Prior Dengue Virus Exposure is Associated with Enhanced Zika Virus-Specific ADCC Activity in a Longitudinal Human Cohort.

BACKGROUND: Prior dengue virus (DENV) infection is common in regions affected by Zika virus (ZIKV) and may shape immune responses to subsequent ZIKV infection. Although cross-reactive neutralizing and disease-enhancing antibodies have been extensively studied, the effect of prior DENV immunity on antibody-dependent cellular cytotoxicity (ADCC) responses to ZIKV remains unclear. METHODS: Longitudinal serum samples were obtained and analyzed from a prospective cohort of 46 PCR-confirmed ZIKV cases enrolled at two U.S. sites between 2016-2018 (follow-up visits 6-409 days). ZIKV cases were classified as DENV-experienced (n=13) or DENV-naïve groups (n=33) based on detection of DENV neutralizing antibodies at baseline. ZIKV-specific ADCC activity was measured using a natural killer cell cytotoxicity assay. RESULTS: DENV-experienced individuals had significantly higher peak ZIKV-specific ADCC responses (geometric mean titers [GMT] 15,104 vs 1,819; P<0.0001) and greater cumulative ADCC responses during early (≤80 days, AUC 918,540 vs 42,752; P = 0.0012) and late convalescent phases (>80 days, AUC 953,694 vs 182,004; P=0.0037). Peak ZIKV ADCC magnitude did not correlate with peak DENV or ZIKV antibody neutralizing titers, and ZIKV neutralization efficiency at the time of peak ZIKV ADCC did not differ between groups. However, ZIKV ADCC normalized to ZIKV IgG was significantly higher among DENV-experienced individuals (GMT 2,230 vs 735.6; P=0.0107). CONCLUSIONS: Prior DENV infection was associated with greater ZIKV-specific ADCC magnitude, despite similar ZIKV neutralization, suggesting that prior DENV exposure shapes Fc-mediated flavivirus immunity beyond neutralization. Future studies are needed to assess the clinical implications of these antibodies in immunopathology and protection.