Human Immunity to Vaccinia Virus

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Current policy to protect Americans against smallpox mandates immunization of naTve and previously vaccinated adults with live vaccinla virus (VV). Knowledge of adaptive immunity to W is limited to descriptions of neutralizing antibodies, cytotoxic T lymphocyte (CTL) activity, and lymphocyte proliferation responses, largely because widespread vaccination ceased before the current era of molecular immunology. Research in this project will examine the evolution of W-specific memory T cells in newly vaccinated and revaccinated (boosted) adults. The relationship of W-specific adaptive immunity to viral load and innate immunity will be determined in conjunction with projects 7 and 9. The specific aims are to: 1. Identify immunodominant VV epitopes that induce CD8 ¿ T cell memory. Artificial neural networks and computational algorithms will initially be used to select peptide epitopes, followed by evaluation of peptide binding to HLA class I alleles and assessment of the ability of peptides to stimulate IFN-? and IL-2 responses by HLA-matched and HLA-mismatched primary vaccinees and adults given booster doses of W. 2. Determine the functional phenotype of CD8 ¿ cells during the inductive and memory phases of adaptive immunity to W. HLA class I tetramer-peptide complexes will be used to identify and quantify CD8 ¿ cells bearing TCR specific for W epitopes before vaccination and 9 days, 6, 12, and 24 months post-vaccination. Lymphocytes producing putative mediators of immunity (IFN-?, perforin, MIP-lcc) and bearing memory markers (CD45RO, CD45RA, CCR7) will be evaluated prospectively in primary vaccinees and boosted adults. 3. Evaluate the clonotypic repertoire of Vv-specific CD8 ¿ cells following primary vaccination and boosting of previously vaccinated adults. TCR VI3 usage and CDR3 length and sequence polymorphism will be evaluated prospectively in selected HLA-A2+ and HLA-A11+ individuals.