Coordinated serum interferon gamma and IL-15 responses to PfRAS vaccination are associated with protection from malaria

Immunization with radiation-attenuated sporozoites (PfRAS) is highly protective against Plasmodium falciparum malaria, but our understanding of protective correlates is incomplete. The IMRAS study used a PfRAS dose aimed at 50% efficacy to enable discovery of protective correlates. We performed serum proteomics, assaying 2925 serum proteins at five IMRAS study timepoints for 6 protected and 5 non-protected donors, to identify secreted proteins that correlate with immunization and/or protection. We next integrated this serum proteomics dataset with whole blood transcriptomic responses and proportions of circulating immune cells to identify involved signaling pathways and cell subsets. We identified 21 vaccine-induced proteins, including IFNG and IL15. IFNG-stimulated PBMCs from protected IMRAS participants showed increased CXCL9 and CXCL10 responses vs. non-protected participants. IFNG levels in protected individuals correlated with IL15, as well as interferon response gene expression levels in whole blood, and circulating activated CD14+ monocytes. Altogether, this analysis showed that PfRAS can prevent blood-stage malaria infection via coordinated IFNG and IL15 production, activation of CD14+ monocytes, and subsequent production of CXCL9, CXCL10, and CXCL11.