Background: Antibody responses to malaria develop slowly, partially due to parasite induced immune-regulatory pathways. Regulatory pathways initiate via type-1 interferon signalling, which drive regulatory T cells that can inhibit antibody development. We tested if blockade of type-I interferon signalling, via the JAK/STAT inhibitor ruxolitinib, could boost humoral immunity in a controlled human malaria infection.
Methods: 20 malaria-naïve individuals were enrolled in a controlled human malaria infection, and randomised to receive either ruxolitinib or placebo therapy alongside antimalarial treatment. We examined the induction of protective immunity, including to a secondary malaria challenge. We analysed B cell responses with scRNAseq, CyTOF and flowcytometry, and humoral immunity via MSP1, MSP2 and merozoite ELISA.
Results: Ruxolitinib inhibited interferon-stimulated gene expression in B cells, and blocked the emergence of interferon stimulated B cells. Ruxolitinib also delayed plasmablast proliferation in primary infection, and allowed greater clonal expansion and somatic hypermutation in secondary infection. Whilst antibody titres were lower in ruxolitinib treated individuals in second infection, their antibodies exhibited enhanced functional capacity, showing increased FcγRIII binding.
Conclusion: Ruxolitinib successfully inhibited type-I interferon responses via JAK/STAT inhibition, resulting in higher quality humoral responses. Data suggest that host directed JAK-STAT inhibition has the potential to improve infection or vaccination induced immunity in malaria.