Year: 2025
Type: article
Abstract: Introduction The WHO declared dengue a grade 3 emergency, underscoring an urgent need for safe and effective vaccines. Challenges have hindered progress with such vaccines, including selection of an appropriate backbone, proper viral attenuation with balanced immunogenicity/reactogenicity, evaluation of vaccine-induced viremia/environmental risks, and vaccination schedule optimization. Along with an overview of the development program of TAK-003, a live-attenuated tetravalent dengue vaccine, we highlight our approaches for overcoming these challenges. Methods Development of TAK-003 involved more than a decade of investigation including pre-clinical studies and an extensive clinical development program conducted with >28,000 volunteers aged 1.5-60 years from 13 countries. These studies, culminating in the pivotal phase III DEN-301(NCT02747927) trial, have evaluated the dosing, formulation, efficacy (including immunogenicity, safety viremia, and reversion/environmental risks) of our vaccine. Results Based on the single backbone of DENV-2 with chimeric DENV-1, -3, and -4 elements and three stable mutations in the 5′untranslated region and the NS genes (NS1 and NS3), TAK-003 demonstrated a balance between immunogenicity and reactogenicity while eliciting high rates of seroconversion in baseline (before vaccination) seronegative participants with low rates and levels of vaccine-induced viremia, indicating optimal attenuation. Subsequent phase I/II trials, and ultimately the DEN-204(NCT02302066) study, supported the two-dose schedule to maximize multivalent seroconversion in all vaccinees. Data analyses from the DEN-301 trial demonstrated that the primary endpoint was met after 1 year with a vaccine efficacy (VE) of 80.2%(95%CI:73.3-85.3) against virologically confirmed dengue (VCD). After 18 months, VE against hospitalization was 90.4%(95%CI:82.6-94.7), which was sustained through 54 months (84.1%[95%CI:77.8-88.6]). The safety profile demonstrated no significant safety risks, irrespective of baseline serostatus/age. Additional immunogenicity analysis across phase I/II/III trials revealed engagement of long-lasting tetravalent, functional antibody, and cell-mediated immune responses directed against the structural and nonstructural components of the vaccine, irrespective of baseline serostatus. Discussion Building on these results, and further assessing the vaccine's impact in the real world, the observational, post-authorization DEN-401 study, will assess vaccine effectiveness of TAK-003 against hospitalized VCD by baseline serostatus and serotype in a planned cohort of 70,000 participants in Southeast Asia. Additional trials for TAK-003 will include assessing the effect of a booster dose as part of the ongoing DEN-301 trial, administrating TAK-003 to children <4 years old, and co-administrating TAK-003 with other vaccines. Cost-effectiveness and budget-impact studies of dengue vaccination as well as a population-based observational study to estimate the impact of vaccination on dengue incidence in Brazil are also ongoing. Conclusion Developed through a comprehensive clinical program, TAK-003 displayed low reactogenicity, balanced immunogenicity, and long-term efficacy and safety, addressing an unmet need for a dengue vaccine with no identified important safety risks.
Authors: Dr Walid Kandeil, Dr Mayuri Sharma
Institution: Takeda (Japan)
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,900
OpenAlex ID: W4408046513