Kobasa, D.; Pfranger, M.; Krause, N.; Fedosyuk, S.; Wiegand, L.; Jordan, I.; Sandig, V.; Leupold, C.; Asbach, B.; Storisteanu, D.; Kalender, A.; Scheer, L.; Brenner, D.; Prevost, J.; Tailor, N.; Vendramelli, R.; Warner, B.; Truong, T.; Parthasarathy, S.; Holbrook, J.; Carnell, G.; Sujit, S. B.; Ashokan, S.; Chan, A.; Whittaker, C.; Ugwu, C.; Happi, C.; Frost, S.; Kinsley, R.; Safronetz, D.; Wagner, R.; Heeney, J. L.

Sub-Saharan Africa continues to experience recurrent outbreaks of zoonotic viral diseases that spill over unpredictably from animal reservoirs into human populations. In many regions, mpox co-circulates with viral hemorrhagic fevers (VHFs) caused by Ebola Sudan virus (SUDV), Marburg virus (MARV), and Lassa fever virus (LASV). Overlapping clinical syndromes that these VHF cause challenge surveillance, diagnostics and timely deployment of effective countermeasures. A single vaccine capable of protecting against these biologically and genetically distinct pathogens would markedly reduce the cost and complexity of outbreak response, lessen dependence on emergency international aid, and strengthen long-term health system resilience. Here, we report on the development of an MVA-based mpox vaccine engineered to express computationally designed, broad-coverage antigens targeting SUDV, MARV and LASV. In preclinical challenge studies, this multivalent vaccine elicited robust immune responses and conferred significant protection against lethal infection from all three pathogens in parallel challenge experiments. These findings establish preclinical proof-of-concept for a single, broadly protective VHF vaccine and support its clinical development for deployment across diverse settings in Sub-Saharan Africa.