Rapid Induction and Maintenance of Virus-Specific CD8(+) T(EMRA) and CD4(+) T(EM) Cells Following Protective Vaccination Against Dengue Virus Challenge in Humans

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.