Immunity to malaria is mediated by antibodies that block parasite replication to limit parasite burden and prevent disease. T follicular helper (Tfh) cells play critical roles in the induction of functional and protective antibody responses in malaria. In humans, Tfh cells have been observed in the circulation and can be differentiated into various subsets including Th1-, Th2-, and Th17-. We have previously shown in volunteer infection studies of naïve adults infected with Plasmodium falciparum that Th2-cTfh (circulating Tfh) cells are strongly associated with induction of functional antibodies, but not Th1- or Th17-cTfh cells. Our group is now focused on developing Th2-Tfh targeting approaches that may be used to boost immunity in at risk populations. However, current knowledge of the pathways driving the heterogeneity in cTfh cells is limited. We have applied single-cell RNA sequencing on cTfh cells isolated during experimental human malaria to delineate pathways underlying the differentiation of specific Tfh subsets and to characterize the transcriptomic dynamics of cTfh cells in malaria. In addition, within the experimental human malaria infection model, we are testing whether host-directed therapy can boost Tfh cell responses in human malaria by blocking Type I Interferon signalling. Excessive Type I Interferon signalling has been linked to sub-optimal Tfh cell responses via activation of different immunoregulatory pathways in malaria. Together, our research will improve upon strategies to better target Tfh cell responses for enhancing vaccine efficacy in at-risk populations of malaria.