@article{375f7059c4044c7c8c8666c427a6c8e9,
title = "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 (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.",
keywords = "CD4, CD8, T, dengue, human challenge, memory, protective immunity, vaccine",
author = "Nancy Graham and Phil Eisenhauer and Diehl, {Sean A.} and Pierce, {Kristen K.} and Whitehead, {Stephen S.} and Durbin, {Anna P.} and Kirkpatrick, {Beth D.} and Alessandro Sette and Daniela Weiskopf and Boyson, {Jonathan E.} and Botten, {Jason W.}",
note = "Funding Information: We thank the study volunteers and clinical staff at the University of Vermont Vaccine Testing Center and the Johns Hopkins Center for Immunization Research. At the University of Vermont, cell sorting and flow cytometric analysis was performed at the Harry Hood Bassett Flow Cytometry and Cell Sorting Facility (with thanks to Roxana del Rio-Guerra, Ph.D.) and supported by National Institutes of Health grants S10-OD018175 and P30GM118228. We also thank Michael A. Angelo and Derek J. Bangs for technical advice on the ELISPOT and ICS assays and Dorothy Dickson for advice on statistical analysis of data. Funding. This study was supported by the Bill and Melinda Gates Foundation grant OPP110470 (AD and BK) and the NIH grants U01AI1141997 (JWB, SD, and BK), P20GM125498 (BK and SD), P01 AI106695 (AS and DW) and P30GM118228 (JWB), and the NIH contract HHSN272201400045C (AS). The clinical trials from which samples were obtained were funded by NIAID Intramural contract HHSN272200900010C (AD and BK). The funders had no role in the study design, in the collection, analysis, and interpretation of data, in the writing of the report, or in the decision to submit the paper for publication. Funding Information: This study was supported by the Bill and Melinda Gates Foundation grant OPP110470 (AD and BK) and the NIH grants U01AI1141997 (JWB, SD, and BK), P20GM125498 (BK and SD), P01 AI106695 (AS and DW) and P30GM118228 (JWB), and the NIH contract HHSN272201400045C (AS). The clinical trials from which samples were obtained were funded by NIAID Intramural contract HHSN272200900010C (AD and BK). The funders had no role in the study design, in the collection, analysis, and interpretation of data, in the writing of the report, or in the decision to submit the paper for publication. Funding Information: We thank the study volunteers and clinical staff at the University of Vermont Vaccine Testing Center and the Johns Hopkins Center for Immunization Research. At the University of Vermont, cell sorting and flow cytometric analysis was performed at the Harry Hood Bassett Flow Cytometry and Cell Sorting Facility (with thanks to Roxana del Rio-Guerra, Ph.D.) and supported by National Institutes of Health grants S10-OD018175 and P30GM118228. We also thank Michael A. Angelo and Derek J. Bangs for technical advice on the ELISPOT and ICS assays and Dorothy Dickson for advice on statistical analysis of data. Publisher Copyright: {\textcopyright} Copyright {\textcopyright} 2020 Graham, Eisenhauer, Diehl, Pierce, Whitehead, Durbin, Kirkpatrick, Sette, Weiskopf, Boyson and Botten.",
year = "2020",
month = mar,
day = "24",
doi = "10.3389/fimmu.2020.00479",
language = "English (US)",
volume = "11",
journal = "Frontiers in immunology",
issn = "1664-3224",
publisher = "Frontiers Media S. A.",
}