Updated publication reference for PubMed record(s): 31554700. Trypanosoma brucei parasites successfully evade the host immune system by periodically switching the dense coat of Variant Surface Glycoproteins (VSG) at the cell surface. Each parasite expresses VSGs in a monoallelic fashion that is tightly regulated. The consequences of exposing multiple VSGs during an infection in terms of antibody response and disease severity remain unknown. In this study, we overexpressed a high mobility group box protein, TDP1, which was sufficient to open the chromatin of silent VSG expression sites, to disrupt VSG monoallelic expression and to generate viable and healthy parasites with a mixed VSG coat. Mice infected with these parasites mounted a multi-VSG antibody response, which rapidly reduced parasitemia. Consequently, we observed a prolonged mice survival in which nearly 90% of the mice survived a 30-day period infection with undetectable parasitemia. Immunodeficient RAG2 knock-out mice were unable to control the infection with TDP1-overexpressing parasites, showing that the adaptive immune response is critical to reduce disease severity. This study shows that simultaneous exposure of multiple VSGs is highly detrimental for the parasite even at the very early stages of infection, suggesting that drugs that disrupt VSG monoallelic expression could be used to treat trypanosomiasis.