Transmission dynamics and evolution of Monkeypox virus (MPXV) during the 2024 global outbreak: implications for surveillance, treatment and vaccination

Monkeypox lineages amid the ongoing COVID-19 pandemic: A global public health concern – Correspondence

Smallpox was eradicated more than 10 years ago, but infection with another Orthopoxvirus, monkeypox virus, can result in a clinical picture resembling smallpox. Human infection with monkeypox virus is extremely rare, not easily transmitted, and confined to the rain forest belt of Africa (Z. Jezek and F. Fenner, p. 81-102, in Human Monkeypox, 1988). Evidence that variola virus, the causative agent of smallpox, might be readily derived from monkeypox virus was presented [S. S. Marennikova and E. M. Shelukhina, Nature (London) 276:291-292, 1978; S. S. Marennikova, E. M. Shelukhina, N. N. Maltseva, and G. R. Matsevich Intervirology 11:333-340, 1979], but this was not confirmed [K. R. Dumbell and L. C. Archard, Nature (London) 286:29-32, 1980] and was subsequently discounted (J. J. Esposito, J. H. Nakano, and J. F. Obijeski, Bull. W.H.O. 63:695-703, 1985). Although enough difference between the genomes of monkeypox and variola viruses to rule out a simple interconversion has been demonstrated [K. R. Dumbell and L. C. Archard, Nature (London) 286:29-32, 1980; J. J. Esposito and J. C. Knight, Virology 143:230-251, 1985; J. J. Esposito, J. H. Nakano, and J. F. Obijeski, Bull. W.H.O. 63:695-703, 1985; M. Mackett and L. C. Archard, J. Gen. Virol. 45:683-701, 1979], the possibility that monkeypox virus was a more remote ancestor of variola virus remained. We have now identified a sequence in monkeypox virus DNA which is a homolog of a 1,065-bp open reading frame in the conserved region of the variola virus genome but which has multiple deletions. This is strong evidence that monkeypox virus is not ancestral to variola virus and strengthens confidence in the long-term success of smallpox eradication.

Monkeypox: Considerations as a New Pandemic Looms

Current Evidence Demonstrates That Monkeypox Is a Sexually Transmitted Infection.

The global spread of the monkeypox virus (MPXV) poses a significant challenge to public health, yet reliable and consistent animal models for evaluating MPXV remain limited, which to some extent restricts the advancement of treatment strategies and transmission-blocking technologies. As natural hosts, African dormice (Graphiurus spp.) represent promising candidates. However, the biological characteristics of MPXV in dormice remain largely unexplored. This study systematically evaluated the pathogenicity and transmissibility of MPXV in dormice. Experimental results demonstrated that dormice are highly susceptible to MPXV infection. Following intranasal inoculation, MPXV induced significant weight loss, lethal infections, and multi-organ pathological damage, with robust viral replication in respiratory and liver tissues. Notably, MPXV can efficiently transmit among dormice through direct contact, with one-third of the contact-exposed dormice shedding infectious viruses and two-thirds exhibiting seropositivity. In addition, one-third of the airborne exposure dormice show seropositivity, yet no infectious viruses were detected in their respiratory tissues, indicating that the airborne transmissibility of MPXV among dormice is relatively restricted. Furthermore, it was observed that infected dormice continuously released large quantities of virus-laden aerosols, with emissions peaking on 12 dpi (3.78±1.01×106copies/dormouse/hour of respiration). Particle size analysis revealed that the viral copies in ≥7 μm coarse particles accounted for >90.9% of exhaled viral aerosols during peak shedding (8–14 dpi). These findings demonstrate that the African dormice serve as an effective animal model for assessing MPXV infection, pathogenicity, and transmission dynamics. Simultaneously, enhanced monitoring of wild dormouse populations is critical due to their potential role in MPXV transmission chains.

