CD8+ T-cell Responses in Flavivirus-Naive Individuals Following Immunization with a Live-Attenuated Tetravalent Dengue Vaccine Candidate.
We are developing a live-attenuated tetravalent dengue vaccine (TDV) candidate based on an attenuated dengue 2 virus (TDV-2) and 3 chimeric viruses containing the premembrane and envelope genes of dengue viruses (DENVs) -1, -3, and -4 expressed in the context of the attenuated TDV-2 genome (TDV-1, TDV-3, and TDV-4, respectively). In this study, we analyzed and characterized the CD8(+) T-cell response in flavivirus-naive human volunteers vaccinated with 2 doses of TDV 90 days apart via the subcutaneous or intradermal routes. Using peptide arrays and intracellular cytokine staining, we demonstrated that TDV elicits CD8(+) T cells targeting the nonstructural NS1, NS3, and NS5 proteins of TDV-2. The cells were characterized by the production of interferon-γ, tumor necrosis factor-α, and to a lesser extent interleukin-2. Responses were highest on day 90 after the first dose and were still detectable on 180 days after the second dose. In addition, CD8(+) T cells were multifunctional, producing ≥2 cytokines simultaneously, and cross-reactive to NS proteins of the other 3 DENV serotypes. Overall, these findings describe the capacity of our candidate dengue vaccine to elicit cellular immune responses and support the further evaluation of T-cell responses in samples from future TDV clinical trials.
Takeda Vaccines, Inc, Deerfield, Illinois.
Haiyan
H
Chu
Department of Internal Medicine, Division of Infectious Diseases, Allergy and Immunology, Saint Louis University School of Medicine St. Louis Veterans Administration Medical Center, Missouri.
Sarah L
SL
George
Takeda Vaccines, Inc, Deerfield, Illinois.
Dan T
DT
Stinchcomb
Takeda Vaccines, Inc, Deerfield, Illinois.
Jorge E
JE
Osorio
Takeda Vaccines, Inc, Deerfield, Illinois.
Charalambos D
CD
Partidos
D000328:Adult; D000956:Antigens, Viral / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D015331:Cohort Studies; D016207:Cytokines / Q000096:biosynthesis; D053059:Dengue Vaccines / Q000008:administration & dosage* / Q000276:immunology*; D003716:Dengue Virus / Q000276:immunology*; D064368:Healthy Volunteers; D006801:Humans; D014611:Vaccination / Q000379:methods; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000276:immunology; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000276:immunology
D000956:Antigens, Viral; D016207:Cytokines; D053059:Dengue Vaccines; D014613:Vaccines, Attenuated; D014614:Vaccines, Synthetic
CD8+ T cells; cytokines; dengue virus; multifunctional T cells; vaccine