The vaccine tested in this study is Takeda's Tetravalent Dengue Vaccine Candidate (TDV) which was administered in 3 different dosing schedules to participants aged from 2 to 17 years resident in dengue endemic countries. This study looked at the titers of antibodies to dengue fever elicited in people who received TDV.

The study randomized 1800 healthy participants. Participants were randomly assigned to one of the four treatment groups in a 1:2:5:1 ratio-which remained undisclosed to the participant and study doctor during the study (unless there was an urgent medical need):

Group 1 - TDV 0.5 mL subcutaneous (SC) injection Days 1 and 91

Group 2 - TDV 0.5 mL SC injection Day 1

Group 3 - TDV 0.5 mL SC injection Days 1 and 365

Group 4 - Placebo (dummy SC) - this is a liquid that looks like the study drug but has no active ingredient

A total of 600 participants were planned to be randomly included in immunogenicity analyses (approximately 100 participants planned in each of Group 1 and Group 4, and 200 participants planned in each of Group 2 and Group 3).

In order to keep the treatment arms undisclosed to the participant and the doctor, participants received a placebo injection at any study visit where TDV was not being administered (Days 1 and/or 91 and/or 365).

Participants were asked to record any symptoms that may be related to the vaccine or the injection site in a diary card for 28 days after each vaccination.

This multi-center trial was conducted in Asia and Latin America. Participants were followed for 48 months with 10 protocol-scheduled visits for participants included in the planned immunogenicity subset of approximately 600 subjects and 7 protocol-scheduled visits for subjects not included in the immunogenicity subset.

Results

Findings: Between Dec 5, 2014, and Feb 13, 2015, 1800 children were randomly assigned to the following groups: two-dose primary series (n=201), one primary dose (n=398), one primary dose plus 1-year booster (n=1002), and placebo (n=199). Of them, 1479 (82%) participants completed the 48-month study. Immunogenicity endpoints were assessed in 562 participants enrolled in the immunogenicity subset, of whom 509 were included in the per-protocol subset. At month 48, antibody titres remained elevated in all TAK-003 groups compared with placebo, irrespective of baseline serostatus. At month 48, geometric mean titres were 378 (95% CI 226-632) in two-dose, 421 (285-622) in one-dose, 719 (538-960) in one-dose plus 1-year booster, and 100 (50-201) in placebo recipients against DENV 1; 1052 (732-1511), 1319 (970-1794), 1200 (927-1553), and 208 (99-437) against DENV 2; 183 (113-298), 201 (135-298), 288 (211-392), and 71 (37-139) against DENV 3; and 152 (97-239), 164 (114-236), 219 (165-290), and 46 (26-82) against DENV 4; and tetravalent seropositivity rate was 89% (79-96), 86% (80-92), 97% (93-99), and 60% (47-72), respectively. Virologically confirmed dengue was recorded in 37 (2%) TAK-003 and 13 (7%) placebo participants, with a relative risk of 0·35 (0·19-0·65). No vaccine-related serious adverse events or severe dengue virus disease were reported.

Interpretation: TAK-003 elicited antibody responses against all four serotypes, which persisted to 48 months post-vaccination, regardless of baseline serostatus. No important safety risks were identified. We observed a long-term reduction in the risk of symptomatic dengue virus disease in vaccinees.

Results from this study provide a long-term safety database and support assessment of the vaccine in the ongoing phase 3 efficacy study.