Dengue virus controlled human challenge reveals that preexisting immunity shapes viral replication and broadly protective responses

Dengue is the canonical viral disease for which immune history is a determinant of protective versus pathogenic responses and immunogenicity. Yet, because of limitations in animal models and clinical presentation after peak viremia, how preinfection and early immune responses affect dengue outcome is not confirmed. We conducted a phase 1 clinical trial with 45 healthy adults to test whether secondary infection challenge with a heterotypic, full-length, attenuated virus increases viremia and immunogenicity compared with primary and tertiary infection. Viremia was associated with more, but still mild, clinical signs and symptoms, and secondary infection resulted in greater viremia, neutralizing antibodies, and protective T cell responses. However, those whose baseline antibodies most efficiently increased dengue virus replication in an in vitro assay experienced delayed inflammatory and adaptive immune activation, the highest viremia, strong acute immune responses, and waning of potent CD8+ T cells and antibodies. In contrast, higher baseline antibodies against the nonstructural protein 1 of multiple serotypes predicted early interferon and balanced immune activation, viremia control, and development of enduring, potent B and T cells, revealing how vaccines can induce broad, long-lasting protection. Last, individuals with potent and neutralizing antibodies and IFN-γ+ T cells at baseline experienced minimal viral replication. Together, these findings demonstrate that controlled human challenge with dengue virus can delineate coordinated versus dysregulated acute immune responses and their effects on immunogenicity, informing therapeutic and vaccine strategies for dengue and other viral diseases.