Early insights into predicted efficacy of Ebola monoclonal antibodies for the 2026 Bundibugyo virus disease outbreak

The 2026 Bundibugyo virus disease (BVD) outbreak in the DRC and Uganda raises urgent questions about the efficacy of existing Ebola virus (EBOV) monoclonal antibodies (mAbs) against Bundibugyo virus (BDBV). Here, we perform genomic and structural analyses of 44 BDBV sequences, including 12 from the 2026 outbreak, to assess mAb binding to the viral glycoprotein (GP). While the MBP134 cocktail epitopes remain conserved, mAb114 (Ebanga) binding is compromised by E112D and P116A mutations, causing off-target binding and reduced affinity. Structural modeling of Inmazeb shows that while Odesivimab maintains epitope binding, Atoltivimab and Maftivimab fail to bind their designated sites individually, though the complete trimeric cocktail demonstrates BDBV synergistic binding. These computational models predict mAb114 efficacy against BDBV may be compromised due to epitope mutations affecting binding affinity, whereas MBP134 retains conserved targeting and holds promise as a broadly protective therapeutic. The complex binding behavior of Inmazeb components points to the importance of antibody combinatorial effects for treatment efficacy. These observations warrant urgent experimental validation through neutralization assays. Rapid predictive methods narrow the solution space in an outbreak setting. In this computational study, the authors find that cocktail treatments for Ebola Zaire could be more effective than monotherapies against the 2026 Bundibugyo strain.