Genomic and Antigenic Differences Between Monkeypox Virus and Vaccinia Vaccines: Insights and Implications for 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 1903 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 were grouped into Clade I (25 genomes) and Clade IIB (1898 genomes), with a new Clade I sub-lineage emerging from samples collected in Sud-Kivu province, Democratic Republic of the Congo (DRC). Comparing six key MPXV neutralization determinants (A29, A35, B6, E8, H3, and M1) of a novel 2024 Clade I MPXV isolate to those of the 1996 Zaire isolate revealed remarkable sequence conservation despite spanning 28 years. Homology-based modeling of the Clade I MPXV antigens (A29, A35, E8, H3, and M1) showed high-match identities (84% to 99%) with VACV templates (current mpox vaccine), with several amino acid variants near potential antibody binding sites. Phylogenomic analysis, combined with structural modeling and variant profiling, has yielded valuable insights into the virus and vaccine, guiding vaccine design and functional studies.