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Antibody Fc characteristics and effector functions correlate with protection from symptomatic dengue virus type 3 infection

Preexisting cross-reactive antibodies have been implicated in both protection and pathogenesis during subsequent infections with different dengue virus (DENV) serotypes (DENV1-4). Nonetheless, humoral immune correlates and mechanisms of protection have remained elusive. Using a systems serology approach to evaluate humoral responses, we profiled plasma collected before inapparent or symptomatic secondary DENV3 infection from our pediatric cohort in Nicaragua. Children protected from symptomatic infections had more anti-envelope (E) and anti–nonstructural protein 1 (NS1) total immunoglobulin G (IgG), IgG4, and greater Fc effector functions than those with symptoms. Fc effector functions were also associated with protection from hemorrhagic manifestations in the pre-symptomatic group. Furthermore, in vitro virological assays using these plasma samples revealed that protection mediated by antibody-dependent complement deposition was associated with both lysis of virions and DENV-infected cells. These data suggest that E- and NS1-specific Fc functions may serve as correlates of protection, which can be potentially applied toward the design and evaluation of dengue vaccines. Description Antibody Fc characteristics and effector functions correlate with protection from symptomatic DENV3 infection. Dengue immune defenses Cross-reactive antibodies against different dengue virus serotypes (DENV1-4) can have either protective or pathogenic effects depending on immune responses to the secondary infection serotype. Dias et al. used systems serology to profile DENV-specific antibody responses of previously infected children in a Nicaraguan cohort study to determine correlates of protection against secondary DENV3 infection. Children protected against secondary symptomatic infection had higher titers of total IgG and IgG4 specific to envelope (E) protein and nonstructural protein 1 (NS1) and had antibodies with greater Fc effector functions relative to symptomatic children. Plasma anti-E and anti-NS1 polyclonal antibodies were associated with protection via Fc-driven complement deposition and lysis of DENV virions or infected cells in vitro. Together, these observations indicate that E- and NS1-specific Abs may have Fc effector functions that serve as correlates of protection against DENV.