Abstract
Orthopoxviruses (OPXVs) belong to a group of nucleo-cytoplasmic large DNA viruses. Human pathogenic OPXVs (hpOPXVs) include at least five viruses, among which smallpox virus and monkeypox virus are the most dangerous viral pathogens. Both viruses are classified as category-one human infectious pathogens in China. Although smallpox was globally eradicated in the 1980 s, it is still a top biosecurity threat owing to the possibility of either being leaked to the outside world from a laboratory or being weaponized by terrorists. Beginning in early May 2022, a sudden outbreak of monkeypox was concurrently reported in more than 100 disparate geographical areas, representing a public health emergency of international concern, as declared by the World Health Organization (WHO). In this review, we present the reasons for hpOPXVs such as monkeypox virus presenting a potential threat to public health. We then systematically review the historical and recent development of vaccines and drugs against smallpox and monkeypox. In the final section, we highlight the importance of viromics studies as an integral part of a forward defense strategy to eliminate the potential threat to public health from emerging or re-emerging hpOPXVs and their variants.