A cocktail vaccine with monkeypox virus antigens confers protection without selecting mutations in potential immune evasion genes in the vaccinia WR strain challenge

The global emergence of the monkeypox virus (MPXV) underscores the urgent need for effective and accessible vaccines. We developed a recombinant vesicular stomatitis virus (rVSV)-vectored cocktail vaccine expressing four conserved MPXV antigens. This multivalent vaccine elicits rapid and potent immune responses in mice, conferring complete protection against lethal vaccinia virus challenge. A critical finding is that while successive viral challenges selected for mutations in key immune evasion proteins in single-antigen vaccine groups, these mutations were absent in the cocktail-vaccinated group. This suggests that the cocktail strategy may suppress viral genetic drift, potentially limiting escape pathways. Combined with the thermostability of the VSV platform, our vaccine presents a promising and scalable candidate for combating monkeypox.