Cell-mediated immune responses to different formulations of a live-attenuated tetravalent dengue vaccine candidate in subjects living in dengue endemic and non-endemic regions

• Published in: Human vaccines & immunotherapeutics Vol. 15; no. 9; pp. 2090 - 2105
• Main Authors: Moris, Philippe, Bauer, Kristen M., Currier, Jeffrey R., Friberg, Heather, Eckels, Kenneth H., Esquilin, Ines O., Gibbons, Robert V., Innis, Bruce L., Jarman, Richard G., Simasathien, Sriluck, Sun, Peifang, Thomas, Stephen J., Watanaveeradej, Veerachai
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 02.09.2019; Taylor & Francis Group
• Subjects: Adolescent; Adult; Antibodies, Viral - blood; Cellular-mediated immune responses; Child; Child, Preschool; Cohort Studies; Dengue - prevention & control; Dengue Vaccines - immunology; Dengue Virus; Dengue-primed and -unprimed populations; Endemic Diseases; Female; Humans; Immunity, Cellular; Immunologic Memory; Infant; Live-attenuated tetravalent dengue candidate vaccine; Male; Middle Aged; Puerto Rico; Research Paper; Thailand; Vaccines, Attenuated - immunology; Young Adult; Thailand; Puerto Rico; Live-attenuated tetravalent dengue candidate vaccine; Dengue-primed and -unprimed populations; Cellular-mediated immune responses
• ISSN: 2164-5515; 2164-554X; 2164-554X
• DOI: 10.1080/21645515.2019.1581536

Three phase II randomized trials evaluated the safety/immunogenicity of two formulations of live-attenuated tetravalent dengue virus (TDEN) vaccine in dengue-endemic (Puerto Rico, Thailand) and non-endemic (US) regions (NCT00350337/NCT00370682/NCT00468858). We describe cell-mediated immune (CMI) responses; safety and humoral responses were reported previously. Participants received two doses of vaccine or control (placebo or the precursor live-attenuated TDEN vaccine) 6 months apart. Selected US participants received a booster 5-12 months post-dose 2. Evaluated subsets of the per-protocol cohorts included 75 primarily dengue virus (DENV)-unprimed US adults, 69 primarily flavivirus-primed Thai adults, and 100 DENV-primed or DENV-unprimed Puerto Rican adults/adolescents/children. T-cell responses were quantified using intracellular cytokine staining (ICS; DENV-infected cell-lysate or DENV-1/DENV-2 peptide-pool stimulation) or IFN-γ ELISPOT (DENV-2 peptide-pool stimulation). Memory B-cell responses were quantified using B-cell ELISPOT. Across populations and age strata, DENV serotype-specific CD4 + T-cell responses were slightly to moderately increased (medians ≤0.18% [ICS]), DENV-2-biased, and variable for both formulations. Responses in unprimed subjects were primarily detected post-dose 1. Response magnitudes in primed subjects were similar between doses. Multifunctional CD8 + T-cell responses were detected after peptide-pool stimulation. T-cell responses were mostly directed to DENV nonstructural proteins 3 and 5. Memory B-cell responses were tetravalent, of low-to-moderate magnitudes (medians ≤0.25%), and mainly observed post-dose 2 in unprimed subjects and post-dose 1 in primed subjects. A third dose did not boost CMI responses. In conclusion, both formulations of the live-attenuated TDEN vaccine candidate were poorly to moderately immunogenic with respect to B-cell and T-cell responses, irrespective of the priming status of the participants. ATP: according-to-protocol; ICS: Intracellular Cytokine Staining; NS3: Nonstructural protein 3; ELISPOT: Enzyme-Linked ImmunoSpot; JEV: Japanese encephalitis virus; PBMC: peripheral blood mononuclear cells