Update on efficacy, safety, and immunogenicity of Dengue vaccines: a systematic review and meta-analysis

Dengue Fever (DF), caused by the Dengue virus (DENV), represents a major and expanding global public health challenge. Vaccination is an important public health tool that could prevent Dengue infection and reduce symptoms, including severe Dengue. Several dengue vaccines have been studied and implemented in selected countries; however, evidence on their efficacy/effectiveness, safety, and optimal use varies across populations and settings, highlighting the need for a comprehensive evaluation.

This systematic review and meta-analyses followed PRISMA guidelines. Literature from 2010 was searched across three databases. Independent reviewers screened and extracted data, resolving conflicts with expert input. Risk of bias was assessed using ROB2 and the Newcastle-Ottawa Scale. Random-effects meta-analyses were conducted, reporting pooled Relative Risk and vaccine efficacy, and Geometric Mean Ratios, when feasible.

Seventy-nine studies were included, evaluating Dengue vaccines in adults (46.8%), children/adolescents (31.6%), and mixed-age populations (20.3%). Chimeric Yellow Fever-Dengue Tetravalent Vaccine (CYD-TDV/Dengvaxia^®) was assessed in 28 trials, 3 of which reported a pooled vaccine efficacy of 55% (95%CI 47%-62, I ²=86.9%; p <0.001) against Dengue. Vaccine-induced Geometric Mean Titers (GMTs) increased 5.5- to 12.4-fold across serotypes, with no significant increase in the control groups. When available, greater effectiveness was observed in baseline seropositive individuals and older children. Takeda-003 (TAK-003/QDENGA^®) was evaluated in 23 trials, showing sustained efficacy against virologically confirmed dengue (43.5%-82.1%) and high protection against hospitalization (approximately 87%-90%). Phase I-II studies for the candidate vaccine TV003/TV005 demonstrated favourable safety and immunogenicity profiles during the available follow-up. Other promising candidates included other investigational vaccines such as subunit (V180) or DNA-based (TVDV, D1ME100). Overall, Dengue vaccines were generally well tolerated, with most adverse events being mild to moderate during follow-up.

This review demonstrates substantial progress in Dengue vaccine development. Importantly, CYD-TDV favorable balance is limited to individuals with prior dengue exposure, whereas vaccination of seronegative individuals has been associated with an increased risk of severe dengue. Both CYD-TDV and TAK-003 showed robust immunogenicity and acceptable safety profiles. Emerging vaccine candidates, including TV003/TV005, Butantan-DV, TDEN, inactivated, subunit, and DNA-based platforms, have also shown promising safety and immunogenicity results in early-phase trials. Future attempts should focus on developing Dengue vaccines that provide safe, balanced, and durable protection against all four Dengue virus serotypes while minimizing the risk of antibody-dependent enhancement, focusing also on special populations.