A multivalent nanoparticle vaccine elicits potent neutralizing antibody response against monkeypox virus.

The global spread of monkeypox virus (MPXV), coupled with the high mortality rates of new clade Ib variants, continues to be a major public health burden worldwide. To achieve global eradication of mpox, there is an urgent need for a safe and more effective MPXV-specific vaccine, particularly for use in high-incidence countries in Africa. Herein, we observed that antibodies targeting the MPXV surface proteins, particularly A29 and M1 antigen, were the principal components in convalescent plasma responsible for neutralizing MPXV infection. To enhance and optimize the immunogenicity of these surface proteins, we designed a multivalent MPXV nanoparticle (NP) vaccine by displaying them on the surface of self-assembled ferritin NPs using the engineered GvTagOpti/SdCatcher (GvO/Sd) covalent conjugation system. Immunization of mice with the multivalent MPXV NP vaccine elicited robust antigen-specific humoral and cellular immune responses, particularly neutralizing antibodies targeting conserved epitopes of the M1 antigen. This conferred protection against lethal vaccinia virus Western Reserve (VACV-WR) infection, reducing viral titers in the lungs of infected mice. Remarkably, a single immunization with the multivalent MPXV NP vaccine conferred potent protection in the lungs of mice against a lethal MPXV or VACV-Tiantan (VTT) challenge. Overall, our results underscore the effectiveness of the multivalent MPXV NP vaccine against MPXV and other orthopoxviruses challenge, highlighting its potential as a universal vaccine platform.