Malaria is a globally important parasitic disease, particularly in Sub-Saharan Africa., It caused approximately 600,000 deaths in 2021 alone, and pregnant women and children under 5 years old are especially vulnerable to infection and severe disease. Repeated exposure to parasites leads to the development of protective immunity that is characterised by an improved ability to control disease-mediated pathology and the production of protective anti-parasitic antibodies. CD4+ T cells, including CXCR3+ IFNγ producing Th1 cells are important for mediating parasite control following infection via the production of pro-inflammatory mediators. However, these cells and their products can also damage tissue. Type I IFNs regulate these responses by driving the differentiation of Th1 cells into IL-10-producing type I regulatory (Tr1) cells, which are important for controlling inflammatory responses. However, the establishment of these immunoregulatory networks is thought to lead to poor parasite control and delayed development of immunity.
Ruxolitinib is a JAK1/2 protein inhibitor that is FDA approved for the treatment of myeloproliferative disorders and type I interferonopathies. We hypothesize that ruxolitinib can transiently block the anti-inflammatory pathways driven by type I IFN signalling and enhance anti-parasitic immune responses during controlled human malaria infection (CHMI). To test the immune boosting potential of ruxolitinib, a double blind phase Ib clinical study was designed in which participants were inoculated with blood-stage Plasmodium falciparum, randomized in a 1:1 ratio and administered the anti-malarial drug artemether/lumefantrine in combination with ruxolitinib or a placebo drug. Preliminary results from the analysis of CD4+ T cells in the clinical trial will be presented.