Qdenga Vaccine: Assessment of immunogenicity in a longitudinal cohort study

About This Grant

Project Summary The global burden of dengue, with nearly 390 million infections annually, and the expanding geographical spread of the disease underscore the urgent need for effective vaccines in both endemic and non-endemic regions. The development of new dengue vaccine candidates has generated considerable interest due to promising preliminary epidemiological evidence suggesting their efficacy. However, substantial gaps remain in our understanding of the immunological mechanisms underlying vaccine performance. This proposal addresses these gaps by conducting a comprehensive analysis of the immune responses elicited by the latest dengue vaccine candidate, Qdenga (Takeda's TAK-003), under real-world conditions. Although Qdenga is currently the only available dengue vaccine recommended for individuals above four years old without restrictions, critical knowledge gaps remain regarding the immunological mechanisms induce by the vaccine, including correlates of protection, the influence of prior dengue exposure, and risks associated with antibody-dependent enhancement (ADE). This proposal aims to move beyond descriptive immune profiling by providing mechanistic insights into how Qdenga shapes protective immunity and identifying potential risks, including suboptimal immune responses. We will conduct longitudinal analysis in a cohort of 110 participants, tracking humoral and cellular immune responses from pre-vaccination to two years post-immunization. Our approach will characterize the magnitude, specificity, and durability of vaccine-induced immunity, stratifying participants by age, sex, and prior DENV exposure to identify key determinants of vaccine response. To address critical gaps, we will employ novel competition assays and bead adsorption methods to distinguish serotype-specific from cross-reactive antibody responses, which are crucial for understanding protection versus potential ADE risks. Furthermore, we will integrate BCR sequencing to map virus-specific plasma and memory B cell diversity, alongside advanced T cell profiling using peptide pools and AIM assays, providing a complete picture of vaccine-induced cellular immunity. Given the emerging evidence linking ADE to breakthrough infections, we will also examine the balance between neutralizing and non-neutralizing antibodies and correlate these findings with observed breakthrough infections in the cohort. By detailing the immunogenic profiles, this research will fill significant gaps in our understanding of dengue vaccine performance. Given the escalating global incidence and wider geographical spread of dengue, this research is particularly relevant. Results are expected to guide future vaccine development strategies, improve current vaccination protocols, and contribute to global dengue prevention efforts.