Genomics reveals zoonotic and sustained human mpox spread in West Africa

Abstract

Five years before the 2022 multi-country mpox outbreak, Nigeria and Cameroon reported their first cases in more than three decades^1,2. Whereas the outbreak in Nigeria is recognized as an ongoing human epidemic, the drivers of the resurgence in Cameroon remain unclear^3,4. The rate of zoonoses remains uncertain in both countries, and gaps in genomic data obscure the timing and zoonotic and geographic origin of monkeypox virus (MPXV) emergence in humans. Here, to address these uncertainties, we sequenced 118 MPXV genomes isolated from cases in Nigeria and Cameroon between 2018 and 2023. We show that in contrast to cases in Nigeria, cases in Cameroon are the result of repeated zoonoses, with two distinct zoonotic lineages circulating across the Nigeria-Cameroon border. Our findings suggest that shared animal populations in the cross-border forest ecosystems drive the emergence and spread of the virus. Accordingly, we identify the closest zoonotic outgroup to the Nigerian human epidemic lineage (hMPXV-1) in a southern Nigerian border state. We estimate that the shared ancestor of the zoonotic outgroup and hMPXV-1 circulated in animals in southern Nigeria in late 2013. We find that hMPXV-1 emerged in humans in August 2014 in the southern Rivers State and circulated undetected for three years. Rivers State was the main source of viral spread during the human epidemic. Our study sheds light on the recent establishment of MPXV in the human population and highlights the risk of persistent zoonotic emergence of MPXV in the complex border regions of Cameroon and Nigeria.

Fig. 1. Drivers of mpox cases in Cameroon and Nigeria.

a, Map of Nigeria and Cameroon, showcasing the ecological setting of zoonotic MPXV. The forest cover is highlighted in green. The border between Nigeria and Cameroon is annotated in red, with the Niger River in Nigeria and Sanaga River in Cameroon highlighted in light blue. Our sampling sites in Cameroon are annotated in orange, and states of interest are annotated with highlighted borders. Sampling sites of zoonotic Nigerian sequences are annotated in blue. NWR, Northwest Region of Cameroon; SWR, Southwest Region of Cameroon. b, Geopolitical regions of Nigeria, with Abia State and Rivers State highlighted with red borders. c, Epidemiological incidence of mpox cases in Nigeria coloured by geopolitical region (top) relative to the temporal and geographic distribution of the Nigerian genomic dataset (bottom). d, Clade IIb phylogeny with reconstructed SNPs mapped onto branches. We performed ancestral state reconstruction across our clade IIb phylogeny to map SNPs to their relevant branches. We annotated APOBEC3 characteristic mutations (CT or GA) in the correct dimer context along branches and calculated their relative proportion across internal branches (f). APOBEC3 mutations along the branches are annotated in yellow and red, with the remainder in grey and black. The hMPXV-1 clade (lineage A) is highlighted in the light blue box, with lineage annotation in text. Our new zoonotic outgroup sequences are annotated as Zx. Our sequences (n = 118) are highlighted as enlarged tips. The lineage sampled from Cameroon and Akwa Ibom in Nigeria is annotated in orange. e, Lineage distribution of our hMPXV-1 sequences. f, The number of APOBEC3 SNPs among all mutations for the zoonotic lineage from Cameroon and Akwa Ibom, the remaining zoonotic subtree (KJ642617 and Zx, annotated in d) and the hMPXV-1 subtree (highlighted and annotated in d).

Fig. 2. Time-resolved global phylogeny of clade IIb.

a, The time-resolved global phylogeny of clade IIb. The new zoonotic outgroup from Abia is annotated as Zx. The distribution along the x axis represents the tMRCA of the node. Sublineages of lineage A in hMPXV-1 are collapsed for visualization. b, Detailed view of the Zx outgroup and hMPXV-1, showing timing of outgroup circulation, transition to sustain human transmission and tMRCA (hMPXV-1).

