In vivo veritas: lessons from immunoglobulin-transfer experiments in malaria patients

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Abstract
In most fields of medicine, experimentation starts with studies in vitro, moves to animal models and eventually proceeds to research on humans. Malaria provides a good example of the limits of this progression. The most important malarial parasite of man, Plasmodium falciparum, only infects man. The specificity of this relationship accounts for the many differences which exist between artificial models of falciparum malaria and natural infections. Ultimately, human infections appear to be the sole, relevant ‘model’ for the study of human-Plasmodium interactions. Immunoglobulin-transfer experiments, for example, clearly indicated that antibodies mediated the state of acquired immunity called premunition. However, further studies in vitro or in animal models led to conflicting results about how the antibodies acted. Transfer experiments in human volunteers, appropriately coupled to in-vitro studies, seemed the only way to help solve this issue. The design of these investigations, with its technical and ethical aspects, is reviewed here, along with the main published and unpublished results. The identification of a monocyte-mediated, antibody-dependent (ADCI) mechanism led to a new merozoite-surface antigen (MSP-3) being identified and provided an explanation for the long delay in the acquisition of protection. It appears that experiments in humans not only help to confirm indications obtained using animal models, but can also have a truly exploratory role, since they can both raise completely new issues and provide answers to them.