A World Health Organization (WHO) analysis of global mpox surveillance from 1958 to 2024reveals highly mobile clade 1 viruses in Central Africa, sustained human-to-human spread of clade 2b lineage A in the Eastern Mediterranean, distinct mutations that can distinguish between sustained transmission among humans with that among animals, and unique clade 1 sequences from Sudan that suggest local circulation in Eastern Africa.
For the study, published last week in Nature Medicine, the team extracted 6,585 mpox sequences from GenBank and 3,914 from GISAID from 64 countries from the past 67 years.
Clade B.1 caused global outbreak
Mpox virus is divided genetically into clades 1 and 2 and further classified into subclades 2a and 2b.6. The zoonotic (spread between animals and people) infection, which is primarily transmitted via close contact, is characterized by fever and a skin or mucosal lesions.
“Monkeypox virus (MPXV) is endemic in Western and Central Africa and, in May 2022, a clade IIb lineage (B.1) caused a global outbreak outside Africa, resulting in its detection in 116 countries/territories,” the study authors noted.
As of August 12, 2024, the outbreak, which is mainly driven by sexual transmission among men who have sex with men, had led to 99,176 infections and 208 deaths, for a case-fatality rate of 0.21%.
Clade 2b, B.1 lineages sampled only in humans
Nearly all (97.7%) mpox sequences cluster in lineage B.1, representing intensive genomic sequencing during the global outbreak. Clades 1, 2a, and 2b A were sequenced far less often. The vast majority (98.6%) of mpox sequences were collected from 2022 to 2024, with limited historical surveillance, resulting in many years without sequence analyses from 1958 to 2015.
Subclades 2a and 1 were the first to be detected, in 1958 and 1970, respectively, and these clades have continued to circulate. From 2022 to 2024, clade 1 was identified in the Democratic Republic of the Congo (DRC), Sudan, and neighboring African countries, with 2024 DRC cases tied to a novel divergent lineage showing signs of human-to-human transmission in South Kivu.
Clade 2a has not been seen since 2018, and except for a 1971 sample, all clade 2b genomes were sampled from 2017 to 2023. Clade 2b A was first observed in Nigeria in 2017 and has continued circulating among humans up to at least 2023. The descendent lineage B.1 was first seen in 2022.
To date, clade 2b A and B.1 lineages have been sampled only in humans. Nearly all (96%) clade 1 sequences have been sampled in humans, with single samples from an outbreak in captive chimpanzees, wild shrews, and rope squirrels. Only 12% of clade 2a samples, however, came from humans in 1970 (2 samples) and 2003 (1).
Most clade 2a samples (60%) have come from chimpanzees, which are likely a spillover host rather than a reservoir, and some have been isolated from a wild sooty mangabey, cynomolgus monkeys, and a prairie dog in Denmark and the United States.
Clade 1 has been isolated primarily from the Congo Basin, where it has been sampled in the DRC, the Republic of the Congo, Central African Republic, Cameroon, and Gabon. Genomic analysis suggests that clade 1 was introduced multiple times into this region.
Now is time to improve surveillance
Reconstruction of a phylogenetic tree over time suggests that the most recent common ancestor of clade 1 appeared in 1917. The researchers noted frequent international and interprovincial spread of clade 1 viruses over the past 30 years and a high similarity of genetic relatedness between viruses seen in different DRC provinces, suggesting the regular migration of viruses.
It is now time to strengthen mpox surveillance, including in Africa, focusing on populations at highest risk and ensuring integration with existing systems to ensure comprehensive and seamless delivery of care.
The Sudan clade 1 sequences diverged from their closest relative (1985 DRC sample) in 1978, likely circulating in an animal reservoir, as suggested by its 8.5% mutation rate, similar to the 8% expected in animals but much lower than the 85% expected in human evolution. This finding was confirmed by the spread among six eastern Sudanese states of the 18 mpox cases confirmed in that country in 2022.
While clades 2a and 2b A both circulate in West Africa and have been exported to other areas, 2a has not been detected outside West Africa since a 2003 US outbreak. Clade 2b A first spread in Nigeria, then to countries in Europe, Asia, North America, and North Africa.
Cocirculation of different clade 1 lineages in countries and provinces shows that wide mpox diversity continues in the clade 1 animal reservoir, which suggests high mpox prevalence and the potential for frequent spillover when humans interact with reservoir hosts.
“It is unknown whether characteristics of lineage B.1 were acquired following adaptation in humans, or whether they may be generalisable across MPXV clades,” the authors wrote. “This can only be revealed with stronger surveillance, sharing of sequences and continued genotypic and functional characterization of the differences between clades and lineages.”
They called for more labs to work to characterize mpox clades and lineages and for countries to continue recording and sharing viral sequences, prioritizing samples for targeted and representative sequencing.
“This will enable tracking of virus circulation and evolution over time,” the researchers wrote. “If we want to prevent the next mpox global outbreak, it is now time to strengthen mpox surveillance, including in Africa, focusing on populations at highest risk and ensuring integration with existing systems to ensure comprehensive and seamless delivery of care.”
