Serotype skewing and immune imprinting shape response to the tetravalent dengue virus Qdenga vaccine

Dengue remains a major global health threat, with over 390 million annual infections. The development of safe, effective, and broadly protective vaccines has been hindered by the need for tetravalent coverage and the risk of antibody-dependent enhancement (ADE). Qdenga (TAK-003) is the only dengue vaccine currently widely available globally, yet its immunological profile remains incompletely defined. Here, we characterized humoral and cellular responses, assessing the impact of the vaccine backbone and immune imprinting on vaccine-induced immunity. We conducted a longitudinal immunological study in 110 adults from a dengue-endemic region, stratified by baseline DENV serostatus, sex, and age, including older adults ([≥]65 years), a population excluded from efficacy trials. Plasma and PBMCs were collected before and up to five months after Qdenga vaccination to assess neutralizing antibody titers, B cell dynamics, and virus-specific T cell responses. Although Qdenga elicited B and T cell activation and memory formation across groups, our findings revealed serostatus-dependent and serotype-skewed humoral immunity. Only 8% of DENV-naive individuals developed tetravalent responses, while one-third responded to a single serotype, almost exclusively DENV-2, the vaccine backbone. In contrast, DENV-previously exposed individuals mounted broader responses shaped by baseline serotype-specific immunity, yet neutralization against DENV-4 remained uniformly poor. Neutralizing antibody titers plateaued after the first vaccination, with no substantial increase following the second dose. These findings clarify why balanced tetravalent immunity is rarely achieved with Qdenga and demonstrate that both immune imprinting and vaccine backbone skewing limit the breadth and magnitude of the responses. This has important implications for deployment strategies, long-term protection in DENV-naive populations, and the need for booster strategies focusing on tetravalent coverage, especially for DENV-4.