Significance Coronaviruses (CoVs) have the largest genome among RNA viruses and a proofreading exoribonuclease (nsp14) responsible for high-fidelity RNA synthesis. These properties make CoVs very attractive for the establishment of vaccine platforms or viral vectors since they can stably store large amounts of information without genome integration. Using Middle East respiratory syndrome coronavirus (MERS-CoV) as a model, a propagation-deficient RNA replicon was generated by removing the envelope (E) gene (essential for viral morphogenesis and involved in virulence) and accessory genes 3, 4a, 4b, and 5 (responsible for antagonism of the innate immune response): MERS-CoV-Δ[3,4a,4b,5,E]. This replicon is strongly attenuated and elicits sterilizing protection after a single immunization, making it a promising vaccine candidate and an interesting platform for vector-based vaccine development.