Genomic epidemiology uncovers the timing and origin of the emergence of mpox in humans

Abstract

Five years before the 2022-2023 global mpox outbreak Nigeria reported its first cases in nearly 40 years, with the ongoing epidemic since driven by sustained human-to-human transmission. However, limited genomic data has left questions about the timing and origin of the mpox virus' (MPXV) emergence. Here we generated 112 MPXV genomes from Nigeria from 2021-2023. We identify the closest zoonotic outgroup to the human epidemic in southern Nigeria, and estimate that the lineage transmitting from human-to-human emerged around July 2014, circulating cryptically until detected in September 2017. The epidemic originated in Southern Nigeria, particularly Rivers State, which also acted as a persistent and dominant source of viral dissemination to other states. We show that APOBEC3 activity increased MPXV's evolutionary rate twenty-fold during human-to-human transmission. We also show how Delphy, a tool for near-real-time Bayesian phylogenetics, can aid rapid outbreak analytics. Our study sheds light on MPXV's establishment in West Africa before the 2022-2023 global outbreak and highlights the need for improved pathogen surveillance and response.

Extended Data Figure 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 Figure 2:

Total number of introductions by region from each start region, annotated as per legend in colour, to each end location on the y-axis.

Extended Data Figure 3:

The distribution of the number of introductions across time by region. 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 Figure 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 Figure 5:

Delphy analog to Extended Data Figure 1. Although Delphy’s naive parsimony propagation of geographical labels on the MCC is particularly crude, the basic outline of the geographical spread is clearly recovered.

Figure 1:

A) Epidemiological incidence of mpox cases in Nigeria coloured by geopolitical region (top panel), relative to our genomic dataset’s temporal and geographic distribution (bottom panel). B) Geopolitical regions of Nigeria, with Abia and Rivers State highlighted with red borders C) Global MPXV phylogeny of Clade I, Clade IIa and Clade IIb. Our Clade IIb sequences are annotated with tip points D) Clade IIb phylogeny with reconstructed SNPs mapped onto branches. 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 annotated and highlighted in the light blue box, with the lineage annotation in text. Our new zoonotic outgroup sequences are annotated as “Zx”. Our sequences are highlighted as enlarged tips relative to the background tips. E) Lineage distribution of our Clade IIb sequences. F) The number of overall reconstructed SNPs that APOBEC3 substitutions accounts for in the hMPXV-1 subtree (highlighted and annotated in blue in Figure D) and the Zoonotic outgroup (KJ642617 and Zx annotated in Figure D).

Figure 2

A). Bayesian maximum clade credibility (MCC) tree of Clade IIb indicating the time of emergence of hMPXV-1 into the human population. The distributions indicate the 95% HPD for 1) the tMRCA of the closest zoonotic outgroup of the hMPXV-1 2) the time of transition to sustained human-to-human transmission and 3) the tMRCA of hMPXV-1. SS: South South; SW: South West; SE: South East; NW: North West; NE: North East’ NC: North Central. B) The effective population size of the epidemic in Nigeria under a Skygrid and exponential coalescent model C) The posterior distribution of the estimated doubling time of the epidemic since emergence D) Estimates of the APOBEC3 and Non-APOBEC3 clock rates.

Figure 3:

A) Phylogeographic reconstruction of the spatiotemporal spread of Clade IIb in Nigeria. The branches of the Maximum Clade Credibility tree (MCC) are coloured by source region, as per legend. SS: South South; SW: South West; SE: South East; NW: North West; NE: North East’ NC: North Central. B) Total number of introductions by state from each start location, annotated as per legend in colour, to each end location on the y-axis. The regions of the end location state on the y-axis are highlighted in colour in the plot background as per the legend. C) The distribution of the number of introductions across time by state. The end location state is coloured by region, as per legend. The start location is highlighted by transparency: all introductions originating from Rivers State are presented with no transparency, whereas introductions originating from other states are more transparent. D) Continuous phylogeography of hMPXV-1 spatiotemporal spread across Nigeria, with timing of viral dissemination highlighted by colour range as per legend.

Figure 4:

A) Persistence of transmission chains across all Nigerian states sampled. 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 red line indicates the date of report for the first case in Bayelsa on 17 September 2017. B) The persistence in years of each transmission chain across its time of origin, coloured by region. C) The number of transmission chains circulating across all regions across time, calculated by a month-sliding window. The red line indicates the date the outbreak was declared on 22 September 2017. SS: South 346 South; SW: South West; SE: South East; NW: North West; NE: North East’ NC: North Central. D) The percentage of transmission chains persisting across time for South South states excluding Rivers.

Figure 5:

A) The GLM coefficients of covariates of spatial spread and their associated Bayes Factors. Significant covariates are highlighted in purple. B) Phylogeographic reconstruction of the migratory pattern of hMPXV-1 from Rivers to other Nigerian states.

Figure 6:

A) Delphy MCC for hMPXV-1 samples, coloured by nomenclature (hosted at https://delphy.fathom.info/?mpox2024-post-spillover-with-metadata.dphy); compare to Figs 2A and 1D. The tMRCA distribution calculated by Delphy (blue) overlaps with that of an analogous BEAST run on the same sequences (green); the run for Figure 2A also includes the remaining zoonotic sequences. B) Delphy MCC for hMPXV-1 sequences from Nigeria only (hosted at https://delphy.fathom.info/?mpox2024-post-spillover-nigeria-only-final-with-metadata.dphy), coloured by geographical origin at the tips and propagated to inner nodes via naive parsimony; compare to Fig 3A.