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Background For most classes of drugs, rapid development of therapeutics to treat emerging infections is challenged by the timelines needed to identify compounds with the desired efficacy, safety, and pharmacokinetic profiles. Fully human monoclonal antibodies (mAbs) provide an attractive method to overcome many of these hurdles to rapidly produce therapeutics for emerging diseases. Methods In this study, we deployed a platform to generate, test, and develop fully human antibodies to Zaire ebolavirus. We obtained specific anti-Ebola virus (EBOV) antibodies by immunizing VelocImmune mice that use human immunoglobulin variable regions in their humoral responses. Results Of the antibody clones isolated, 3 were selected as best at neutralizing EBOV and triggering FcγRIIIa. Binding studies and negative-stain electron microscopy revealed that the 3 selected antibodies bind to non-overlapping epitopes, including a potentially new protective epitope not targeted by other antibody-based treatments. When combined, a single dose of a cocktail of the 3 antibodies protected nonhuman primates (NHPs) from EBOV disease even after disease symptoms were apparent. Conclusions This antibody cocktail provides complementary mechanisms of actions, incorporates novel specificities, and demonstrates high-level postexposure protection from lethal EBOV disease in NHPs. It is now undergoing testing in normal healthy volunteers in preparation for potential use in future Ebola epidemics.

Background. A striking feature of Zaire Ebola virus (ZEBOV) infection in nonhuman primates is the rapid depletion of T and NK lymphocytes by apoptosis. In a mouse model of ZEBOV infection, lymphocyte death is a prominent finding; however, the mechanism of death and the lymphocyte subsets that are targeted remain unknown. Methods. We extended the characterization of lymphocyte death in a mouse model of ZEBOV infection by evaluating lymphocytes during the course of disease, using flow cytometry, electron microscopy, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL). Results. B cell, CD4 + and CD8 + T cell, and NK cell counts all dropped dramatically in the blood of infected BALB/c mice, and lymphocyte death was observed in the spleen by means of TUNEL staining and in the blood by means of electron microscopy. Morphologically, lymphocyte death occurred by both classic apoptosis and apoptosis-like programmed cell death. Conclusions. The early and severe loss of peripheral blood NK and CD8 + lymphocytes in ZEBOV-infected mice is similar to that seen in macaques. The morphological basis of lymphocyte death in ZEBOV-infected mice appears to be both classic apoptosis and apoptosis-like programmed cell death, although lymphocyte apoptosis in ZEBOV-infected nonhuman primates seems to occur primarily via classic apoptosis. The mouse model of ZEBOV infection may be useful for the screening of therapeutics directed against limiting lymphocyte death.