Overcoming challenges of developing a live-attenuated dengue vaccine and the path forward

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 > 28,0 0 0 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(NCT023020 6 6) 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 ).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, postauthorization DEN-401 study, will assess vaccine effectiveness of TAK-003 against hospitalized VCD by baseline serostatus and serotype in a planned cohort of 70,0 0 0 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.