The Importance of Human FcγRI in Mediating Protection to Malaria

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Abstract
The success of passive immunization suggests that antibody-based therapies will be effective at controlling malaria. We describe the development of fully human antibodies specific for Plasmodium falciparum by antibody repertoire cloning from phage display libraries generated from immune Gambian adults. Although these novel reagents bind with strong affinity to malaria parasites, it remains unclear if in vitro assays are predictive of functional immunity in humans, due to the lack of suitable animal models permissive for P. falciparum. A potentially useful solution described herein allows the antimalarial efficacy of human antibodies to be determined using rodent malaria parasites transgenic for P. falciparum antigens in mice also transgenic for human Fc-receptors. These human IgG1s cured animals of an otherwise lethal malaria infection, and protection was crucially dependent on human FcγRI. This important finding documents the capacity of FcγRI to mediate potent antimalaria immunity and supports the development of FcγRI-directed therapy for human malaria. Malaria rivals HIV and tuberculosis as the world's most deadly infection killing a child every 30 seconds. Antibodies and their receptors (Fc-receptors) have been shown to be vital for the development of protective immunity, and as such they act as correlates of protection in studies aimed at defining the best antigens to incorporate into current vaccines. Understanding antibody types and Fc-receptors that optimally induce immunity is therefore vital to developing the best vaccines. Surrogate markers of antibody efficacy currently rely on in vitro assays that are laborious and difficult to reproduce. It remains unclear if such in vitro assays are predictive of functional immunity in humans due to the lack of suitable animal models permissive for Plasmodium falciparum. Here, we create a transgenic in vivo mouse model that has significant advantage over the use of new world primates, the only other model for human malaria. We demonstrate that this model defines an Fc-dependent mechanism of parasite destruction that cannot be assessed in current in vitro assays. The model provides both a test for therapeutic antibody efficacy prior to clinical trials in humans and an important tool in malaria vaccine development.