Controlled human malaria infection in adults identify combinations of merozoite antigens associated with clinical immunity.

Two vaccines are currently licensed against Plasmodium falciparum malaria but offer only partial protection that wanes, necessitating repeated dosing that is challenging to implement where it is needed most. We previously identified a subset of Kenyan adults with naturally acquired clinical immunity using controlled human malaria infection studies (CHMI, n = 86/142; ClinicalTrials.gov - NCT02739763). Subsequent studies showed that clinical immunity was strongly correlated with IgG Fc-mediated functional activity against whole merozoites. Here, to zoom in on specific targets associated with clinical immunity, we use samples from the CHMI study and a custom protein microarray (KILchip) to measure IgG antibody reactivity against seventy recombinant merozoite antigens. We identify the top-ranking antigens by analyzing the data using five distinct statistical methodologies: the nonparametric Wilcoxon rank sum test, a Cox proportional hazards model, a modified Poisson regression model, and the machine learning Least Absolute Shrinkage and Selection Operator (LASSO) and random forest models. Antibodies against MSP1, MSP11, RAMA, MSP7, PF3D7_1401600 (PHISTB) and PTEX150 were consistently associated with clinical immunity and in combination predicted complete protection. These findings may be useful to prioritize the next generation of malaria blood stage vaccine candidates.