Trypanosoma brucei brucei evades host immune responses by multiple means, including the disruption of B-cell homeostasis. This hampers anti-trypanosome vaccine development. Because the cellular mechanism underlying this pathology has never been addressed, our study focuses on the fate of memory B cells (MBCs) in vaccinated mice upon trypanosome challenge. A trypanosome variant surface glycoprotein (VSG) and fluorescent phycoerythrin were used as immunization antigens. Functional and cellular characteristics of antigen-specific MBCs were studied after homologous and heterologous parasite challenge. Immunization with AnTat1.1 VSG triggers a specific antibody response and isotype-switched CD73+CD273+CD80+ MBCs, delivering 90% sterile protection against a homologous parasite challenge. As expected, AnTat1.1 VSG immunization does not protect against infection with heterologous VSG-switched parasites. After successful curative drug treatment, mice were shown to have completely lost their previously induced protective immunity against the homologous parasites, coinciding with the loss of vaccine-induced MBCs. A phycoerythrin immunization approach confirmed that trypanosome infections cause the general loss of antigen-specific splenic and bone marrow MBCs and a reduction in antigen-specific immunoglobulin G. Trypanosomosis induces general immunological memory loss. This benefits the parasites by reducing the stringency for antigenic variation requirements.