Key PointsQuestionIs exposure to Middle East respiratory syndrome coronavirus (MERS-CoV) infection and SARS-CoV-2 vaccination associated with the generation of broadly reactive antibody responses?FindingsIn this cohort study of 18 sera samples collected from 14 patients with MERS-CoV infection before and after COVID-19 vaccination, there were significantly boosted cross-reactive immune responses toward other human coronaviruses, with the strongest cross-recognition between SARS-CoV-2, SARS-CoV, and MERS-CoV.MeaningThese results suggest that COVID-19 vaccination might enhance preexisting immunity against MERS-CoV and SARS-CoV, and to a lesser extent, against other human coronaviruses.