Examining homology between MPXV and immunogenic VACV-derived peptides

The mpox virus (MPXV) came to global attention with the 2022 global outbreak. Current vaccination and post-exposure prophylaxis against MPXV consists of live vaccinia whole virus-based vaccines including ACAM2000®, JYNNEOS™, and LC16m8 originally developed against smallpox. Here, we analyzed 152 vaccinia-derived peptides we identified by mass spectrometry for homology with MPXV-1 and MPXV-2 sequences to evaluate their potential relevance to MPXV-specific immunity. We found that 93 (61.2 %) of these sequences were 100 % homologous to both clades. This supports the long-standing hypothesis that immunologic cross-reactivity is due to sequence homology between poxviruses. Our results also suggest the utility of VACV-derived peptides for an mpox peptide-based vaccine candidate. The development of peptide-based vaccines against MPXV could offer significant advantages over currently available vaccines, such as no cold chain requirement, stability, and reduced manufacturing costs.