State of the Art on Vaccine Development Against Dengue Infection: Scoping Review of the Literature.

Background: Dengue virus infection is a significant challenge for global health, with 100 million symptomatic cases, 2.3 million DALYs and 20,000 deaths annually. Dengue vaccines must provide long-lasting immunity against all four virus serotypes, especially in dengue-naïve individuals, in order to avoid the severe manifestations of secondary infections. Methods: This scoping review summarizes current evidence on licensed dengue vaccines and vaccine candidates, focusing on immunogenicity, efficacy, and safety outcomes. To identify relevant trials, in October 2023 we queried ClinicalTrials.gov using the search term "dengue vaccines" to identify past and present vaccine candidates; the search was repeated in February 2025. Vaccines were categorized into licensed (CYD-TDV and TAK-003), late-stage (TV003/TV005), and early-stage candidates (TDEN, DPIV, V180, TVDV). Results: CYD-TDV (Dengvaxia^®) showed moderate efficacy in large trials, with higher efficacy in seropositive than in seronegative individuals. Following commercialization, an increased hospitalization risk was discovered in the latter group. Due to these findings and impossibility of screening for prior exposure in endemic settings newer vaccines are now preferred and CYD-TDV production has recently been discontinued due to declining demand. TAK-003 (Qdenga^®) demonstrated high efficacy against virologically confirmed dengue (VCD) and dengue-related hospitalization. This vaccine was generally well tolerated and is currently recommended by scientific societies and national authorities for travelers and by WHO for routine use in adults and children in endemic settings. TV003 and TV005, developed by NIAID, showed strong immunogenicity and efficacy in phase II trials and human challenge models. Preliminary results show that a single-dose of TV003 has an efficacy of 79.6% in seronegatives and 89.2% in seropositives against VCD at a 2-year follow-up. Both formulations elicited tetravalent responses with an acceptable safety profile. Other vaccine strategies, including TDEN (live-attenuated), DPIV (purified inactivated), V180 (subunit), and TVDV (DNA-based) are still in early-phase development and suffer from waning antibody titers and limited efficacy in naïve subjects. Conclusions: The development of a safe and effective vaccine remains complex due to immunologic challenges. Currently, TAK-003 is regarded as the best option for broad implementation, while TV003 and TV005 remain promising candidates due to their shorter schedule and robust immunogenicity. Further research is needed to optimize vaccine strategies in seronegative populations, immunocompromised subjects, older adults, and travelers.