Natural immunity to malaria develops slowly and malaria vaccine trials have been disappointing, with low efficacy and poor longevity, particularly in areas with high malaria exposure. Many pathogens (Malaria, Leishmania, Trypanosoma, Mycobacterium tuberculosis (Mtb) and HIV) can persist in the human and murine bone marrow (BM), where B lymphocytes develop. As they mature, B cells that bind to molecules present in this environment undergo negative selection and are deleted from the repertoire to prevent autoimmunity. Our research investigates the hypothesis that through persistence in the BM, pathogens can exploit this endogenous mechanism for self-tolerance. This would lead to pathogen-specific tolerance and could contribute to inefficient acquisition of natural and vaccine-induced immunity. Using human samples from a malaria-endemic region in Mali, as well as a chronic malaria mouse model, experimental approaches involve cellular immunology, immunofluorescence analysis and next-generation sequencing of the B cell receptor (BCR) repertoire. It will be elucidated whether pathogen persistence in the BM can undermine efficient acquisition of immunity and illuminate underlying mechanisms, that will ultimately prove critical for the development of an effective vaccine against pathogens such as malaria, HIV and Mtb.