Transmission dynamics and evolution of Monkeypox virus (MPXV) during the 2024 global outbreak: implications for surveillance, treatment and vaccination

Monkeypox virus (MPXV) has emerged as a significant public health concern due to its potential for human transmission and its severe clinical manifestations. This review synthesizes findings from peer-reviewed articles spanning the last two decades, shedding light on diverse aspects of MPXV research. The exploration commences with an analysis of transmission dynamics, including zoonotic and human-to-human transmission, and potential reservoir hosts. Detailed insights into viral replication mechanisms illuminate its influence on disease progression and pathogenicity. Understanding the genomic and virion structure of MPXV is pivotal for targeted interventions. Genomic characteristics contributing to virulence are examined, alongside recent advancements in virion structure elucidation through cutting-edge imaging techniques. Emphasizing combat strategies, the review lists potential protein targets within the MPXV lifecycle for computer-aided drug design (CADD). The role of protein-ligand interactions and molecular docking simulations in identifying potential drug candidates is highlighted. Despite the absence of approved MPXV medications, the review outlines updates on ongoing small molecules and vaccine development efforts, spanning traditional and innovative platforms. The evolving landscape of computational drug research for MPXV is explored, encompassing advanced algorithms, machine learning, and high-performance computing. In conclusion, this review offers a holistic perspective on MPXV research by integrating insights spanning transmission dynamics to drug design. Equipping researchers with multifaceted understanding underscore the importance of innovative methodologies and interdisciplinary collaborations in addressing MPXV's challenges as research advances.

First case of mpox diagnosed in Queensland, Australia: clinical and molecular aspects.

The development and evolution of viruses that cause disease have presented a formidable challenge to contemporary medicine and the global economy, not to mention a catastrophic risk to human health. Almost all of these viruses are zoonotic, meaning they were first identified in animals and then spread to humans. An emerging virus may cause only a few isolated instances, resulting in a limited outbreak, or it may cause widespread infection and spread to other parts of the world, triggering a full-blown epidemic. These kinds of emerging occurrences have occurred frequently and in many different forms during the past few decades. Monkeypox is a zoonotic disease caused by the monkeypox virus, a member of the orthopox family that also includes variola, cowpox, and vaccinia. Both animals and humans can get infected by this virus. Similar to smallpox this disease shows less severe rashes and lower mortality rate. The outbreak of monkeypox was declared a global public health emergency by the World Health Organization in July 2022. Unknown mutations and variations are linked to the recent epidemic. Presently, FDA approved tecovirimat, cidofovir and brincidofovir are there in market to treat monkeypox virus. But there are some side effects of these drugs as they are synthetic. So, scientists are working on natural remedies that can be used as alternative to these drugs. In the present study virtual screening of phytochemicals (N-(2-Allylcarbamoyl-4-chloro-phenyl)-3,4-dimethoxy-benzamide, 6-Dimethylaminonaphthene-1-sulfonicacid amide, Oleic Acid and dipentyl ester) from Allophylus serratus were employed against core viral cysteine proteases from monkeypox virus was done. The docking study revealed that selected ligands bind with target viral protein with binding affinity in the range of -5.0 to -6.7 kcal/mol. N-(2-Allylcarbamoyl-4-chloro-phenyl)-3,4-dimethoxy-benzamide showed the highest binding affinity of -6.7 kcal/mol which can be investigated in the future to design potential drugs against monkeypox virus. Thus, this study foresees the possibility of bioactive phytochemicals functioning as template molecules for further experimental evaluation of their efficiency against monkeypox virus.

Monkeypox virus (MPXV) has demonstrated significant variability regarding its virulence and transmission dynamics across different clades, particularly between those originating from Central Africa, referred to as clade I, and those from West Africa, known as clade II. The emergence of new subclades has triggered two public health emergencies of international concerns since 2022. The 2022 global mpox outbreak caused by clade IIb MPXV has lead to over 150,000 infections, while the most recent outbreak caused by clade Ib MPXV, initially detected in the Democratic Republic of the Congo (DRC) in late 2023, has reported more than 40,000 confirmed cases worldwide. Unlike historical clade Ia and IIa strains which are largely associated with zoonotic transmission events, clade IIb and Ib MPXV have demonstrated sustained human-to-human transmission, including sexual, household, and vertical transmission. Currently available therapeutics for Orthopoxvirus infections, namely tecovirimat, cidofovir, and brincidofovir, have been shown to be effective in treating animals infected with MPXV from clades Ia, IIa, and IIb, but not Ib. Here we describe the development of a lethal mouse model for clade Ib MPXV infection and its successful treatment using approved antivirals. Our results suggest that tecovirimat, cidofovir and brincidofovir remain suitable therapeutic options to treat clade Ib MPXV infection.

