Inhibiting the host inflammatory response to malaria represents a potential strategy to improve clinical outcomes and inhibit immunoregulatory pathways that underlie suboptimal development of antiparasitic immunity. Ruxolitinib is a JAK 1/2 inhibitor that reduces inflammatory biomarkers when used in myeloproliferative disorders, and inhibits type-1 interferons and enhances CD4+ T cell immunity when combined with anti-parasitic drugs in animal models. Here we report the results of a double-blind randomised placebo-controlled trial evaluating the ability of ruxolitinib to reduce inflammatory responses and boost anti-parasitic immunity in malaria-naive volunteers inoculated with blood-stage Plasmodium falciparum. Twenty participants were inoculated, and randomized on day 8 to receive artemether-lumefantrine with either ruxolitinib or placebo. Ninety days later, participants who remained eligible were re-inoculated with a second infection. Ruxolitinib was safe and well-tolerated, and attenuated the host inflammatory response to the initial infection, with reduced post-treatment increases in the inflammatory biomarker CRP, as well as markers of disease severity including angiopoietin-2 and ICAM-1. Further, ruxolitinib enhanced the immune memory response following a second inoculation, with increased plasma levels of HLA-DR and CXCL13, indicating enhanced immune activation and germinal centre responses, respectively. These data support the further evaluation of ruxolitinib as an adjunctive treatment to improve clinical outcomes and boost anti-parasitic immunity in clinical malaria.

The authors have declared no competing interest.

Australian New Zealand Clinical Trials Registry (ACTRN12621000866808).

This study was funded by the Australian National Health and Medical Research Council (NHMRC); Ideas Grant to BEB and MJB (GNT2002957). BEB and JCM are supported by NHMRC Investigator Grants (2016792 and 2016396 respectively); MJB is supported by a Snow Medical Fellowship (2022/SF167) and CSL Centenary Fellowship. The QIMR Berghofer Clinical Malaria group receives core funding from Medicines for Malaria Venture (MMV) to support the conduct of malaria volunteer infection studies. Work in the Stanford Human Immune Monitoring Center was supported by the Gates Foundation [INV-008378]. The conclusions and opinions expressed in this work are those of the author(s) alone and shall not be attributed to the Foundation. Under the grant conditions of the Foundation, a Creative Commons Attribution 4.0 License has already been assigned to the Author Accepted Manuscript version that might arise from this submission. Please note works submitted as a preprint have not undergone a peer review process.

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This study was approved by the QIMR Berghofer Medical Research Institute Human Research Ethics Committee (P3696) and ethically reviewed in minimising duplication of ethics by the Australian Departments of Defence and Veterans Affairs Human Research Ethics Committee.

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All data produced in the present study are available upon reasonable request to the authors. NUlisa and phospho CyTOF whole blood data is publicly available: DOI 10.5281/zenodo.15080321 and DOI 10.5281/zenodo.14872946