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Background. Human infection by orthopoxviruses is being reported with increasing frequency, attributed in part to the cessation of smallpox vaccination and concomitant waning of population-level immunity. In July 2015, a female resident of interior Alaska presented to an urgent care clinic with a dermal lesion consistent with poxvirus infection. Laboratory testing of a virus isolated from the lesion confirmed infection by an Orthopoxvirus. Methods. The virus isolate was characterized by using electron microscopy and nucleic acid sequencing. An epidemiologic investigation that included patient interviews, contact tracing, and serum testing, as well as environmental and small-mammal sampling, was conducted to identify the infection source and possible additional cases. Results. Neither signs of active infection nor evidence of recent prior infection were observed in any of the 4 patient contacts identified. The patient's infection source was not definitively identified. Potential routes of exposure included imported fomites from Azerbaijan via the patient's cohabiting partner or wild small mammals in or around the patient's residence. Phylogenetic analyses demonstrated that the virus represents a distinct and previously undescribed genetic lineage of Orthopoxvirus, which is most closely related to the Old World orthopoxviruses. Conclusions. Investigation findings point to infection of the patient after exposure in or near Fairbanks. This conclusion raises questions about the geographic origins (Old World vs North American) of the genus Orthopoxvirus. Clinicians should remain vigilant for signs of poxvirus infection and alert public health officials when cases are suspected.

The global emergence of zoonotic viruses, including poxviruses, poses one of the greatest threats to human and animal health. Forty years after the eradication of smallpox, emerging zoonotic orthopoxviruses, such as monkeypox, cowpox, and vaccinia viruses continue to infect humans as well as wild and domestic animals. Currently, the geographical distribution of poxviruses in a broad range of hosts worldwide raises concerns regarding the possibility of outbreaks or viral dissemination to new geographical regions. Here, we review the global host ranges and current epidemiological understanding of zoonotic orthopoxviruses while focusing on orthopoxviruses with epidemic potential, including monkeypox, cowpox, and vaccinia viruses.

Although variola virus (VARV) has been eradicated through widespread vaccination, other orthopoxviruses pathogenic for humans circulate in nature. Recently, new orthopoxviruses, including some able to infect humans, have been found and their complete genomes have been sequenced. Questions about the orthopoxvirus mutation rate and the emergence of new threats to humankind as a result of the evolution of circulating orthopoxviruses remain open. Based on contemporary data on ancient VARV DNA and DNA of new orthopoxvirus species, an analysis of the molecular evolution of orthopoxviruses was carried out and the timescale of their emergence was estimated. It was calculated that the orthopoxviruses of the Old and New Worlds separated approximately 40,000 years ago; the recently discovered Akhmeta virus and Alaskapox virus separated from other orthopoxviruses approximately 10,000–20,000 years ago; the rest of modern orthopoxvirus species originated from 1700 to 6000 years ago, with the exception of VARV, which emerged in approximately 300 AD. Later, there was a separation of genetic variants of some orthopoxvirus species, so the monkeypox virus West African subtype originated approximately 600 years ago, and the VARV minor alastrim subtype emerged approximately 300 years ago.

Understanding secondary attack rates is a key knowledge gap in the ongoing clade Ib mpox virus (MPXV) outbreak in the Democratic Republic of the Congo. Here, we report the first cross-sectional serological study to investigate local MPXV clade Ib transmission in South Kivu, DRC. Seropositivity was defined as a detectable titer in a cell lysate-based screening ELISA and confirmation by virus neutralization test. Sera were collected in November and December 2023 ( n  = 120), and in May 2024 ( n  = 48) from professional sex workers (PSW) and visitors of 25 bars with reports of mpox cases. We detected serological evidence for MPXV infection in 18% and 17% of these sera, respectively, indicating that PSW played an important role in MPXV clade Ib transmission in this region. Additionally, sera from 108 direct contacts of mpox cases from 34 households were collected between September 2023 and May 2024. Serological evidence for MPXV infection was found in at least one serum sample in 50% of households, including in nine households with seropositive minors, providing evidence for close-contact household transmission. Serological studies are needed to comprehend the extent and severity of the ongoing MPXV outbreak, and may be used to guide targeted vaccination strategies, particularly for high-risk groups. Serological studies are needed to understand the ongoing clade Ib mpox outbreak in the Democratic Republic of the Congo and neighboring countries. Here, the authors conduct a cross-sectional serological study in South Kivu, highlighting the role of professional sex workers and household transmission in mpox epidemiology.