The 2022 outbreak of monkeypox virus (MPXV), a double-stranded DNA virus, is remarkable for an unusually high number of single-nucleotide substitutions compared to earlier strains, with a strong bias toward C→T and G→A transitions consistent with the APOBEC3 cytidine deaminase activity. While APOBEC3-induced mutagenesis is well documented at the DNA level, its potential impact on MPXV RNA transcripts remains unclear. To assess whether APOBEC3 enzymes act on MPXV RNA, we analyzed RNA-seq data from infected samples. The enrichment of APOBEC signature substitutions among high-frequency mismatched positions led us to consider two possibilities: RNA editing at hotspots or fixed DNA mutations. Multiple lines of evidence support the conclusion that these substitutions arise from DNA-level mutagenesis rather than RNA editing. These include a substantial number of G→A substitutions remaining after normalization by gene strand direction, a largely neutral impact of substitutions on protein-coding sequences, the lack of positional correlation with transcriptional features or RNA secondary structure typically associated with APOBEC action hotspots, and an overlap with known genomic mutations in MPXV strains. Analysis of the nucleotide context of observed substitutions indicated that APOBEC3A or APOBEC3B was likely a driver of DNA-level mutagenesis.IMPORTANCEThe 2022 monkeypox virus (MPXV) outbreak showed an unusually high number of mutations thought to result from human antiviral enzymes of the APOBEC3 family. While such mutations have been clearly documented in the viral DNA, whether APOBEC3 also edits viral messenger RNA molecules remained unclear. In this study, we analyzed multiple publicly available MPXV RNA sequencing datasets to address this question. We found that the apparent APOBEC-like changes in RNA are best explained by fixed DNA mutations rather than active RNA editing. This finding helps clarify how MPXV evolves and adapts, suggesting that APOBEC3's role in shaping the virus likely operates at the DNA level. Understanding where and how these mutations occur provides insight into the virus's interaction with the human immune system and informs future studies on viral evolution and antiviral defenses.

BackgroundMonkeypox is a viral zoonotic disease caused by the monkeypox virus, a double‐stranded DNA‐enveloped virus that can be transmitted from animal to human or human to human. Consequently, it emerged as the most important orthopoxvirus for public health. Based on available online literature, this study reviewed the majority of the data representing the outbreak, diagnosis, treatment, and prevention of monkeypox.MethodsThe literature search was conducted between July 5 and September 15, 2022. In addition to reviewing the databases of World Health Organization (WHO), Centers for Disease Control and Prevention (CDC), Africa CDC, and United Kingdom Health Security Agency monkey pox advice, 43 papers were studied in depth.Results and DiscussionHuman monkeypox was first identified in 1970 in a child in the Democratic Republic of the Congo. Until May 6, 2022, it was endemic in West and Central African countries and infrequently occurred outside of Africa. However, many cases have been identified in several nonendemic countries since May 13, 2022, with no prior human or animal travel from endemic areas; that was the first time to document the cases and long‐term transmission in countries with no epidemiological ties to endemic African countries. Seven travel‐related human monkeypox cases were recorded outside of Africa from September 2018 to November 2021: one in Israel, one in Singapore, and two in the US Youth are most affected. Monkeypox's unanticipated development in places with no known epidemiological linkages raises concerns about the virus's evolution, which permits undetected transmission for a long period.ConclusionMonkeypox is no longer a rare, self‐limiting disease limited to endemic countries. Its ever‐changing epidemiology and transmission dynamics have increased the possibility of its evolving into a much deadlier pathogen. Therefore, improved surveillance and detailed case and contact investigation are required to comprehend the ever‐changing epidemiology of monkeypox.

