Adjunctive ruxolitinib attenuates inflammation and enhances immunity in volunteers experimentally infected with <i>Plasmodium falciparum</i>

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 <i>Plasmodium falciparum</i>. 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.

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Publication Details

Journal
Science Translational Medicine
Published
2025-11-26
DOI
https://doi.org/10.1126/scitranslmed.aea2531
Citations
1
Primary Topic
Malaria Research and Control
Type
article
Field-Weighted Citation Impact
1.88
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article

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

Julianne Hamelink, Indika Leelasena, Fiona H. Amante, Adam J. Potter et al.
1 citations
Science Translational Medicine
Malaria Research and Control
1.88
article

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

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

Abstract

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 <i>Plasmodium falciparum</i>. 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.

Science Translational MedicineVol. 17(826)
Griffith University (AU), Burnet Institute (AU), Swiss Tropical and Public Health Institute (CH), The University of Queensland (AU), University of the Sunshine Coast (AU), University of Basel (CH), QIMR Berghofer Medical Research Institute (AU), Royal Brisbane and Women's Hospital (AU), Department of Defence (AU), Menzies School of Health Research (AU), Sunshine Coast University Hospital (AU), Peter Doherty Institute (AU), The George Institute for Global Health (AU), Medicines for Malaria Venture (CH), Stanford University (US)
Openalex Percentile: Top 10%
Malaria Research and Control
1.88
DOIOpen Access PDFOpenAlex
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