Predictive value of PfEMP1 antibody profiles for the course of controlled human malaria infections

Antibody-mediated immunity directed against Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is an important immune mechanism for protection against clinical malaria and control of parasitemia. Current studies on PfEMP1-based immunity are constrained by the protein's high molecular weight, complex multidomain architecture, and extensive polymorphism. Controlled human malaria infection (CHMI) studies uniquely enable the assessment of strain-specific PfEMP1 immunity prior to exposure and its correlation with infection outcomes using the same parasite strain. In this study, different serological assays targeting both full-length native PfEMP1 and individual domains were applied to plasma samples obtained prior to challenge infection at study baseline from 25 individuals enrolled in a CHMI study of PfSPZ Challenge (NF54), that included malaria-naïve Europeans and lifelong malaria-exposed Africans with varying degrees of immunity. All assays showed strong predictive value of both PfEMP1 antibody levels and breadth at study baseline for CHMI outcome. A random forest machine learning analysis of antibody recognition profiles, measured by AlphaScreen nearly covering all extracellular PfEMP1 domains of the NF54-CHMI parasite strain, suggested that a broad antibody repertoire, including antibodies against the most diversified group B PfEMP1s, represents a discriminative feature distinguishing volunteers with high versus low susceptibility to CHMI. In parasites re-isolated from the volunteers, dominant var transcripts encoded PfEMP1 variants are not recognized by the individuals' pre-existing antibodies at study baseline. Given that the CHMI strain NF54 predominantly expresses B-type var genes at the onset of blood-stage infection, effective control of CHMI was associated with a broad antibody repertoire, particularly including antibodies targeting B-type PfEMP1. In line with the "hole-in-the-wall" theory, this likely reflects an antibody-mediated restriction of the parasite population emerging from the liver to parasites expressing PfEMP1 variants not previously encountered by the host immune system.