The recent outbreak of the Monkeypox (Mpox) virus has raised significant concerns. First identified in 1958, Monkeypox virus (MPXV) belongs to the Orthopoxvirus genus, sharing similarities with the Smallpox virus. It is a zoonotic disease mainly harboured by rodents and transmitted through direct interaction with infected animals, respiratory droplets, contaminated materials, or body fluids and from mother to child during pregnancy. The MPXV has a brick-shaped lipoprotein envelope, usually containing conserved genes essential for viral replication and variable genes that influence pathogenicity. The virus exists in two genetic clades: West African (Clade II) with lower mortality (∼1%) and Central African (Clade I) with higher mortality (∼10%). The spread of Mpox was primarily limited to Congo Basin (West Africa), which eventually increased globally. In the year 2022, World Health Organisation (WHO) declared Mpox an 'International Public Health Emergency Concern', indicating vital need to develop robust strategies to combat Mpox. As per 2022 outbreak, 40% patients required medical treatment (antiviral, antibacterials, and pain killer), 1%-13% patients required hospitalisation and 0.1% cases ended in fatality. The contemporary pre- and post-prophylactic therapies, include non-replicating modified vaccinia Ankara vaccination, are not yet available in endemic countries in Africa. Moreover, since January 1, 2024, there have been 812 deaths reported linked to the clade Ib Mpox outbreak in Central Africa, mostly in the Democratic Republic of the Congo. This corresponds to a case-fatality rate of about 3% among the nearly 29,000 assumed cases by September 2024. Hence, this review outlines routes of Mpox transmission and early and chronic symptoms of infection. The mechanisms employed by the virus for immune evasion or immune suppression to promote viral survival inside the host are discussed in detail. The review illustrates Mpox therapeutics and medications, including anti-viral drugs that help to treat symptoms, prevent complications, and support recovery, particularly in the immunocompromised patients. In addition, we discuss recent advancements in the development of prophylactic vaccine for Mpox, including ACAM2000, LC16m8, JYNNEOS (MVA), and others. Future research directions include exploiting the conserved Mpox antigens to develop safer and more broadly protective vaccines. There is also an urgent need for international collaborations in surveillance, rapid response systems and comprehensive OMICS studies for understanding the viral evolution and mutations, which will greatly aid vaccine design and therapeutic strategies to combat Mpox.

Monkeypox virus (MPXV) genomics: A mutational and phylogenomic analyses of B.1 lineages

Monkeypox virus (MPXV) experienced an unprecedented global outbreak in 2022, characterized by a significant departure from historical patterns: a rapid spread of the epidemic to more than 110 non-traditional endemic countries, with more than 90,000 confirmed cases; a fundamental shift in the mode of transmission, with human-to-human transmission (especially among men who have sex with men (MSM)) becoming the dominant route (95.2%); and genetic sequencing revealing a key adaptive mutation in a novel evolutionary branch (Clade IIb) that triggered the outbreak. These features highlight the significant evolution of MPXV in terms of host adaptation, transmission efficiency, and immune escape ability. The aim of this paper is to provide insights into the viral adaptive evolutionary mechanisms driving this global outbreak, with a particular focus on the role of immune escape (e.g., novel mechanisms of M2 proteins targeting the T cell co-stimulatory pathway) in enhancing viral transmission and pathogenicity. At the same time, we systematically evaluate the cross-protective efficacy and limitations of existing vaccines (ACAM2000, JYNNEOS, and LC16), as well as recent advances in novel vaccine platforms, especially mRNA vaccines, in inducing superior immune responses. The study further reveals the constraints to outbreak control posed by grossly unequal global vaccine distribution (e.g., less than 10% coverage in high-burden regions such as Africa) and explores the urgency of optimizing stratified vaccination strategies and facilitating technology transfer to promote equitable access. The core of this paper is to elucidate the dynamic game between viral evolution and prevention and control strategies (especially vaccines). The key to addressing the long-term epidemiological challenges of MPXV in the future lies in continuously strengthening global surveillance of viral evolution (early warning of highly transmissible/pathogenic variants), accelerating the development of next-generation vaccines based on new mechanisms and platforms (e.g., multivalent mRNAs), and resolving the vaccine accessibility gap through global collaboration to build an integrated defense system of “Surveillance, Research and Development, and Equitable Vaccination,” through global collaboration to address the vaccine accessibility gap.