The Evolutionary Dynamics and Regional Spread of Mpox in Africa: Insights from Multi-country Genomic Surveillance

The Evolutionary Dynamics and Regional Spread of Mpox in Africa: Insights from Multi-country Genomic Surveillance

Abstract

The recent MPXV epidemic across Africa revealed extensive viral diversity and complex transmission dynamics, prompting a continent-wide genomic investigation. We analysed three thousand four hundred fifty high-quality MPXV virus whole genomes from twenty-four African Union Member States, revealing the complex and concurrent circulation of Sub-clades Ia, Ib, IIa, and IIb. Subclade Ia showed high levels of virus diversity in reservoir hosts in Central Africa, detected through zoonotic transmission and some sustained human outbreak lastly detected. In contrast, Clade Ib exhibited signatures of sustained human-to-human transmission across Eastern and Southern Africa. Clade IIa remains largely zoonotic in West Africa. Like Ia, IIb shows continued zoonotic transmission, and sustained human outbreak linked to lineage G1 and G2 circulation. Phylogeographic analyses revealed frequent cross-border transmission and interconnectedness, which was aligned with both human mobility corridors and international boundaries. For instance, the Democratic Republic of the Congo or Sierra Leone seems to emerge as a source of regional exportation, while the Cameroon-Nigeria, CAR-Cameroon or CAR-DRC interfaces reflected ongoing cross-border zoonotic spillovers. These findings underscore the need for harmonised genomic surveillance, APOBEC3-aware triage, and integrated One Health strategies to prevent local outbreaks from escalating into regional epidemics and to inform vaccine deployment and public health preparedness.

Background

Mpox, formerly known as monkeypox, is a historically zoonotic viral disease caused by the mpox virus in the Orthopoxvirus genus. It was first identified in humans in nineteen seventy in the Democratic Republic of Congo. For decades, it remained largely confined to the rural areas of Central and West Africa, with sporadic outbreaks and limited regional and global attention. Between twenty twenty-two and twenty twenty-five, over one hundred forty-eight thousand cases and nearly one thousand eight hundred deaths were reported across twenty-three African countries. The detection of new variants, such as clade Ib in eastern Democratic Republic of Congo, and the spread to previously unaffected countries like Burundi, Rwanda, Uganda, Kenya and others, underscores the evolving threat. In response, Africa CDC declared a Public Health Emergency of Continental Security in August twenty twenty-four, followed by the WHO's declaration of a Public Health Emergency of International Concern - both signalling the urgent need for strengthened surveillance, diagnostics, and coordinated public health action.

The MPXV epidemic has highlighted a complex and evolving viral landscape across the African continent, shaped by ecological diversity and human mobility, of which there is novel insight given the increasing sophistication of genomic surveillance. Sampling worldwide and across the African continent has described four major clades of MPXV - Ia, Ib, IIa, and IIb. The number of documented zoonotic MPXV cases has risen sharply in recent years, likely reflecting either a true increase in spillover events or improved detection through enhanced surveillance; nonetheless, MPXV is now recognised as a re-emerging pathogen with epidemic potential.

While each clade has been linked to sporadic zoonotic infections at different levels, three sustained human-to-human outbreaks have been documented and have been named shtwenty seventeen (IIb), shtwenty twenty-three (Ib), and shtwenty twenty-four (Ia), respectively. The IIb-associated global outbreak of twenty twenty-two to twenty twenty-three (shtwenty seventeen) spread across continents and exhibited enrichment of APOBEC3-like mutations accumulating in the virus population as it transmitted in humans. In Africa, lineage A within clade IIb exhibited high proportions of APOBEC3-type mutations compared to earlier outbreaks, indicating sustained human-to-human transmission. Notably, the G1 lineage deriving from A point two point two was traced from Sierra Leone to Germany and the USA, confirming travel-associated exportation. The Ib-associated Eastern Democratic Republic of Congo outbreak in twenty twenty-three (shtwenty twenty-three) showed localised but persistent transmission in South-Kivu before spreading to neighbouring countries, including Kenya, Rwanda and Burundi. Finally, Clade Ia, previously unrecognised diversity in the Democratic Republic of Congo, suggests an undersampled reservoir population. Added to the cross-border spread between CAR and Democratic Republic of Congo, the Clade Ia-associated outbreak in twenty twenty-four (shtwenty twenty-four) emerged after repeated introductions in urban settings such as Kinshasa, Democratic Republic of Congo.

Broader drivers-urbanisation, cessation of smallpox vaccination, intensified human-wildlife contact, and high population mobility-likely modulate both spillover risk and onward transmission.

The emergence of multiple clades capable of sustained transmission, coupled with evidence of sexual transmission networks, particularly among MSM populations, signals a need for targeted public health interventions.

Several studies have explored the molecular epidemiology of MPXV clade Ia, Ib, IIa, and IIb separately in the endemic and affected countries. A few of them have provided in one report a detailed, large-scale genomic analysis, transmission dynamics, and over an extended period, specifically focused on most of the countries in Africa. In a recent paper, global genomic surveillance of MPXV, about ten thousand six hundred seventy MPXV complete sequences from sixty-five countries collected between nineteen fifty-eight and twenty twenty-four have been analyzed. The results reveal high mobility of clade I viruses within Central Africa, sustained human-to-human transmission of clade IIb lineage A viruses within the Eastern Mediterranean region, and distinct mutational signatures that can distinguish sustained human-to-human from animal-to-animal transmission. The study highlights the importance of genomic surveillance in tracking the spatiotemporal dynamics of MXPV clades. It emphasises the need to enhance such surveillance, particularly in certain parts of Africa.

Here, we present a continent-wide genomic and epidemiological overview of MPXV in Africa, integrating available and high-quality genome sequences from twenty-three African Union Member States, including data up until twenty twenty-five-September-first. This dataset not only refines our understanding of clade structure and diversity but also provides critical insights into the dynamics of cross-border transmission. This study contributes not only a pan-continental genomic atlas of MPXV but also a framework for understanding its evolutionary and transmission dynamics. By combining genomics with surveillance data, we not only map the current situation across the continent but also introduce substantial new genomic evidence to refine our understanding and to inform outbreak prediction, diagnostic and vaccine development, and tailored control strategies.