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Protective Ebola virus (EBOV) antibodies have neutralizing activity and induction of antibody constant domain (Fc)-mediated innate immune effector functions. Efforts to enhance Fc effector functionality often focus on maximizing antibody-dependent cellular cytotoxicity, yet distinct combinations of functions could be critical for antibody-mediated protection. As neutralizing antibodies have been cloned from EBOV disease survivors, we sought to identify survivor Fc effector profiles to help guide Fc optimization strategies. Survivors developed a range of functional antibody responses, and we therefore applied a rapid, high-throughput Fc engineering platform to define the most protective profiles. We generated a library of Fc variants with identical antigen-binding fragments (Fabs) from an EBOV neutralizing antibody. Fc variants with antibody-mediated complement deposition and moderate natural killer (NK) cell activity demonstrated complete protective activity in a stringent in vivo mouse model. Our findings highlight the importance of specific effector functions in antibody-mediated protection, and the experimental platform presents a generalizable resource for identifying correlates of immunity to guide therapeutic antibody design. [Display omitted] • Ebola virus disease survivors develop diverse profiles of antibody responses • Fc engineering of monoclonal antibodies can replicate human functional profiles • A Fc variant panel was generated using an anti-Ebola virus neutralizing Fab domain • Fc variants with high complement yet moderate ADCC activity were protective in vivo Gunn et al. profile Ebola virus disease survivors and apply a platform for engineering antibody Fc domains to define protective profiles. Fc variants with complement deposition yet moderate NK cell activity completely protected infected mice from disease. This experimental platform can be used for identifying correlates of immunity to other pathogens and to guide therapeutic antibody design. [ABSTRACT FROM AUTHOR]