Australia
3 Division of Immunology and Genetics, John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia
4 Division of Translational Immunology and Biodefense, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121

CORRESPONDENCE David Tscharke: davidT{at}qimr.edu.au or Jonathan Yewdell: jyewdell{at}niaid.nih.gov

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.

Abbreviations used: CPXV, cowpox virus; ECTV, ectromelia virus; ICS, intracellular cytokine staining; ID, immunodominance; IDD, immunodominant determinant; MVA, modified vaccinia virus ankara; ORF, open reading frame; SDD, subdominant determinant; VACV, vaccinia virus; VARV, variola virus.


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