CircRNA vaccine encoding a chimeric immunogen of B6 and M1 demonstrates robust immune responses against MPXV

The mpox outbreak has been declared a Public Health Emergency of International Concern on two occasions, with the status remaining effective, highlighting the urgency of this global health crisis. Developing safe and effective vaccines specifically targeting the MPXV is therefore critical. Our current study presents a bivalent circular RNA (circRNA) vaccine encoding a chimeric immunogen comprising the tandem fusion of MPXV extracellular enveloped virions antigen B6 and intracellular mature virions antigen M1 (CircRNA^B6M1). The B6M1 chimeric immunogen preserves the conformation of the major neutralizing epitopes derived from both antigens. Furthermore, the CircRNA^B6M1 vaccine elicits potent neutralizing antibodies against both MPXV and VACV, while also inducing antigen-specific T cell responses. Notably, the CircRNA^B6M1 vaccine confers complete protection to immunized mice against the lethal VACV challenge. Collectively, these findings identify promising immunogen candidates for developing next-generation circRNA vaccines against the MPXV and other orthopoxviruses.