Ebola virus (EBOV; also known as Zaire ebolavirus) (family Filoviridae) is among the most lethal infectious agents known, producing sporadic outbreaks of severe, and highly lethal hemorrhagic fever in humans and nonhuman primates (NHPs). Owing to high morbidity and mortality rates in natural outbreaks, lack of prophylactic and treatment options, aerosol transmission potential, and their highly virulent nature, Ebola viruses have been identified as both NIAID Category A Priority pathogens and CDC Category A Agents of Bioterrorism. Despite this, the current standard of care is limited to palliative treatment and no therapeutic interventions have been approved against EBOV infection. Among many prophylactic and therapeutic platforms currently under development, monoclonal antibody (mAb) technology has emerged as one of the most promising treatment methods. Worldwide, there exist ~100 mAbs against EBOV that have been characterized to varying degrees. Six of these mAbs have demonstrated complete to partial protection of NHPs when administered from 1 to 4- 5 days after lethal infection. The goal of Project 1 is to achieve total protection in NHPs as late as possible in the course of infection with an ideal cocktail. To this end, the -100 mAbs identified will be produced in a plant expression system and tested in vitro and in vivo for efficacy against EBOV infection. All mAbs will be tested for efficacy in mice and the top performs will subsequently be tested in guinea pigs, individually and in combination. The best mAb combinations will be further tested in NHPs. This downselection process will take into consideration efficacy, binding site, function and complementarity of each mAb. Overall, this proposal is to lay down the scientific foundation for evidence-based selection of the most effective mAb countermeasure against EBOV infection. This will provide an immediate option for compassionate use in post-exposure situations, a research benchmark for evaluation and comparison of additional mAb therapies that might be developed in the future, and essential components of the treatment that will precede complete pharmacokinetics and toxicology studies prior to FDA licensure.