Mpox virus poses rising global epidemic and pandemic threat

By Dr. Priyom Bose, Ph.D.Reviewed by Benedette Cuffari, M.Sc.Apr 7 2025

A new study highlights the urgent need for deeper research into monkeypox (mpox), citing gaps in pathogenesis, transmission, and immunity as key barriers to developing effective control strategies.

Study: Mpox poses an ever-increasing epidemic and pandemic risk. Image Credit: Shutterstock AI Generator / Shutterstock.com

In a recent Nature Medicine study, researchers discuss the epidemic and pandemic risk of the monkeypox (mpox) virus and how insufficient research in this field is delaying the formulation of effective control strategies.

Orthopoxviruses: prevalence, etiology, and symptoms

Orthopoxviruses (OPXV) are a group of 13 zoonotic viruses in the Poxviridae family and Chordopoxvirinae subfamily, some of which include cowpox, mpox, and smallpox. Following widespread vaccination with vaccinia virus (VACV), smallpox, which is caused by variola virus (VARV), was declared officially eradicated in 1980.

For many years, only sporadic OPXV zoonosis cases have been documented from mpox (MPXV) in Africa, cowpox virus in North Europe, Akhmeta virus in West Asia, Alaskapox virus in North America, and Abatino poxvirus in South Europe.

Except for MPXV, OPXV zoonoses are not transmitted through human-to-human (H2H) contact. Previous studies have reported that MPXV has limited H2H chains, as its virulence ends after two or three transmissions.

All OPXV zoonoses manifest a local lesion at the injection site. However, as compared to other OPXVs, mpox infection is centrifugally distributed in secondary lesions.

Mpox clade and infection

The higher prevalence of MPXV zoonoses is attributed to multiple factors including more frequent human interactions with rodent reservoirs, as well as greater severity and susceptibility for secondary transmission.

In addition to humans, mpox infection causes severe disease through epizootic transfer to non-human primates. Experimental studies have shown that, except for North American ground squirrels, rodents are resistant to infection and disease.

Since rodents are frequently used for laboratory studies, their resistance to MPXV has prevented crucial research needed to understand mpox pathogenesis and immunity. As a result, the exact mechanisms through which mpox infection is disseminated in humans remains unclear.

The 2022 mpox outbreak

In 2022, a rapid clade IIb mpox outbreak originated in Nigeria and subsequently reached several nations throughout the world. This led the World Health Organization (WHO) to declare the outbreak as a Public Health Emergency of International Concern (PHEIC).  

Mpox transmission during this outbreak, which primarily occurred through sexual contact between men who have sex with men, may have been due to the waning of anti-OPXV herd immunity after smallpox vaccination ceased. Soon thereafter, skin-to-skin and mucosal contact likely mediated the rapid and global spread of clade IIb MPXV after 2022.

As early as 2018, mpox cases also exhibited this novel clinical manifestation, which suggests that MPXV may have been in the process of developing a sexual contact transmission route. Mutational drift and the emergence of new variants also contribute to the increased risk of future epidemics and pandemics due to mpox infection.

A new symptom reported during the 2022 mpox outbreak was the incidence of multiple lesion primary rash at an anogenital infection site, which was not always followed by a secondary disseminated rash. Rapid H2H transmission through the primary lesion at the injection site was also observed.

Additional research is needed to confirm whether the primary rash due to mpox infection was a viral adaptation or the result of abrasive skin-to-skin contact after the initial infection.

Emerging epidemic concerns

The rapid emergence of mpox suggests that this virus has the potential to cause epidemics in the future. The possibility of a future mpox epidemic depends on the emergence of an alternative transmission route either through primary rash or establishment in a different demographic such as high tactile contact.

Scientists are concerned about the continual increase in clade Ia zoonotic events among children. However, there has been no evidence of sustained H2H transmission in the population.

In urban settings, a clade Ib outbreak through H2H transmission among children has been documented. Epidemiological studies are warranted to identify whether clade Ib transmission is linked with adults or other children.

Based on the history of smallpox, researchers believe that mpox will induce robust immunity after the infection resolves; however, in certain cases, reinfection could occur. Notably, the number of mpox cases beyond zoonotic regions has significantly reduced from its peak between 2022 and 2023. Nevertheless, mpox continues to circulate at low levels within the global sexual network.

The constant accumulation of apolipoprotein B messenger ribonucleic acid (mRNA) editing enzyme, catalytic subunit 3 (APOBEC3)-driven mutations in mpox strains further contributes to the potential risk of future epidemics. Clade Ia MPXV transmission is also possible and concerning, as these viruses are historically more virulent in humans than clade II viruses with higher morbidity and mortality.

Despite the WHO’s efforts to prevent H2H transmission of mpox in 2022, success was hindered by the lack of vaccine availability, point-of-care (POC) rapid diagnostics, and broad-ranging antivirals. Thus, to fully eradicate mpox infection, scientists must focus on breaking H2H transmission.