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.
Highlights
Dengue virus (DENV), a mosquito-borne flavivirus, is the most prevalent cause of arboviral disease in humans
We studied two cohorts: one that was vaccinated with dengue live attenuated tetravalent vaccine (DLAV) and boosted 180 days later [31] and the other that was vaccinated with DLAV and challenged 180 days later with DENV2 30 (Tonga/74), an American genotype DENV2 strain that was isolated during an outbreak of DENV in the Kingdom of Tonga in 1974 and is heterotypic to the parent of the vaccine strain (DENV2 strain New Guinea C) [32, 43]
We have previously reported on the ability of the NIH DENV tetravalent live-attenuated vaccine (DLAV) to induce DENVspecific T cells [19, 20] and neutralizing antibodies [31, 32], as well as its ability to protect against challenge with an underattenuated strain of DENV [32]
Summary
Dengue virus (DENV), a mosquito-borne flavivirus, is the most prevalent cause of arboviral disease in humans. While many individuals experience a relatively undifferentiated febrile illness, others develop severe clinical syndromes (dengue hemorrhagic fever and dengue shock syndrome) that are associated with severe thrombocytopenia and clotting disorders, as well as plasma leakage. These more severe disease syndromes are associated with increased risk of death, in areas lacking sufficient medical care or in the very young or old [3]. A vaccine for the prevention of DENV disease was recently approved by the United States Food and Drug Administration (FDA), its use is restricted to individuals 9–16 years of age with laboratory-confirmed previous dengue infection [4]. There remains a critical need for a broadly effective vaccine that protects dengue-naïve individuals
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
