Three-year Efficacy and Safety of Takeda's Dengue Vaccine Candidate (TAK-003)

Abstract

Background: Takeda's live attenuated tetravalent dengue vaccine candidate (TAK-003) is under evaluation in a long-term clinical trial across 8 dengue-endemic countries. Previously, we have reported its efficacy and safety in both seronegative and seropositive participants and that its performance varies by serotype, with some decline in efficacy from first to second year postvaccination. This exploratory analysis provides an update with cumulative and third-year data.

Methods: Healthy 4-16 year olds (n = 20099) were randomized 2:1 to receive TAK-003 or placebo (0, 3 month schedule). The protocol included baseline serostatus testing of all participants and detection of all symptomatic dengue throughout the trial with a serotype specific reverse transcriptase-polymerase chain reaction.

Results: Cumulative efficacy after 3 years was 62.0% (95% confidence interval, 56.6-66.7) against virologically confirmed dengue (VCD) and 83.6% (76.8-88.4) against hospitalized VCD. Efficacy was 54.3% (41.9-64.1) against VCD and 77.1% (58.6-87.3) against hospitalized VCD in baseline seronegatives, and 65.0% (58.9-70.1) against VCD and 86.0% (78.4-91.0) against hospitalized VCD in baseline seropositives. Efficacy against VCD during the third year declined to 44.7% (32.5-54.7), whereas efficacy against hospitalized VCD was sustained at 70.8% (49.6-83.0). Rates of serious adverse events were 2.9% in TAK-003 group and 3.5% in placebo group during the ongoing long-term follow-up (ie, second half of the 3 years following vaccination), but none were related. No important safety risks were identified.

Conclusions: TAK-003 was efficacious against symptomatic dengue over 3 years. Efficacy declined over time but remained robust against hospitalized dengue. A booster dose evaluation is planned.

Trial registration: ClinicalTrials.gov NCT02747927.

Keywords: children; dengue; efficacy; safety; vaccine.

Figure 1.

(A) Number of virologically confirmed dengue (VCD) cases by serotype and total number of hospitalized VCD cases in the placebo group occurring from the first dose to 3 years after the second dose (approximately month 39 after first dose; safety set data) and (B) the number of VCD cases in the placebo group in each year of the study after completing vaccination by country (per protocol set data).

Figure 2.

Forest plots of vaccine efficacy of TAK-003 vs placebo in preventing virologically confirmed dengue (VCD), hospitalized VCD, severe dengue, and DHF from the first dose to 3 years after the second dose (approximately month 39 after first dose; safety set data). Only the first instance of VCD was included in efficacy evaluation. Participants were classified as seronegative when testing seronegative for all dengue serotypes at baseline. Participants were classified as seropositive when demonstrating a reciprocal neutralizing antibody titer ≥ 10 against at least 1 dengue serotype at baseline. DHF included cases of virologically confirmed dengue meeting World Health Organization 1997 criteria for dengue hemorrhagic fever in a programmed algorithm to analyze data. DHF cases: Philippines: DENV-3 (n = 5), DENV-4 (n = 1); Sri Lanka: DENV-1 (n = 1), DENV-2 (n = 4), DENV-3 (n = 4); Thailand: DENV-1 (n = 1), DENV-2 (n = 1), DENV-3 (n = 1); Colombia: DENV-1 (n = 3); Nicaragua: DENV-2 (n = 1). Except for 1 case of DHF, all required hospitalization. Cases of severe dengue were determined by the Dengue Case Adjudication Committee (DCAC). Severe dengue cases: Philippines: DENV-3 (n = 6); Nicaragua: DENV-2 (n = 1); Colombia: DENV-1 (n = 1). All cases required hospitalization. One case in the placebo group and 2 cases in the TAK-003 group met criteria for both DCAC-defined severe dengue and DHF. Abbreviations: DHF, dengue hemorrhagic fever; NE, not estimable; VCD, virologically confirmed dengue.

Figure 3.

Cumulative incidence of (A) virologically confirmed dengue (VCD) cases and (B) hospitalized VCD cases, from the first dose to 3 years after the second dose (approximately month 39 after first dose; safety set data). Number of cases prevented per 100000 participants vaccinated is calculated as 100000/number needed to treat (NNT). NNT is calculated as the reciprocal of risk difference. Risk difference is calculated as the number of events divided by the number of participants evaluated in the placebo group, subtracted by the number of events divided by the number of participants evaluated in the TAK-003 group.

Figure 4.

Serotype-specific geometric mean titers (GMTs; 95% confidence interval) by serostatus at baseline (per protocol set for immunogenicity data). Number of participants evaluated at each timepoint may vary. MNT results were expressed as the reciprocal of the highest dilution of test serum that shows a 50% reduction in plaque counts compared with that of virus controls (MNT₅₀).