Background: Understanding the immune mechanisms that differentiate protective from pathogenic responses during dengue virus (DENV) infection is critical for effective vaccine development. Objective: To investigate how CD4⁺ T cell depletion alters viral control and the humoral immune response during primary DENV2 infection in a non-human primate (NHP) model. Methods: Rhesus macaques were depleted of CD4⁺ T cells prior to DENV2 infection. Viral kinetics, B cell activation, antibody specificity, and functional outcomes were evaluated longitudinally, including cross-reactivity and antibody-dependent enhancement (ADE) potential. Results: CD4⁺ T cells were essential for early viral clearance and the generation of robust, type-specific neutralizing antibodies. In their absence, animals exhibited early non-specific polyclonal B cell activation, delayed isotype switching, and an expanded repertoire of cross-reactive antibodies to DENV and Zika virus (ZIKV), with diminished neutralizing capacity. CD4-depleted macaques also showed increased ADE potential, particularly against ZIKV, and elevated anti-NS1 IgG titers that persisted one-year post-infection. Conclusion: CD4⁺ T cells play a critical role in orchestrating effective, durable, and type-specific antibody responses during primary DENV infection. Their absence leads to delayed antibody maturation, greater cross-reactivity, and higher ADE potential. These findings emphasize the need for DENV and ZIKV vaccines to include CD4⁺ T cell epitopes that promote high-quality, type-specific antibody responses and minimize ADE risk.

Background: Understanding the immune mechanisms that differentiate protective from pathogenic responses during dengue virus (DENV) infection is critical for effective vaccine development. Objective: To investigate how CD4+ T cell depletion alters viral control and the humoral immune response during primary DENV2 infection in a non-human primate (NHP) model. Methods: Rhesus macaques were depleted of CD4+ T cells prior to DENV2 infection. Viral kinetics, B cell activation, antibody specificity, and functional outcomes were evaluated longitudinally, including cross-reactivity and antibody-dependent enhancement (ADE) potential. Results: CD4+ T cells were essential for early viral clearance and the generation of robust, type-specific neutralizing antibodies. In their absence, animals exhibited early polyclonal B cell activation, delayed isotype switching, and an expanded repertoire of cross-reactive antibodies to DENV and Zika virus (ZIKV), with diminished neutralizing capacity. CD4-depleted macaques also showed increased ADE potential, particularly against ZIKV, and elevated anti-NS1 IgG titers that persisted one-year post-infection. Conclusion: CD4+ T cells play a critical role in orchestrating effective, durable, and type-specific antibody responses during primary DENV infection. Their absence leads to delayed antibody maturation, greater cross-reactivity, and higher ADE potential. These findings emphasize the need for dengue and Zika vaccines to include CD4+ T cell epitopes that promote high-quality, type-specific antibody responses and minimize ADE risk.