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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.

Competing Interests: Potential conflicts of interest. S. B., S. S. P., and M. R. are employees of the Vaccines Business Unit of Takeda and may hold stock/stock options (equities and nonvested options) in Takeda. S. B. also reports consulting fees and support for attending meetings and/or travel as a full-time employee of Takeda Vaccines. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Background: An unmet medical need remains for an effective dengue tetravalent vaccine that can be administered irrespective of previous dengue exposure. TAK-003, a dengue tetravalent vaccine, has demonstrated efficacy in an ongoing phase 3 trial in children and adolescents living in dengue-endemic areas, with an acceptable safety profile in both dengue-naive and dengue-exposed individuals., Methods: Safety findings are presented herein from an integrated analysis of data for healthy 4-60-year-olds from two phase 2 and three phase 3 double-blind, placebo-controlled clinical trials of TAK-003 (TAK-003, n = 14 627; placebo, n = 7167). Safety evaluation included analyses of postinjection reactogenicity, unsolicited adverse events (AEs), serious AEs (SAEs), and deaths. Subgroup analyses were performed by age group, baseline serostatus, and gender., Results: The most common local and systemic AEs were injection site pain (43% for TAK-003 and 26% for placebo) and headache (34% and 30%, respectively). Injection site AEs were mostly mild and resolved within 1-3 days. Unsolicited AEs and AEs leading to discontinuation occurred with similar frequency across both groups, while SAEs were fewer for TAK-003 recipients (6% vs 8% for placebo). Four of the 5 vaccine-related SAEs (which included hypersensitivity, dengue fever, and dengue hemorrhagic fever) occurred in the placebo group. No deaths were considered vaccine-related. Subgroup analyses showed no differences in safety by baseline serostatus or by gender, albeit analysis by age indicated greater local reactogenicity rates for adolescents (46% for TAK-003 and 28% for placebo) and adults (56% and 19%, respectively) than for children (37% and 25%, respectively)., Conclusions: No important safety risks were identified, and TAK-003 was well tolerated irrespective of age, gender, or baseline dengue serostatus in recipients aged 4-60 years., Competing Interests: Potential conflicts of interest . S. S. P., M. R., and H. P. are employees of Takeda Pharmaceuticals. M. K. was an employee of Takeda Pharmaceuticals when the integrated analysis was conducted. S. S. P., M. R., and H. P. also own stock in Takeda Pharmaceuticals. H. P. reports royalties or licenses related to their PhD in biostatistics; support from Takeda Pharmaceuticals for attending meetings and/or travel; and stock or stock options from Takeda Pharmaceuticals. S. S. P. and M.R. report support from Takeda Pharmaceuticals for attending meetings and/or travel and stock/stock options from Takeda Pharmaceuticals. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.)