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

Nancy Graham, Phil Eisenhauer, Sean A. Diehl, Kristen K. Pierce, Stephen S. Whitehead, Anna P. Durbin, Beth D. Kirkpatrick, Alessandro Sette, Daniela Weiskopf, Jonathan E. Boyson, Jason W. Botten

Research output: Contribution to journalArticlepeer-review

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 (TEM) and effector memory T cells re-expressing CD45RA (TEMRA), with TEM cells predominating until day 21 post-vaccination and TEMRA cells thereafter. The majority of virus-specific CD4+ T cells were TEM with a small fraction being TEMRA. The frequency of virus-specific CD8+ and CD4+ T cells were further skewed to the TEMRA 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.

Original languageEnglish (US)
Article number479
JournalFrontiers in immunology
Volume11
DOIs
StatePublished - Mar 24 2020

Keywords

  • CD4
  • CD8
  • T
  • dengue
  • human challenge
  • memory
  • protective immunity
  • vaccine

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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