Relevance of the antibody Fc fragment and epitope valency in protection against malaria sporozoites

Protection against infection by Plasmodium falciparum sporozoites is mediated in part by antibodies that recognize the repeated (NPNA)3 epitopes of the circumsporozoite protein (CSP). To evaluate the role that the antibody Fc region plays in neutralizing sporozoite infectivity, we assess the protective efficacy of Fab fragments obtained from protective human monoclonal antibodies and use antibodies bearing the LALA and KA mutations known to reduce Fc functions. To determine the impact of multiple-antibody binding to CSP on protection, we use sporozoites from genetically modified P. berghei strains expressing a CSP containing different numbers of (NPNA)3 epitopes. Our results indicate that Fab fragments and Fc-mutated antibodies have a protective efficacy comparable to intact antibodies, indicating a limited role, if any, of Fc functions in sporozoites in this model system. We also determine that antibody binding to multiple adjacent epitopes and the establishment of homotypic interactions between bound antibodies may not be necessary for protection, as binding to one epitope is sufficient to strongly reduce liver burden while only two separate epitopes are needed to achieve sterile protection.