Biophysical and Structural Characterization of Antibody Responses to Malaria Antigens

Abstract

Malaria is a global health priority: 214 million malaria cases were reported in 2015 alone, predominantly in Africa and resulting in 438,000 deaths - 70% of which were in children below five years of age. Reverse vaccinology holds promise to design effective immunogens for the development of malaria vaccines. This concept is based on interrogating the B cell repertoire of vaccinated or infected subjects to identify protective antibodies that will guide immunogen design. Our efforts have focused on plasmodium falciparum targets associated with the development of pre-erythrocytic and transmission-blocking vaccines. We isolated B cells from individuals naturally exposed to plasmodium falciparum, and from vaccinated animals and humans having undergone controlled infection. We performed extensive binding experiments to characterize affinities and competition of dozens of antibodies by isothermal titration calorimetry and biolayer interferometry. These studies uncovered several epitope bins, which give biophysical insights into immunodominant and protective B cell responses. X-ray crystallography, small-angle X-ray scattering and single-particle electron microscopy were used and integrated to define antibody recognition at the molecular level. Our structural delineation of protective epitopes provides the blueprints to engineer optimized antigens that can be formulated and tested as pre-erythrocytic and transmission-blocking malaria vaccines.