Therapeutic immunomodulation in dengue with hyperinflammation

Dengue causes up to 96 million clinical infections annually. Despite this burden, there are currently no licensed therapeutics. Severe dengue is characterized by shock, organ dysfunction, cytopaenias, and vasculopathy, which occur late in the disease, during viral clearance, driven by an excessive host immune response and hypercytokinaemia. One of the most targeted ways of controlling this excessive inflammation is through interleukin-1 receptor (IL-1R) blockade (anakinra). My overarching hypothesis is IL-1 mediated pathways drive hyperinflammation and severe disease in dengue. I hypothesize that therapeutic IL-1R blockade in selected patients with dengue will improve clinical outcomes through attenuation of the inflammatory response. The accompanying immunology and transcriptomic analyses aims to reveal any additional pathophysiological pathways involved in severe dengue. I will test this hypothesis by conducting a phase 2 clinical trial of anakinra in dengue patients with hyperinflammation. I will also perform detailed mechanistic studies, investigating the effect of IL-1R blockade on dengue pathogenesis by assessing kinetics of inflammatory markers, cytokine trajectories, inflammasome and endothelial activation markers, cellular immune responses and antibody studies in trial patients with and without anakinra treatment. I will also investigate immune cell genetic signatures by disease severity and if IL-1R blockade can normalize these signatures over time.