Since the earliest times of history, smallpox left deep traces in the memory of humanity with the great epidemics and destruction (deaths) it caused. Variola virus, which is the causative agent of smallpox, and some other viruses in the same family have been a part of many extraordinary changes in the field of science and medicine. Poxviruses have a privileged position in the scientific world due to the fact that the first examples of immunization (variolation) in ancient civilizations, the first safe vaccines developed for use in humans (cowpox virus, vaccinia virus), first infection model of viral pathogenesis (ectromelia virus), and the first human infection eradicated globally (smallpox). Smallpox virus (variola major) is classified as a biological warfare agent (category A), causing high-mortality infections and epidemics, and remains a worldwide concern. These viruses are also unique with their various biological features. Poxviruses, one of the largest viruses associated with human infections, are widely used as a convenient model in vaccine development and vector-based treatment studies, with large number of protein coding, ability to replicate primarily in the cell cytoplasm (unlike other DNA viruses), and their other advantageous features. More than 10 species of poxviruses cause infections in humans, and except for a few species that are only isolated from humans, these viruses are generally associated with zoonotic infections. Monkeypox virus (MPXV), one of these species, was regarded far from being a threat to humanity in the past due to possible cross-immunity caused by smallpox vaccine. However, local monkeypox cases reported in Central and West Africa in the early 1970s were replaced by small-scale outbreaks in the United States and Sudan in the 2000s, and in the following periods, this virus is considered to be the most important species of the Poxviridae family after the eradication of smallpox virus due to the increasing number of case reports in African countries, especially in the Democratic Republic of Congo and Nigeria. In addition to epidemiological changes that increase the risk of contact with animal reservoirs, the growing proportion of the unvaccinated population and the new and unexpected transmission pattern indicate that human monkeypox infections may continue to intensify. In recent days, while many countries and health authorities have been re-evaluating the existing and potential risks related to monkeypox virus and smallpox virus, some countries have started to take various measures against the possibility of epidemic and biosecurity risks. The main purpose of this article is to consider the general biological characteristics of poxvirus strains, to examine their host distribution, and to provide an overview of the risks attributed to poxvirus strains associated with human infections.

While the eradication of smallpox virus, which is a success story achieved through a common struggle in human history, eliminated a major threat, the most important advantage was that the agent (variola virus) was not of zoonotic origin. The absence of smallpox infections around the world and the termination of extensive vaccination programs have led to a decrease in global orthopoxvirus immunity day by day. The increasing number of non-immune (for poxviruses) individuals and immunocompromised (general) patients around the world brings along new risks. The predictions that monkeypox virus (MPXV), which is known to cause milder infections in humans compared to smallpox, is seen as one of the 10 infectious agents with pandemic potential, and its spread area may expand, became a reality with the virus placed on the world agenda with the last epidemic in 2022. The approval of newly developed antiviral drugs and vaccines in the last few years shows that some countries are preparing for this change. Although it has been declared by the health authorities that MPXV infections have a low rate of spread among humans and that there is no risk of a new pandemic, the fact that changes in the transmission and spread pattern of the infection carried the virus out of the African continent indicates that new endemic areas may be occur outside the continent, via transmission of the virus from domestic animals to potential reservoir animals in the wild life, continues to be a cause for concern. The spreading possibility of MPXV infections by long transmission chains in immunocompromised populations is considered as another important risk. The risk of increasing cases turning into a growing epidemic and potential biosecurity threats have also raised concerns about the production, storage, and accessibility of preventive vaccines and antiviral drugs to be used in treatment. Considering the unusual rate of human-to-human transmission observed in the recent MPXV outbreak, the spreading of the virus to multiple countries unrelated to endemic areas, and other public health risks; the importance of monitoring MPXV and other poxvirus-related human and animal infections, informing the population at risk and health care workers, and other preventive activities is clearly apparent.