Salivarian trypanosomes are single-celled extracellular parasites that reside in the blood, lymphatics, and various tissues. They cause infections in humans, livestock, and game animals. Trypanosomes thrive in plain sight of the immune system, by deploying multiple evolutionary acquired evasion strategies, which aim at avoiding antibody-mediated destruction as much as possible. Interestingly, assessing experimental infections has shown that trypanosomes trigger a very rapid induction of specific high-affinity IgGs and other immunoglobulin classes, within the first days of infection. Hence, it appears as if the induction of Ig class switching, and even accelerated Ig somatic hypermutation, might be induced as a decoy mechanism by trypanosomes, to avoid being confronted with IgMs that have a superior parasite killing capacity. Hence, this project will start (Work package / WP1) with the characterization of the protective IgM responses, the mechanism of trypanosome killing, and cellular IgM source. As core experimental tool we will use AID-/- mice that are ‘IgM-locked’ and recently have been shown by us to have a much- improved trypanosomosis control capacity. Next (WP2 & WP3), AID-/- derived IgMs (including monoclonals) will be used for trypanosome target antigen identification. Lastly (WP4) an active vaccination approach with these targets will aim at skewing and boosting the immune response towards generation of protective IgMs against a Trypanosoma brucei challenge.