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Primary infection with one of four dengue virus serotypes (DENV1-4) may generate antibodies that protect or enhance subsequent secondary heterotypic infections. However, the characteristics of heterotypic cross-reactive antibodies associated with protection from symptomatic infection and severe disease are not well-defined. We selected plasma samples collected before a secondary DENV heterotypic infection that was classified either as dengue fever (DF, n = 31) or dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS, n = 33) from our longstanding pediatric cohort in Nicaragua. We screened various antibody properties to determine the features correlated with protection from DHF/DSS. Protection was associated with high levels of binding of various antibody isotypes, IgG subclasses and effector functions, including antibody-dependent complement deposition, ADCD. Although the samples were derived from DENV-exposed, Zika virus (ZIKV)-naïve individuals, the protective ADCD association was stronger when assays were conducted with recombinant ZIKV antigens. Further, we showed that a complement-mediated virion lysis (virolysis) assay conducted with ZIKV virions was strongly associated with protection, a finding reproduced in an independent sample set collected prior to secondary heterotypic inapparent versus symptomatic DENV infection. Virolysis was the main antibody feature correlated with protection from DHF/DSS and severe symptoms, such as thrombocytopenia, hemorrhagic manifestations, and plasma leakage. Hence, anti-DENV antibodies that cross-react with ZIKV, target virion-associated epitopes, and mediate complement-dependent virolysis are correlated with protection from secondary symptomatic DENV infection and DHF/DSS. These findings may support the rational design and evaluation of dengue vaccines and development of therapeutics., Competing Interests: Competing interests EH laboratory received research funds from Takeda Vaccines Inc. to test samples from vaccine recipients. EH served on one-time advisory boards for Merck and Takeda. The other authors declare no competing interests.

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.