ABSTRACT The central hypothesis of this proposal is that the development of effective vaccines and therapeutic antibodies will benefit from careful evaluation of the full range of potentially protective or harmful antiviral antibody responses throughout all stages of preclinical testing. Small animal models are often used to assess antibody- based interventions to provide sterilizing immunity, but these models may also hold value for studying pathology and mechanisms of protection beyond neutralization. At present, ferrets (Mustela putorius furo) and Syrian hamsters (Mesocricetus auratus) are thought to be good small-animal models for diverse respiratory pathogens as both support infection, manifest disease, and transmit virus. To optimally use these models, there is a critical need to understand the suitability and/or shortfalls of ferrets and hamsters in recapitulating antibody effector functions that affect human clinical outcomes—requiring basic research into the genetic diversity, expression patterns, and functional profiles of both antibodies as well as Fc receptors in these animals. The goal of this project is to perform initial biophysical and functional Fc and FcR profiling in ferrets and Syrian hamsters to elucidate key variables that impact species-specific Fc-FcR-dependent effector functions. Achieving this goal is a prerequisite for optimal translation of insights gained from emerging protective and therapeutic small-animal studies to the clinic and to best prioritize strategies for human clinical trials. Guided by strong preliminary data, and using a combination of gold-standard and state-of-the art approaches, the project goal will be achieved though completion of two Specific Aims: 1) Define the biophysical interactions between FcR and IgG that determine effector functions in ferrets and Syrian hamsters, 2) Develop novel cell lines and assays for evaluating ferret and hamster Fc-mediated antibody effector functions in vitro. The data and results obtained by completing the aims of this proposal will be significant and innovative because they will generate knowledge that will identify the antibody and FcR interactions capable of tuning immune response towards potent antiviral activity versus promoting pathological inflammation in ferrets and hamsters. This knowledge will provide a roadmap for effective translation of studies performed in these small animals, often used to model respiratory pathogens, to outcomes in human trials.