A Perspective on the Growing Threat of Monkeypox Virus

In a paper published in Nature Microbiology, Bernard Moss of the Laboratory of Viral Diseases of the National Institute of Allergy and Infectious Diseases summarizes and discusses the available scientific knowledge about the zoonotic MPX virus smallpox disease (formerly known as "monkeypox"). Given its sudden and alarming global increase in prevalence (from 38 reported cases between 1970-1979 to over 91,000 cases between 2022-2023) and the first documented documentation of sexual transmission (mostly among men who have sex with men [MSM]), the disease is now included in World Health Organization (WHO) External Situation Report #30, highlighting the need to better understand the virus to combat new cases.

This review study examines the biology and genetics of MPXV, its epidemiology, potential animal reservoirs, functional genetics, and the feasibility of using animal models in research to limit the spread of the disease. The article highlights the lack of current scientific knowledge in this area and the need for additional research to elucidate the mechanisms of disease interaction in humans, with a focus on interpreting the mechanisms of action of the three known types of MPXV (1, 2a and 2b).

What is MPXV and why are doctors concerned about this disease?

Monkeypox virus (MPXV) is a zoonotic pathogen from the family of poxviruses, belonging to the genus Orthopoxviruses (subfamily Chordopoxvirinae). It is closely related to variola virus (VARV, the causative agent of smallpox), vaccinia virus (CPXV), and ectomelia virus (ECTV, the causative agent of the rodent disease murine pox). MPXV was first isolated and described from captive cynomolgus fish in 1958, and infections in humans were identified in central and western Africa in the early 1970s.

Although this virus is not clinically as dangerous as the now eradicated smallpox, smallpox is known for its symptoms of flushed skin, high fever, vesiculopustular rashes, and lymphadenopathy. Mortality rates for this disease are reported to range from <3.6% (West Africa) to ~10.6% (Central Africa). Alarmingly, the number of reported cases of smallpox has increased dramatically, from 38 cases between 1970-79 to more than 91,000 cases between 2022-23. Previously limited to Central and Western Africa, the disease has now been identified in the UK, Israel, the United States of America, Singapore and (as of November 2023) 111 countries worldwide.

Increasing global prevalence, detection of human-to-human transmission, and increasing global mortality (167 confirmed deaths between 2022-23) prompted the World Health Organization (WHO) to declare MPXV an "international public health emergency" and include it in an external report about situation No. 30. Unfortunately, despite a long history of the disease, research on MPXV remains insufficient. This review aims to synthesize, compile, and discuss the available scientific literature on the epidemiology of the three known MPXV clades in order to provide clinicians and policymakers with the information needed to contain the disease and potentially achieve eradication similar to smallpox.

Biology, genetics and functional genetics MPXV

Like all other vaccinia viruses, MPXV is a large, double-stranded DNA virus that uses the cytoplasm of its (usually mammalian) host cells for survival and replication. Given the paucity of MPXV-specific studies, much of our understanding of MPXV biology is based on observations of the biology, epidemiology, and functional genetics of vaccine virus (VACV). Briefly, the virus first binds to the host cell, fuses with the cell membranes, and then releases its nucleus into the cytoplasm of the cell. This release triggers the transcription of viral mRNAs that encode 1. Enzymes for viral genome replication, 2. Transcription intermediate step mRNAs, and 3. Surface proteins for host immune evasion and defense.

"The rate of viral evolution is determined primarily by mutation rates. Vaccine proofreader DNA polymerase has a low error rate, and analyzes of VARV in humans and MPXV in chimpanzees show 1 × 10−5 and 2 × 10−6 nucleotide substitutions per site per year respectively, this rate is significantly lower than the 0.8–2.38 × 10−3 and 2 × 10−3 nucleotide substitutions per site per year estimated for SARS-CoV-223 and influenza virus24, respectively, in vitro studies suggest transient gene duplications. (known as the accordion model) may precede further mutational events in orthopoxviruses, allowing accelerated adaptation to host antiviral defenses."

Recent genetic studies have shown that the previously assumed single strain of MPXV actually consists of three clades - clade 1, mainly found in Central African countries, and clade 2a and 2b, mainly found in West Africa. Genomic difference between clades ranges from 4-5% (clade 1 vs clades 2a/2b) and ~2% between clades 2a and 2b.

"Most of the differences between clades are nonsynonymous nucleotide polymorphisms and could potentially affect replication or host interaction. However, almost all genes in clades I, IIa, and IIb appear intact, as indicated by the conserved length of host interaction genes." p>

Functional genetics studies have found that deletions significantly reduce viral replication in nonhuman primate (NHP) models, but this field of science is still in its infancy and more research is required before genetic interventions can be implemented used to combat MPXV.

Epidemiology and animal reservoirs

Until the recent global outbreaks in 2018-19 and 2022-23, cases of MPOX were largely limited to Central and Western Africa. However, due to civil conflict in the region, a lack of medical testing facilities in remote rural areas, and the misidentification of MPoxa as smallpox before its eradication, estimates of the prevalence of MPoxa are believed to be underestimated.

"Case reports, which are required in the DRC but not confirmed, showed an upward trend of cases: from 38 in 1970-1979 to 18,788 in 2010-2019 and 6,216 in 2020. From January 1 to November 12, 2023 12,569 cases were reported in other central African countries, including the Central African Republic, Cameroon, Congo, Gabon and South Sudan, where reporting is not mandatory. Primary zoonotic infection is believed to be due to hunting., processing or consumption of wild animals in tropical forests."

Animal reservoirs are considered the most common route of transmission of MPOX, with men who have sex with men (MSM) following in prevalence. Although the source of the first MPXV identified was captive Asian monkeys, studies of their wild counterparts have failed to identify infected populations in Asia. In contrast, large populations of rodents (usually arboreal), monkeys and bats infected with the disease were found in the lowlands of central and western Africa. The highest prevalence was found among rodents of the genera Funisciuris and Heliosciuris, which are considered the main zoonotic reservoirs of this disease.

Despite several decades since the discovery of MPox, our knowledge of the disease and its viral mechanisms remains extremely insufficient. Future research into the biology of MPXV, particularly its ways of evading the host immune system and interactions, would help contain its transmission, especially in Africa.

"A more equitable distribution of vaccines and therapeutics, a better understanding of the epidemiology of MPXV, identification of animal reservoirs of MPXV that can transmit MPXV to humans, and a better understanding of human-to-human transmission are necessary if we are to better manage or even prevent future outbreaks mpoxa."