Mpox clade Ib is significant as it is associated with human cases and plays a key role in understanding the transmission and public health implications of mpox outbreaks. Here we present a case report of the first confirmed human infection of clade Ib in China, which occurred in December 2024 in Zhejiang Province. The case was a 28-year-old woman from South Africa who had sexual contact with an asymptomatic man from the Democratic Republic of the Congo. She presented with disseminated vesicular lesions on the extremities, face, buttocks, trunk, palms, and dorsum of the hands, but lesions were absent from the oral cavity, perineum, and anus. By the 18th day post-onset (DPO), only vesicles remained on the dorsum of the right foot and in the finger web spaces, with complete resolution by the 24th DPO. Among 59 consecutive samples collected, 55 tested positive for mpox virus. Oropharyngeal swabs turned negative by the 16th DPO, while skin lesion samples, urine samples, and scab specimens remained positive through the 20th DPO. Consecutive scab samples consistently exhibited high viral loads. In total, 211 contacts of the symptomatic patient were identified, and no secondary cases occurred. This study underscores the importance of multisite sampling for diagnostic sensitivity, highlights the transmission risk associated with asymptomatic sexual contact, and emphasizes the need for refined contact definitions and management strategies. Further research is needed to explore infection risks across different types of exposure. The first outbreaks of mpox outside Africa in 2022 were caused by clade II but cases of a new clade Ib have been increasing in the Democratic Republic of Congo and neighbouring countries since 2024. Here, the authors describe a case report and public health investigation of the first detected case of mpox clade Ib in China.

This study continues earlier work aimed at identifying potential natural reservoirs of camelpox virus (CMLV) during interepizootic periods. In 2023–2024, field expeditions in western Kazakhstan led to the collection and analysis of biological samples from camels, rodents and hematophagous insects. Despite the absence of clinical symptoms, PCR-positive results were obtained from camel blood samples. These samples underwent molecular genetic analysis, including viral DNA detection and whole-genome sequencing. Using next-generation sequencing, the complete genome of the Camelpox virus/Beineu/2023 isolate (202.273 bp) was obtained and deposited in the NCBI database (accession number PV920573.1). The isolate showed >98% genetic similarity to the previously described Kazakhstan strain M-96, indicating long-term local circulation of a genetically stable variant. Phylogenetic analysis confirmed the isolate’s evolutionary conservatism and close relationship with other CMLV strains. The findings suggest that camels serve as a natural reservoir, enabling viral persistence and potential reactivation under stress-related conditions. The observed geographic clustering underscores the need for region-specific molecular surveillance to ensure timely detection of new variants and prevent cross-border spread.

Since the eradication of smallpox, there have been increases in poxvirus infections and the emergence of several novel poxviruses that can infect humans and domestic animals. In 2015, a novel poxvirus was isolated from a resident of Alaska. Diagnostic testing and limited sequence analysis suggested this isolate was a member of the Orthopoxvirus (OPXV) genus but was highly diverged from currently known species, including Akhmeta virus. Here, we present the complete 210,797 bp genome sequence of the Alaska poxvirus isolate, containing 206 predicted open reading frames. Phylogenetic analysis of the conserved central region of the genome suggested the Alaska isolate shares a common ancestor with Old World OPXVs and is diverged from New World OPXVs. We propose this isolate as a member of a new OPXV species, Alaskapox virus (AKPV). The AKPV genome contained host range and virulence genes typical of OPXVs but lacked homologs of C4L and B7R, and the hemagglutinin gene contained a unique 120 amino acid insertion. Seven predicted AKPV proteins were most similar to proteins in non-OPXV Murmansk or NY_014 poxviruses. Genomic analysis revealed evidence suggestive of recombination with Ectromelia virus in two putative regions that contain seven predicted coding sequences, including the A-type inclusion protein.

