Rebecca Webster, Damian A. Oyong, Stacey Llewellyn, Azrin N. Abd‐Rahman, Adam J. Potter, Reena Mukhiya, Nischal Sahai, Indika Leelasena, Eniko Ujvary, Sue Mathison, Dean Andrew, Luzia Bukali, Fabian de Labastida Rivera, Jessica A. Engel, Megan S. F. Soon, Teija Frame, Julianne Hamelink, Mayimuna Nalubega, Nicholas L. Dooley, Jessica R. Loughland, Tran Thuy Nguyen, Yael Rosenberg‐Hasson, Sofia Maysel-Auslender, N H Sigal, Kira Foygel, Jeremy Gower, Jenny Peters, Ria Woo, Fiona H. Amante, Timothy N. C. Wells, Stephan Chalon, Joerg J. Moehrle, James McCarthy, Geoffrey W. Birrell, Michael D. Edstein, Michael D. Leipold, Gerlinde Obermoser, Holden Maecker, Christian Engwerda, Bridget E. Barber, Michelle J. Boyle
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.