SummaryIdentification of human leucocyte antigen (HLA) class I-restricted T cell epitopes is important to develop methods to track the evolution of T cell memory to new generation smallpox vaccines and allow comparison to older vaccinia virus preparations known to induce protection against smallpox. We evaluated the relative predictive values of four computational algorithms to identify candidate 9-mer HLA-A2 supertype epitopes that were confirmed to stimulate preferentially T cell interferon (IFN)-g responses by subjects last vaccinated with Dryvax 27-54 years previously. Six peptides encoded by I4L, G1L, A8R, I8R, D12L and H3L open reading frames that were identical for Vaccinia (Copenhagen), Variola major (Bangledesh 1975) and modified vaccinia Ankara strain preferentially stimulated IFN-g responses by healthy HLA-A2 supertype adults last given Dryvax 27-49 years earlier relative to remotely vaccinated non-HLA-A2 supertype and unvaccinated HLA-A2 supertype adults. Combining results from at least two computational algorithms that use different strategies to predict peptide binding to HLA-A2 supertype molecules was optimal for selection of candidate peptides that were confirmed to be epitopes by recall of T cell IFN-g responses. These data will facilitate evaluation of the immunogenicity of replication incompetent smallpox vaccines such as modified vaccinia Ankara and contribute to knowledge of poxvirus epitopes that are associated with long-lived T cell memory.
Memory CD8+ T cells play a significant role in mediating protective immunity from pathogens, particularly viruses and intracellular bacteria. Inducing the optimal response, from both a quantitative and qualitative perspective, has been a research priority for determining the effectiveness of new vaccines. Depending on the pathogen, central memory (TCM) or effector memory (TEM) may be more important in providing adequate protection. Therefore, when developing new vaccines, it is important to realize which memory CD8+ T cell subset is vital and potentially ‘drive’ the response to elicit a protective level ratio in favor of one subset. Here we describe the phenotype of vaccinia specific memory CD8+ T cells. TEMRA+ memory T cells produce the most IFN-γ of any memory subset and are present in individuals last vaccinated over 30 years ago. Concurrently, we address the development of memory CD8+ T cells upon administration of Dryvax, as well as new smallpox vaccines such as Modified Vaccinia Ankara (MVA) in a murine model. Previous studies have indicated that TEM appear to provide better secondary protection than TCM and the data presented here indicate that these cells are maintained long term (>30 years). Therefore, we propose that new smallpox vaccines, such as MVA, should elicit a memory cell population in favor of TEM similar to that induced by Dryvax or other traditional smallpox vaccines.
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