Adjunctive ruxolitinib attenuates inflammation and enhances immunity in volunteers experimentally infected with Plasmodium falciparum.

Inhibiting the inflammatory response to malaria offers a promising strategy to improve clinical outcomes and overcome immunoregulatory barriers that hinder development of antiparasitic immunity. We conducted a double-blind, randomized, placebo-controlled trial assessing whether ruxolitinib, a Janus-activated kinase (JAK) 1/2 inhibitor, can reduce inflammatory responses and enhance antiparasitic immunity in malaria-naïve volunteers inoculated with blood-stage Plasmodium falciparum. Twenty participants were inoculated and, on day 8, randomized to receive artemether-lumefantrine with either ruxolitinib or placebo. Ninety days later, participants underwent a second inoculation. Ruxolitinib was safe and well tolerated; moreover, it attenuated inflammatory responses to the initial infection, with reduced posttreatment increases in C-reactive protein and markers of disease severity, including angiopoietin-2 and intercellular adhesion molecule-1. Ruxolitinib also enhanced immune memory after the second infection, with elevated human leukocyte antigen-DRA and 4-1BB, consistent with increased T cell activation. These data support the further evaluation of ruxolitinib as an adjunctive treatment to improve clinical outcomes and boost antiparasitic immunity in clinical malaria.