Vaccine development for DENV is challenging in that the vaccine must induce long-lasting immunity against all four DENV serotypes (DENV1-4), as pre-existing immunity against a heterologous serotype may contribute to severe dengue disease (DHF/DSS). In particular, DENV-specific antibody responses may mediate antibody-dependent enhancement (ADE) of DENV infection under certain conditions. In 2010, we formally demonstrated ADE by developing a mouse mode of ADE-mediated disease, and we began to dissect the contribution of humoral vs. cellular immune components in dengue vaccine-mediated protection using model vaccine candidates as tools to probe the mechanisms by which the vaccine-induced immune responses in mice contribute to protection vs. ADE. Our studies have revealed a critical role for CD8 T-cell responses in dengue vaccine-mediated protection, and showed that the vaccine-induced antibody response can mediate ADE. Thus, contrary to the dogma that emphasizes the importance of humoral immunity alone, our findings imply that a DENV vaccine should induce both humoral and cellular responses to maximize efficacy and safety. In support of this assertion, our recent studies exploring the role of T cells in DENV reinfection and ADE settings have revealed that CD8 T-cells can actually abrogate ADE, suggesting a DENV vaccine that does not elicit CD8 T-cell responses may be dangerous. Since DENV and ZIKV are closely related and cross-reactive in many immunologic assays, it is currently uknown whether a first infection with one virus might protect or worsen a subsequent infection with the other virus. We are currently investigating the role of various T-cell costimulatory pathways in regulating the humoral and cellular responses to and between DENV and ZIKV, and are defining the particular pathways that should be targeted to maximize safety and efficacy of vaccines.