Malaria caused >600,000 deaths in 2020. Although it is hoped that Mosquirix – the only licensed malaria vaccine – will reduce this mortality, Mosquirix is only 36% efficacious in children overall and 20% efficacious in children with the highest malaria exposure. Children represent 77% of malaria deaths, meaning this most vulnerable population receives the least protection from the vaccine. New strategies to boost vaccine efficacy are therefore needed.
One potential strategy to boost vaccine efficacy is blockade of type I interferon pathways. We have previously shown that type I interferon pathways are rapidly upregulated during malaria, driving the development of tolerogenic immune responses. It is thought that these tolerised responses can impair memory B cell and antibody responses, altering disease outcomes. It is therefore possible that blockade of type I interferon pathways may prevent such immunoregulation, thus boosting anti-parasite immunity.
To test this theory, we are conducting a phase 1b clinical trial of the drug Ruxolitinib – a JAK1/2 inhibitor that blocks type 1 interferon signaling – using the induced blood stage malaria model. Participants (n=26) will be inoculated with P. falciparum parasites, then treated with the anti-malarial artemether-lumefantrine 8 days later. Participants will also receive either Ruxolitinib treatment or placebo. On day 90 of the trial, participants will be re-infected with P. falciparum parasites, allowing us to determine if Ruxolitinib therapy improves the development of anti-malarial immunity.
To study B cell responses throughout the trial, antibody type, titre and activity will be assessed via ELISA and functional antibody assays, whilst variance in B cell populations will be analysed using flow cytometry, mass spectrometry and scRNAseq. Together these analyses will determine if blockade of type I interferon signaling reduces parasite driven immunoregulation, thus allowing protective B cell responses to develop. As the trial is ongoing, preliminary data will be presented.