Lethal VSV-based surrogate mouse models for Sudan and Bundibugyo ebolaviruses enable antibody evaluation under BSL-2 conditions.

Sudan (SUDV) and Bundibugyo (BDBV) ebolaviruses are major outbreak pathogens lacking approved vaccines or therapeutics. Research progress has been hampered by biosafety level 4 (BSL-4) restrictions. Here, we generated recombinant vesicular stomatitis viruses expressing SUDV or BDBV glycoproteins (VSV∆G-SUDV GP, VSV∆G-BDBV GP) and established lethal infection models in Type I interferon receptor knockout (IFNAR -/ -) mice under BSL-2 conditions. Both surrogate viruses induced rapid, dose-dependent mortality with median lethal dose (LD 5 0) values below 2 PFU. Infected mice developed high viral loads in the liver, spleen, and lungs, along with leukopenia, thrombocytopenia, and elevated transaminases indicating systemic infection and liver injury. Treatment with a single monoclonal antibody rEBOV-515 (mAb 515) completely protected mice from lethal challenge, reducing viral loads and restoring body weight. These findings establish reproducible surrogate models for studying SUDV and BDBV infection and provide an accessible experimental platform for evaluating GP-targeting therapeutic strategies under BSL-2 conditions.