Safer, More Effective Mpox/Smallpox Vaccine

We have recently shown that mpox/monkeypox virus (MPXV) is unique amongst the orthopoxviruses in being at least partially sensitive to the anti-viral effects of type I interferon (IFN). IFN-sensitivity of MPXV is dependent on the host IFN-inducible Z-nucleic acid sensor ZBP1, acting through RIPK3 and MLKL. VACV contains an IFN-resistance protein, E3, that contains an N-terminal Z-NA binding domain that competes with ZBP1 for binding virus-induced Z-RNA, and thus inhibits sensing of virus infection by ZBP1. This domain is truncated in the MPXV homologue of E3 (the MPXV F3L gene), likely leading to the IFN sensitivity of MPXV. Since both current vaccines for protection against MPXV contain full-length E3L genes, both of the current vaccines could potentially repair the F3L truncation in MPXV-infected individuals who are then vaccinated. In this grant we will establish a MPXV skin CAST/EiJ mouse model. We will use this model to evaluate virulence of multiple strains of MPXV, including clade 1, clade IIA and clade IIB MPXV. We will then use this model to evaluate efficacy as a vaccine, of a novel highly attenuated, replication-competent strain of vaccinia virus that cannot repair the truncation of the MPXV F3L gene.