Monkeypox Virus and Vaccinia Vaccines: Genomic and Antigenic Differences Relevant to Outbreaks and Vaccinology

Amid the current multi-country mpox outbreak, analyzing monkeypox virus (MPXV) and vaccinia virus (VACV) genomes is vital for understanding evolutionary processes that may impact vaccine efficacy and design. This study aimed to elucidate the phylogenetic relationships and structural features of viral antigens, which are crucial for developing effective vaccines. By aligning 1,903 MPXV genomes from the NCBI Virus repository (released between 2022 and 2024), an increase in phylogenetic diversity was observed compared to previous studies. These genomes grouped into Clade I (25 genomes) and Clade IIB (1,898 genomes), with a new Clade I sub-lineage emerging from samples collected in Sud-Kivu province, Democratic Republic of the Congo. Homology-based modeling of six key neutralization determinants encoded by the highly conserved Clade I MPXV genes revealed several amino acid variants near potential antibody binding sites compared to those of vaccinia and variola virus templates. Despite these structural differences, the long-standing vaccinia vaccines, initially created for smallpox, still play a crucial role in safeguarding humanity against mpox today. The findings have deepened our understanding of disparate evolutionary mechanisms for MPXV and VACV, influencing vaccine efficacy. The workflows for viral genomic analysis and structural modeling in CLC Genomics Workbench will facilitate MPXV research and vaccinology. Finally, this study highlights the critical role of MPXV metagenomic surveillance in identifying viral evolution and potential vaccine resistance.