Fig. 3. Spatiotemporal spread of hMPXV-1 in Nigeria.

a, Phylogeographic reconstruction of the spatiotemporal spread of clade IIb in Nigeria. The branches of the maximum clade credibility tree are coloured by source region. b, Distribution of total number of introductions by state from each start location summarized across the posterior of 10,000 trees to each end location on the y axis. The distribution represents the 95% HPD. The regions of the end location are indicated by background colour. c, Distribution of the number of introductions over time by state, summarized across the posterior of 10,000 trees. The end location is coloured by region. The start location is highlighted by transparency. d, Continuous phylogeography of hMPXV-1 spatiotemporal spread across Nigeria, with timing of viral dissemination indicated by colour. NC, North Central; NE, North East; NW, North West; SE, South East; SS, South South; SW, South West.

Fig. 4. Transmission dynamics of hMPXV-1 in Nigeria.

a, Persistence of transmission chains across all sampled Nigerian states. Individual chains are coloured by region, with the boundary of each individual state highlighted by a filled background and annotated in text on the right. The start of each transmission chain is coloured by its state of origin. The dashed red line indicates the date on which the first case in was reported in Bayelsa (17 September 2017). b, The persistence of each transmission chain versus time of origin, summarized across the posterior of 10,000 trees, coloured by region. Colour scheme as in c. c, The number of transmission chains circulating across all regions over time, calculated using a one-month sliding window. The dashed red line indicates the date on which the outbreak was declared (22 September 2017). d, The percentage of transmission chains that persist over time for South South states, excluding Rivers. Colour bands represent 95% HPD.

Fig. 5. Drivers of spatiotemporal patterns of hMPXV-1 in Nigeria.

a, Generalized linear model coefficients for spatial spread covariates, with corresponding Bayes factors. Significant covariates are highlighted in purple. Covariates are defined in Extended Data Table 1. b, Phylogeographic reconstruction of the migratory pattern of hMPXV-1, showing Rivers State as the origin (highlighted in purple) and other Nigerian states are shown in grey, in accordance with the posterior probability of location.

Extended Data Fig. 1. Phylogeographic analyses of Clade IIb in Nigeria.

The branches of the MCC are coloured by source state, as per legend. Non-Rivers state were grouped by region. SS: South South; SW: South West; SE: South East; NW: North West; NE: North East’ NC: North Central.

Extended Data Fig. 2. Total number of introductions by region from each start region.

Data are summarised across the posterior of 10 000 trees, annotated as per legend in colour, to each end location on the y-axis.

Extended Data Fig. 3. The distribution of the number of introductions across time by region.

Data are summarised across the posterior of 10 000 trees. Distribution represents the 95% highest posterior density. The end location state is coloured by region, as per legend. The start location is highlighted by transparency: all introductions originating from the South-South region are presented with no transparency, whereas introductions originating from other regions are transparent.

Extended Data Fig. 4. Persistence of transmission chains across all regions.

As annotated in text. The start of each transmission chain is coloured by its region of origin. The red line indicates the date of report for the first case in Bayelsa.

Extended Data Fig. 5. Root-to-tip regression of the accumulation of 1) non-APOBEC 2) APOBEC and 3) all mutations (APOBEC and non-APOBEC combined) across the human epidemic (hMPXV-1) and the zoonotic parts of the tree.

Each data point represents a sequence in the tree. The hMPXV-1 subtree’s sequences are displayed in blue, and the zoonotic sequences in green. Lines represent the linear model fitted to the respective (hMPXV-1 and zoonotic) data.

Extended Data Fig. 6. APOBEC and non-APOBEC driven clock rates.

A) Root-to-tip regression of the accumulation of APOBEC3 mutations across the human epidemic. Line represents mean and error bands represent the 95% highest posterior densities B) Comparison of the evolutionary rates under the two-epoch partitioned model summarised across the posterior of 10 000 trees. Distribution represents the 95% highest posterior density, and boxplot represents 25th, 50th and 75% percentile.