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Clinical Trial
. 2023 Mar 8;17(3):e0011124.
doi: 10.1371/journal.pntd.0011124. eCollection 2023 Mar.

Immunogenicity and safety of concomitant and sequential administration of yellow fever YF-17D vaccine and tetravalent dengue vaccine candidate TAK-003: A phase 3 randomized, controlled study

Vianney Tricou  1 , Brandon Essink  2 , John E Ervin  3 , Mark Turner  4 , Ian Escudero  5 , Martina Rauscher  1 , Manja Brose  1 , Inge Lefevre  1 , Astrid Borkowski  1 , Derek Wallace  6
Affiliations
Clinical Trial

Immunogenicity and safety of concomitant and sequential administration of yellow fever YF-17D vaccine and tetravalent dengue vaccine candidate TAK-003: A phase 3 randomized, controlled study

Vianney Tricou et al. PLoS Negl Trop Dis. .

Abstract

Background: Yellow fever (YF) vaccination is often mandatory for travelers to YF-endemic areas. The areas with risk of YF partially overlap with those of dengue, for which there is currently no recommended vaccine available for dengue-naïve individuals. This phase 3 study assessed the immunogenicity and safety of concomitant and sequential administration of YF (YF-17D) and tetravalent dengue (TAK-003) vaccines in healthy adults aged 18-60 years living in areas of the US non-endemic for either virus.

Methods: Participants were randomized 1:1:1 to receive the following vaccinations at Months 0, 3, and 6, respectively: YF-17D+placebo, TAK-003, and TAK-003 (Group 1); TAK-003+placebo, TAK-003, and YF-17D (Group 2); or YF-17D+TAK-003, TAK-003, and placebo (Group 3). The primary objective was to demonstrate non-inferiority (upper bound of 95% confidence interval [UB95%CI] of difference <5%) of YF seroprotection rate one month following concomitant administration of YF-17D and TAK-003 (Group 3) compared with YF-17D plus placebo (Group 1). The secondary objectives included demonstration of non-inferiority of YF and dengue geometric mean titers (GMTs) (UB95%CI for GMT ratio <2.0), and safety.

Results: 900 adults were randomized. YF seroprotection rates one month post-YF-17D (Month 1) were 99.5% and 99.1% in Group 1 and 3, respectively, and non-inferiority was demonstrated (UB95%CI = 2.69% i.e. <5%). Non-inferiority was also demonstrated for GMTs against YF one month post-YF-17D, and against DENV-2, -3, and -4 (UB95%CI <2), but not DENV-1 (UB95%CI: 2.22), one month post-second TAK-003 vaccination. Adverse event rates following TAK-003 were consistent with previous results, and no important safety risks were identified.

Conclusions: In this study, YF-17D vaccine and TAK-003 were immunogenic and well tolerated when sequentially or concomitantly administered. The non-inferiority of immune responses to YF-17D and TAK-003 was demonstrated for concomitant administration of the 2 vaccines compared to separate vaccination, except against DENV-1 but with GMTs similar to those observed in other TAK-003 trials.

Trial registration: ClinicalTrials.gov identified: NCT03342898.

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Conflict of interest statement

I have read the journal’s policy and the authors of this manuscript have the following competing interests: VT, IE, MR, MB, IL and DW are full-time employees of Takeda. AB was employee of Takeda at the time of the study (current affiliation of AB: HilleVax GmbH, Zurich, Switzerland). BE, JEE, and MT received funding from Takeda Vaccines to perform the trial.

Figures

Fig 1
Fig 1. Study design.
TAK-003, tetravalent dengue vaccine candidate; YF-17D, live attenuated yellow fever vaccine.
Fig 2
Fig 2. Participant flowchart.
aThis includes 1 participant who received YF-17D vaccine instead of Placebo at 3rd vaccination. AE, adverse event; LTF, lost to follow-up; PD, protocol deviation; TAK-003, tetravalent dengue vaccine candidate; WOC, withdrawal of consent; YF-17D, live attenuated yellow fever vaccine.
Fig 3
Fig 3. Geometric mean titers (GMTs) of neutralizing antibodies against each DENV serotype in each of the vaccine groups (PPS).
Number of participants included at each time point are given in the table below the graphs. DENV, dengue virus; PPS, per-protocol set.
Fig 4
Fig 4. Seropositivity rates (95% confidence intervals) against individual and multiple DENV serotypes in each vaccine group (PPS).
Number of participants included at each time point are given in the table below the graphs. DENV, dengue virus.
See this image and copyright information in PMC

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