Three phase II randomized studies in dengue-endemic and non-endemic (US) regions assessed the safety/immunogenicity of two formulations of live-attenuated tetravalent dengue virus (TDEN) vaccine. Cell-mediated immune (CMI) responses are described here; safety and humoral responses have already been documented. Participants were given two doses of vaccination or a placebo six months apart. Selected US participants received a booster 5–12 months after the initial dosage 2. Subsets of the per-protocol cohorts that were evaluated comprised 75 predominantly dengue virus (DENV)-unprimed US adults, 69 primarily flavivirus-primed Thai adults, and 100 Puerto Rican adults/adolescents/children who were either DENV-primed or DENV-unprimed. DENV serotype-specific CD4+ T-cell responses were marginally to moderately enhanced, DENV-2–biased, and varied across populations and age strata for both formulations. Unprimed individuals’ responses were largely found post-dose 1. The magnitudes of responses in primed participants were comparable across dosages. Following peptide-pool stimulation, multifunctional CD8+ T-cell responses were seen. The majority of T-cell responses were directed against DENV nonstructural proteins 3 and 5.

Memory B-cell responses were tetravalent, of low-to-moderate magnitudes, and were mostly detected after dose 2 in unprimed participants and after dose 1 in primed patients. CMI responses were not improved by a third dosage. In conclusion, regardless of the participants’ priming status, both formulations of the live-attenuated TDEN vaccine candidate were immunogenic in terms of B-cell and T-cell responses.