ACAM2000 vaccine safety and immunogenicity considerations for smallpox and mpox

INTRODUCTION: Smallpox, eradicated globally in 1980, remains a major biodefense concern due to retained Variola virus stocks and the absence of population immunity following cessation of routine vaccination. Monkeypox virus (MPXV), a related orthopoxvirus, has reemerged as a global public health threat, with major outbreaks in 2022 and renewed spread from 2024 onward. AREAS COVERED: This review evaluates ACAM2000®, a second-generation live smallpox vaccine, summarizing its development, immunogenicity, efficacy, safety, regulatory status, and potential role in mpox prevention. EXPERT OPINION: ACAM2000 remains a critical medical countermeasure for smallpox preparedness and a valuable, though selective, tool for mpox prevention. Its high immunogenicity, rapid protection, and broad orthopoxvirus coverage must be balanced against a well-characterized safety risk profile.