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To explore the human T cell response to acute viral infection, we performed a longitudinal analysis of CD8⁺ T cells responding to the live yellow fever virus and smallpox vaccines—two highly successful human vaccines. Our results show that both vaccines generated a brisk primary effector CD8⁺ T cell response of substantial magnitude that could be readily quantitated with a simple set of four phenotypic markers. Secondly, the vaccine-induced T cell response was highly specific with minimal bystander effects. Thirdly, virus-specific CD8⁺ T cells passed through an obligate effector phase, contracted more than 90% and gradually differentiated into long-lived memory cells. Finally, these memory cells were highly functional and underwent a memory differentiation program distinct from that described for human CD8⁺ T cells specific for persistent viruses. These results provide a benchmark for CD8⁺ T cell responses …