IgA-driven neutrophil activation underlies severe dengue disease after primary Zika virus infection 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 a long-standing Pediatric Dengue Cohort Study in Nicaragua, we show that anti-NS1 immunoglobulin A (IgA) antibodies in plasma, 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 and dengue shock syndrome (DHF–DSS). Moreover, increased neutrophil degranulation in paired plasma 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, anti-NS1 IgA in plasma enhances neutrophil activation in severe dengue disease, with implications for prognostics, therapeutics and vaccines. This study reveals that anti-NS1 IgA antibodies in plasma, induced by prior Zika virus infection, activate neutrophils, underlying severe dengue disease upon a subsequent DENV2 infection, uncovering a pathogenic mechanism relevant for vaccines and therapeutics.