Humoral and cellular responses to a tetravalent dengue vaccine (TAK-003) in adults from a dengue non-endemic region: An open-label phase 2 trial

BACKGROUND: Robust humoral and cell-mediated immune responses are associated with protection against dengue. In this study, we assessed the humoral and cellular immunogenicity of TAK-003, a live attenuated tetravalent dengue vaccine, in flavivirus seronegative and dengue seropositive adults in the US (NCT03746015). METHODS: Adults (18 to ≤60 years) received a two-dose series of TAK-003 administered three months apart. The primary study objective was assessment of neutralising antibody geometric mean titres (GMTs) through 12 months post-vaccination. Secondary objectives included assessment of the responder rate, magnitude and multifunctionality of T cell responses, vaccine RNAemia, and safety. Flavivirus seronegative participants had no previous flavivirus (dengue, Zika, yellow fever, Japanese Encephalitis, West Nile virus) exposure, determined by serological testing. Dengue seropositive participants were seropositive for DENV-1 or DENV-3 at baseline. RESULTS: TAK-003 induced neutralising antibodies across all DENV serotypes by Day 30 in all thirty flavivirus seronegative and dengue seropositive adult participants, which were sustained for 12 months. IFN-γ expressing T cell responder rates to any peptide pool spanning sequences of prME, NS1, NS3, and NS5 from all four serotypes were 100% for both flavivirus seronegative and dengue seropositive participants, from one month after the first vaccination through 12 months. T cell reactivity against NS proteins of all 4 serotypes was observed after vaccination - responses were durable and remained above baseline levels throughout. Multifunctional (expression of ≥2 cytokines of IFN-γ, IL-2 and TNF-α) CD4 and CD8 T cell responses were observed from Day 15 post vaccination and remained above baseline levels throughout. Vaccine RNAemia and safety findings were consistent with the known TAK-003 safety profile. CONCLUSION: TAK-003 was well tolerated and elicited tetravalent humoral and cellular immune responses sustained for at least 12 months in flavivirus seronegative and dengue seropositive adults residing in areas without DENV circulation.