An open-label, Phase 3 trial of TAK-003, a live attenuated dengue tetravalent vaccine, in healthy US adults: immunogenicity and safety when administered during the second half of a 24-month shelf-life

Abstract

Dengue is caused by a mosquito-transmitted flavivirus. The disease is now endemic to many tropical and subtropical regions, manifesting as approximately 96 million symptomatic cases of dengue each year. Clinical trials have shown TAK-003 (Qdenga®), a live attenuated dengue tetravalent vaccine, to be well-tolerated, immunogenic, and efficacious in adults with no prior exposure to dengue virus infection living in non-endemic regions, as well as in adults and children living in dengue-endemic areas. This open-label, single-arm phase 3 trial (NCT03771963) was conducted in two dengue non-endemic areas of the USA, and it evaluated the immunogenicity and safety of naturally-aged TAK-003 administered to adult participants. Overall, the immunogenicity data from this trial are consistent with those reported from other TAK-003 phase 2 and 3 trials, and the safety data are consistent with the broader integrated safety data analysis. The data show that naturally-aged TAK-003 had a well-tolerated reactogenicity and adverse events profile when administered in the second half of its clinical 24-month shelf-life and that it still elicited an immune response that persisted up to 6 months after the second dose against all four dengue serotypes, with no important safety risks identified during the trial.

Keywords: Dengue fever; dengue vaccine; immunogenicity; live attenuated; safety; shelf-life; tetravalent.

Figure 1.

Genetic structure of the four TAK-003 vaccine strains. Abbreviations: C, capsid; E, envelope; NS, nonstructural protein; prM, premembrane; TDV-1/2/3/4, dengue serotype 1/2/3/4 strain. Reproduced with permission from Patel et al..

Figure 2.

Trial visits schematic. Abbreviations: MAAEs, medically attended adverse events; SAEs, serious adverse events. Safety assessments were as follows: solicited local events (recorded up to 30 minutes, and up to 7 days after each TAK-003 dose), solicited systemic events (recorded up to 30 minutes, and up to 14 days after each TAK-003 dose), unsolicited events (recorded up to 28 days after each TAK-003 dose), and MAAEs and SAEs recorded for the entire duration of trial. Solicited local AEs comprised injection site pain, injection site erythema, and injection site swelling. Solicited systemic AEs comprised asthenia, headache, malaise, myalgia, and fever. MAAEs were defined as AEs leading to an unscheduled visit to, or by, a healthcare professional including visits to an emergency department, but not fulfilling seriousness criteria.

Figure 3.

(a) Participant allocation to safety, full analysis and per-protocol sets. *Any participant not included in the per-protocol set if he/she experienced one or more trial protocol deviation(s) and (b) Participant disposition for the DEN-307 clinical trial. Abbreviations: AE, adverse event; LTF, lost to follow up; WOC, withdrawal of consent.

Figure 4.

(a) Percentage (95% CI) of participants who were seropositive against each DENV serotype at days 120 and 270 and (b) Percentage (95% CI) of trivalent and tetravalent baseline seropositive participants (per-protocol set). Baseline seropositive defined as a reciprocal neutralizing antibody titer ≥ 10 to $\ge$ 1 dengue virus serotypes. Baseline seronegative defined as titer < 10 to all dengue serotypes. Abbreviations: CI, confidence interval; DENV, dengue virus.

Figure 5.

Geometric mean titers (95% confidence interval) of neutralizing antibodies measured by MNT₅₀ for each dengue serotype (per-protocol set). Abbreviations: DENV, dengue virus; MNT₅₀, microneutralization test 50%.

Figure 6.

Baseline dengue seronegative participant geometric mean titers (95% confidence interval) at day 120 and day 270 after TAK-003 administration in trials DEN-301,^,, DEN-304 and DEN-307. Abbreviation: DENV, dengue virus.

Figure 7.

Baseline dengue seronegative participant geometric mean titers (95% confidence interval) at day 120 and day 270 following administration of TAK-003 in trial DEN-307. Abbreviation: DENV, dengue virus.