This article investigates the role of local fauna in Western Kazakhstan as potential reservoirs of the camelpox virus (CMLV). The study emphasizes analyzing possible sources and transmission pathways of the virus using polymerase chain reaction (PCR) and serological methods, including virus neutralization tests and enzyme-linked immunosorbent assays (ELISA). Samples were collected from both young and adult camels, as well as rodents, ticks and blood-sucking insects in the Mangystau and Atyrau regions. The PCR results revealed the absence of viral DNA in rodents, ticks and blood-sucking insects; also, the ELISA test did not detect specific antibodies in rodents. These findings suggest that these groups of fauna likely do not play a significant role in the maintenance and spread of CMLV. Consequently, the primary sources of transmission are likely other factors, potentially including the camels themselves. The study’s results indicate the need to reassess current hypotheses regarding infection reservoirs and to explore alternative sources to enhance strategies for the control and prevention of the camelpox virus.

The antiviral protein kinase R (PKR) is an important host restriction factor, which poxviruses must overcome to productively infect host cells. To inhibit PKR, many poxviruses encode a pseudosubstrate mimic of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2), designated K3 in vaccinia virus. Although the interaction between PKR and eIF2α is highly conserved, some K3 orthologs from host-restricted poxviruses were previously shown to inhibit PKR in a species-specific manner. To better define this host range function, we compared the sensitivity of PKR from 17 mammals to inhibition by K3 orthologs from closely related orthopoxviruses, a genus with a generally broader host range. The K3 orthologs showed species-specific inhibition of PKR and exhibited three distinct inhibition profiles. In some cases, PKR from closely related species showed dramatic differences in their sensitivity to K3 orthologs. Vaccinia virus expressing the camelpox virus K3 ortholog replicated more than three orders of magnitude better in human and sheep cells than a virus expressing vaccinia virus K3, but both viruses replicated comparably well in cow cells. Strikingly, in site-directed mutagenesis experiments between the variola virus and camelpox virus K3 orthologs, we found that different amino acid combinations were necessary to mediate improved or diminished inhibition of PKR derived from different host species. Because there is likely a limited number of possible variations in PKR that affect K3-interactions but still maintain PKR/eIF2α interactions, it is possible that by chance PKR from some potential new hosts may be susceptible to K3-mediated inhibition from a virus it has never previously encountered. We conclude that neither the sensitivity of host proteins to virus inhibition nor the effectiveness of viral immune antagonists can be inferred from their phylogenetic relatedness but must be experimentally determined.

Annotated whole genome sequences of three isolates of the Akhmeta virus (AKMV), a novel species of orthopoxvirus (OPXV), isolated from the Akhmeta and Vani regions of the country Georgia, are presented and discussed. The AKMV genome is similar in genomic content and structure to that of the cowpox virus (CPXV), but a lower sequence identity was found between AKMV and Old World OPXVs than between other known species of Old World OPXVs. Phylogenetic analysis showed that AKMV diverged prior to other Old World OPXV. AKMV isolates formed a monophyletic clade in the OPXV phylogeny, yet the sequence variability between AKMV isolates was higher than between the monkeypox virus strains in the Congo basin and West Africa. An AKMV isolate from Vani contained approximately six kb sequence in the left terminal region that shared a higher similarity with CPXV than with other AKMV isolates, whereas the rest of the genome was most similar to AKMV, suggesting recombination between AKMV and CPXV in a region containing several host range and virulence genes.