Antibodies to PfEMP1 and variant surface antigens: Protection after controlled human malaria infection in semi-immune Kenyan adults.

Acquisition of antibodies to Plasmodium falciparum variant surface antigens (VSA) expressed on infected red blood cells (iRBCs) is associated with naturally acquired immunity to malaria. We have previously shown that antibodies to VSA on iRBCs are associated with protection against parasite growth in the context of controlled human malaria infection (CHMI). This study explored whether antibodies to recombinant antigens derived from Pf EMP1 domains were independently associated with protection during CHMI in semi-immune Kenyan adults. We used a multiplex bead assay to measure levels of IgG antibody against a panel of 27 recombinant Pf EMP1 antigens derived from the Pf EMP1 repertoire of the 3D7 parasite clone. We measured IgG levels in plasma samples collected from the CHMI participants before inoculation with Sanaria® PfSPZ Challenge, on the day of diagnosis, and 35 days post-inoculation. Univariable and multivariable Cox regression analysis was used to evaluate the relationship between the levels of antibodies to the antigens and CHMI outcome. We also adjusted for previous data including antibodies to VSA on iRBCs, and we assessed the kinetics of antibody acquisition to the different Pf EMP1 recombinant antigens over time. All study participants had detectable antibodies to multiple Pf EMP1 proteins before inoculation. All Pf EMP1 antigens were associated with protection against parasite growth to the threshold criteria for treatment in CHMI, albeit with substantial collinearity. However, individual Pf EMP1 antigens were not independently associated with protection following adjustment for breadth of reactivity to VSA on iRBCs and schizont extract. In addition, antibodies to Pf EMP1 antigens derived from group B Pf EMP1 were induced and sustained in the participants who could not control parasite growth. This study shows that the breadth of antibody response to VSA on iRBCs, and not to specific Pf EMP1 antigens, is predictive of protection against malaria in CHMI. • Naturally acquired Antibodies to recombinant Pf EMP1 were linked to protection in Controlled Human Malaria Infection (CHMI). • Antibodies to the Pf EMP1 domains were highly correlated with each other and with antibody breadth to P. falciparum VSAs • Breadth of antibody responses to VSAs on iRBCs is an independent predictor of protection in CHMI. [ABSTRACT FROM AUTHOR]