Review 2: "Genomic Epidemiology Uncovers the Timing and Origin of the Emergence of Mpox in Humans"

Gavin C Conant

doi:doi:10.1162/2e3983f5.0017a3c1

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

by Edyth Parker, Ifeanyi F. Omah, Patrick Varilly, Andrew Magee, Akeemat Opeyemi Ayinla, Ayotunde E. Sijuwola, Muhammad I. Ahmed, Oludayo O. Ope-ewe, Olusola Akinola Ogunsanya, Alhaji Olono, Philomena Eromon, Christopher H Tomkins-Tinch, James Richard Otieno, Olusola Akanbi, Abiodun Egwuenu, Odianosen Ehiakhamen, Chimaobi Chukwu, Kabiru Suleiman, Afolabi Akinpelu, Adama Ahmad, Khadijah Isa Imam, Richard Ojedele, Victor Oripenaye, Kenneth Ikeata, Sophiyah Adelakun, Babatunde Olajumoke, Delia Doreen Djuicy, Loique Landry Messanga Essengue, Moïse Henri Moumbeket Yifomnjou, Mark Zeller, Karthik Gangavarapu, Áine O’Toole, Daniel J Park, Gerald Mboowa, Sofonias Kifle Tessema, Yenew Kebede Tebeje, Onikepe Folarin, Anise Happi, Philippe Lemey, Marc A Suchard, Kristian G. Andersen, Pardis Sabeti, Andrew Rambaut, Richard Njoum, Chikwe Ihekweazu, Idriss Jide, Ifedayo Adetifa, and Christian T Happi

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Published on Jun 19, 2024
www.medrxiv.org

Description

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.

RR\ID Evidence Scale rating by reviewer:

Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.

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Review: The manuscript identifies the geographic and temporal source of the pox outbreak using phylogenomic and phylogeographic methods. The authors find that the human outbreak was associated with a 20-fold increase in mutation rate due to interactions with host factors. They show that the current outbreak was preceded by a number of years of cryptic human-to-human spread near the geographical point of outbreak.

I will note that while I am generally familiar with the approaches of this manuscript, I do not model infectious disease evolution in my own research and cannot claim to be familiar with all of the intricacies of running the models.

Instead, I will make a few broader suggestions.

First, I think the use of the term “evolutionary rate” in the manuscript could be better qualified. In particular, my understanding is that what has changed is actually the viral mutation rate due to host-induced mutations. I would make this point clear early in the manuscript, because there is otherwise the danger of interpreting this change as one perhaps due to changes in the selective environment.

Second, while the manuscript is generally very good at giving confidence intervals for estimates, there are a few places where conclusions are given where we might question the model’s power to draw those conclusions. On lines 204 and following, the authors show that the model suggests continued slow exponential growth of the outbreak through the COVID pandemic. It would be nice, if possible, to compare this model against an alternative where the exponential rate changed in the pandemic. The reason for doing so is not that the currently conclusions are likely wrong—I suspect they are correct. But I am not sure I know that the model has enough statistical power to distinguish between these possibilities.

I would also encourage the authors to rework some of the figures so that they read more legibly on a printed page.

Review 2: "Genomic Epidemiology Uncovers the Timing and Origin of the Emergence of Mpox in Humans"

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