SUMMARY: OVERALL This proposal, Consortium for Immunotherapeutics Against Emerging Viral Diseases, addresses a critical gap in the biodefense portfolio by building an academic-industry partnership to advance effective, fully human, antibody-based immunotherapeutics against three major families of emerging/re-emerging viruses: Lassa virus, Ebola and other Filoviruses, and mosquito-transmitted Alphaviruses that threaten millions worldwide. This program follows directly from our significant body of preliminary data (the largest available for these families of viruses), therapeutics in hand, multidisciplinary expertise, and demonstrated collaborative success. Included in the proposed CETR portfolio are: (1) the only available immunotherapeutics against endemic Lassa virus, with reversal of late-stage disease and complete survival in infected non-human primates, (2) novel Ebola and pan- ebolavirus therapeutics that also completely protect non-human primates from disease, and that were built by the paradigm-shifting and comprehensive analysis of a global consortium, and (3) much needed, first-in-class therapeutics against the re-emerging alphaviruses that have tremendous epidemic potential in the United States and around the globe. These multidisciplinary studies, founded upon pioneering structural biology of the antigen targets, include innovations such as agnostic, high-throughput Fc profiling and optimization, coupled with Fv evolution to enhance potency and developability, as well as a sophisticated statistical and computational analysis core to evaluate thresholds and correlates of protection across the major families of pathogens. Together, we aim to understand what findings represent general rules and what data are specific to each virus family. We also aim to provide streamlined systems for antibody choice and optimization that do not yet exist, and to build a broadly applicable platform for mAb discovery and delivery against any novel pathogen as they emerge. The recent resurgence of Lassa, the epidemic nature of Ebola virus and other re-emerging filoviruses, as well as the major population at risk by global movement of mosquito-borne alphaviruses together demonstrate the tremendous global need for immunotherapeutics developed and advanced by this program.