Human CD4+ T Cell Epitopes from Vaccinia Virus Induced by Vaccination or Infection

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Abstract
Despite the importance of vaccinia virus in basic and applied immunology, our knowledge of the human immune response directed against this virus is very limited. CD4+ T cell responses are an important component of immunity induced by current vaccinia-based vaccines, and likely will be required for new subunit vaccine approaches, but to date vaccinia-specific CD4+ T cell responses have been poorly characterized, and CD4+ T cell epitopes have been reported only recently. Classical approaches used to identify T cell epitopes are not practical for large genomes like vaccinia. We developed and validated a highly efficient computational approach that combines prediction of class II MHC-peptide binding activity with prediction of antigen processing and presentation. Using this approach and screening only 36 peptides, we identified 25 epitopes recognized by T cells from vaccinia-immune individuals. Although the predictions were made for HLA-DR1, eight of the peptides were recognized by donors of multiple haplotypes. T cell responses were observed in samples of peripheral blood obtained many years after primary vaccination, and were amplified after booster immunization. Peptides recognized by multiple donors are highly conserved across the poxvirus family, including variola, the causative agent of smallpox, and may be useful in development of a new generation of smallpox vaccines and in the analysis of the immune response elicited to vaccinia virus. Moreover, the epitope identification approach developed here should find application to other large-genome pathogens. Although the routine use of vaccinia virus for vaccination against smallpox was stopped after eradication of this disease, there is a possibility for an accidental or intentional release of this virus. In response to this challenge, vaccination of at least emergency personnel has been suggested. However, adverse reactions induced by the smallpox vaccine have had a negative impact in the success of this program. For these reasons development of new smallpox vaccines is a public health priority. Identification of strong helper T cell epitopes is central to these efforts. However, identification of T cell epitopes in large genomes like vaccinia is difficult using current screening methods. In this work, we develop a new computational approach for prediction of T cell epitopes, validate it using epitopes already identified by classical methods, and apply it to the prediction of vaccinia epitopes. Twenty-five of 36 peptides containing predicted sequences were recognized by T cells from individuals exposed to vaccinia virus. These peptides are highly conserved across the orthopox virus family and may be useful in development of a new generation of smallpox vaccines and in the analysis of the immune response against vaccinia virus.