Gravidity-dependent protection against placental malaria is associated with enhanced natural killer cell-mediated antibody-dependent cellular activation: a nested cohort study

BACKGROUND: Placental malaria disproportionately affects primigravid women and is a leading cause of morbidity in endemic settings. IgG specific to VAR2CSA, a placenta-binding Plasmodium falciparum protein, accumulates with successive pregnancies, but protective mechanisms remain incompletely understood. We investigated whether natural killer antibody-dependent cellular activation (NK-ADCA) was acquired in a gravidity-dependent manner and associated with improved birth outcomes. METHODS: We characterised second trimester NK-ADCA and VAR2CSA-specific antibody features among pregnant women in Eastern Uganda (NCT04336189). NK-ADCA (n = 53) against VAR2CSA-expressing P. falciparum-infected erythrocytes was assessed using primary NK cells with autologous or pooled donor plasma with characterised IgG Fc-fucosylation profiles. VAR2CSA-specific IgG abundance and Fc-fucosylation (n = 71) were quantified by ELISA and mass spectrometry. Responses were compared across gravidity and associations with placental malaria and birth weight determined. FINDINGS: ) mediated most NK-ADCA and was preferentially activated by Fc-afucosylated antibodies. INTERPRETATION: Gravidity-dependent protection against placental malaria was associated with enhanced NK-ADCA driven by accumulation of Fc-afucosylated VAR2CSA-specific antibodies, identifying NK-ADCA as a potentially important component of protective immunity to placental malaria. FUNDING: This work was supported by the National Institutes of Health, the Blavatnik Family Foundation, the Stanford University Office of the Vice Provost for Graduate Education, the Stanford Maternal and Child Health Research Institute, and the Danish Research Council for Development Research.