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Dengue virus (DENV) is a mosquito-borne flavivirus that causes serious human disease. The current lack of an effective vaccine to simultaneously protect against the four serotypes of DENV in seronegative individuals is a major unmet medical need. Further, the immunological basis for protective immunity in the setting of DENV infection or vaccination is not fully understood. Our team has developed a live attenuated tetravalent dengue virus vaccine that provides complete protection in a human model of dengue virus challenge. The goal of this study was to define, in the context of protective human vaccination, the quality of vaccine-induced DENV-specific CD8 +  and CD4 +  T cells and the temporal dynamics associated with their formation and maintenance. Multifunctional, DENV-specific CD8 +  and CD4 +  T cells developed 8–14 days after vaccination and were maintained for at least 6 months. Virus-specific CD8 T +  cells were a mixture of effector memory T cells (T EM ) and effector memory T cells re-expressing CD45RA (T EMRA ), with T EM  cells predominating until day 21 post-vaccination and T EMRA  cells thereafter. The majority of virus-specific CD4 +  T cells were T EM  with a small fraction being T EMRA . The frequency of virus-specific CD8 +  and CD4 +  T cells were further skewed to the T EMRA  phenotype following either a second dose of the tetravalent vaccine or challenge with a single serotype of DENV. Collectively, our study has defined the phenotypic profile of antiviral CD8 +  and CD4 +  T cells associated with protective immunity to DENV infection and the kinetics of their formation and maintenance.

frontiers in immunology

Rapid Induction and Maintenance of Virus-Specific CD8+ TEMRA and CD4+ TEM Cells Following Protective Vaccination Against Dengue Virus Challenge in Humans