IgA-driven neutrophil activation underlies post-Zika severe dengue disease in humans

The four dengue virus serotypes (DENV1-4) and the related Zika flavivirus (ZIKV) are major public health concerns worldwide. Primary immunity against ZIKV increases the risk of a subsequent severe DENV2 infection, presenting a significant challenge for developing safe and effective ZIKV vaccines. However, the mechanisms driving this phenomenon remain unclear. Leveraging our long-standing Pediatric Dengue Cohort Study in Nicaragua, we show that serum anti-NS1 IgA antibodies elicited after a primary ZIKV infection drive neutrophil activation and correlate with increased risk of subsequent severe DENV2 disease. Depletion experiments combined with ex vivo functional NETosis assays confirmed that anti-NS1 IgA antibodies drive neutrophil activation in dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Moreover, increased neutrophil degranulation in paired serum samples obtained during the acute DENV2 infection from the same individuals correlated with IgA binding to DENV2 NS1 and preceded the development of vascular leakage. This finding was corroborated in an orthogonal hospital-based study. Thus, serum anti-NS1 IgA enhances neutrophil activation in severe dengue, with implications for prognostics, therapeutics, and vaccines.