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

Abstract

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.

Keywords: CD4; CD8; TEMRA; dengue; human challenge; memory; protective immunity; vaccine.