Abstract The four serotypes of dengue virus (DENV1–4) are the leading cause of mosquito-borne viral diseases in humans. Dengvaxia, the first licensed dengue vaccine, was recommended for individuals aged 9–45 years in 2016. In the Philippines, a school-based vaccination program was launched in April 2016 with >830,000 children receiving Dengvaxia without prior serological testing. Subsequently, DENV-seronegative children who received Dengvaxia developed severe disease after breakthrough DENV infection (BTDI). This resulted in the revised recommendation in 2018 that Dengvaxia be administered only to DENV-seropositive individuals. Thus, thousands of Filipino children are at higher risk of severe dengue disease. Studies have shown the efficacy of Dengvaxia waned over time especially among baseline DENV-seronegative recipients, underscoring a critical need for elucidation of antibody and T-cell responses induced by Dengvaxia. Our understanding of Dengvaxia was primarily based on efficacy trials with 3-dose regimen. A knowledge gap exists regarding the risk of severe disease and effectiveness in the real world, where most individuals received only 1 or 2 doses and presented with BTDI. In collaboration with the Research Institute for Tropical Medicine, our recent study demonstrated the feasibility of our DENV1–4 nonstructural protein 1 (NS1) IgG ELISA to determine the baseline DENV serostatus of Dengvaxia recipients during both BTDI and other febrile illness (OFI) in the Philippines. Our long-term goal is to facilitate the development of next-generation dengue vaccines and to reduce the global disease burden of dengue. The objective is to understand the long-term effects of Dengvaxia, a chimeric yellow fever tetravalent dengue vaccine, and the immune responses induced in the Filipino population. The central hypothesis is that Dengvaxia induces antibody and T-cell responses inferior to natural infection, leading to limited type-specific neutralizing antibodies, weak T-cell responses and waning vaccine efficacy especially for baseline DENV-naïve recipients. The first aim is to determine the baseline DENV serostatus of Dengvaxia recipients in the Philippines and assess the long-term safety and effectiveness of Dengvaxia. The second aim is to characterize antibody and T-cell responses induced by Dengvaxia prior to and after BTDI. The proposed research is innovative as it combines RT-PCR and IgM ELISA used in routine dengue fever surveillance and our recently validated DENV1−4 NS1 IgG ELISA to determine baseline DENV serostatus under field conditions and provides new insights into the safety and effectiveness of Dengvaxia after mass vaccination through a manufacturer-independent study as opposed to that derived from vaccine efficacy trials. Given that previous immunogenicity studies of Dengvaxia primarily focused on neutralizing antibody titers, our in-depth study of antibody responses both qualitatively and quantitatively and T-cell responses to structural ...