An Ad26.RSV.preF/RSV preF protein combination vaccine demonstrated 80.0% vaccine efficacy for the prevention of respiratory syncytial virus (RSV)-mediated lower respiratory tract disease in a phase 2b study. In addition to neutralizing antibodies, Fc-effector functions are associated with protective immunity against RSV. Here, vaccine-induced Fc-effector functions were evaluated for the Ad26.RSV.preF/RSV preF protein vaccine in a subset of participants enrolled in a phase 1/2a study. RSV preF-specific antibody subclasses, isotypes, Fcy receptor binding, and Fc-effector functions were evaluated on days 1 (pre-vaccination), 15, 29, and 183. Compared with Ad26.RSV.preF or RSV preF protein alone, the combination vaccine induced greater Fc-effector functions, including antibody-dependent neutrophil phagocytosis and antibody-dependent natural killer cell activation. Despite RSV pre-exposure, antibody-dependent neutrophil phagocytosis and antibody-dependent natural killer cell activation were not observed at baseline but were induced de novo following vaccination. Compared with the individual vaccine components, the combination vaccine induced a more polyfunctional antibody response. [ABSTRACT FROM AUTHOR]