Mpox multiprotein virus-like nanoparticle vaccine induces neutralizing and protective antibodies in mice and non-human primates

Abstract The upsurge of mpox in Africa and the recent global outbreak have stimulated the development of new vaccines and therapeutics. We describe the construction of virus-like particle (VLP) vaccines in which modified M1, A35 and B6 proteins from monkeypox virus (MPXV) clade Ia are conjugated individually or together to a scaffold that accommodates up to 60 ligands using the SpyTag/SpyCatcher nanoparticle system. Immunisation of female mice with VLPs induces higher anti-MPXV and anti-vaccinia virus (VACV) neutralizing antibodies than their soluble protein (SP) counterparts or modified VACV Ankara (MVA). Vaccination with individual single protein VLPs provides partial protection against lethal respiratory infections with VACV or MPXV clade IIa, whereas combinations or a chimeric VLP with all three antigens provide complete protection that is superior to SPs. Additionally, the VLP vaccine reduces the replication and spread of the virus at intranasal and intrarectal sites of inoculation. VLPs induce higher neutralizing activity than the Jynneos vaccine in rhesus macaques, and the VLP-induced antiserum provides better protection against MPXV and VACV than the Jynneos-induced antiserum when passively transferred to female mice. These data demonstrate that an mpox VLP vaccine derived from three MPXV clade Ia proteins protects against clade IIa MPXV and VACV, indicating cross-reactivity for orthopoxviruses.