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Review 3: "Clade I Mpox Virus Genomic Diversity in the Democratic Republic of the Congo, 2018 - 2024: Predominance of Zoonotic Transmission"

Overall, the reviewers appreciated the authors' candid acknowledgment of the study's limitations, including potential sampling biases, and recognized the urgent need for enhanced genomic surveillance to mitigate the mpox epidemic in the DRC. 

Published onOct 05, 2024
Review 3: "Clade I Mpox Virus Genomic Diversity in the Democratic Republic of the Congo, 2018 - 2024: Predominance of Zoonotic Transmission"
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Clade I Mpox virus genomic diversity in the Democratic Republic of the Congo, 2018 - 2024: Predominance of Zoonotic Transmission
Clade I Mpox virus genomic diversity in the Democratic Republic of the Congo, 2018 - 2024: Predominance of Zoonotic Transmission
Description

ABSTRACT Background Recent reports raise concerns on the changing epidemiology of mpox in the Democratic Republic of the Congo (DRC), with increasing case counts, sexual contact-mediated clusters, and sustained human-to-human transmission driven by a novel monkeypox virus (MPXV) subclade, clade Ib. However, only a limited number of clade I MPXV genomes have been characterized so far, from a limited number of regions.Methods We conducted whole genome sequencing of 603 mpox-positive samples that were collected from 581 patients between 2018-2024 in 17 of the 26 provinces of the DRC.Results Genome coverage was at least 70% for 429/603 (71.1%) samples and near full-length MPXV genomes (>90% coverage) were obtained for 348/603 (57.7%) samples from 337 patients. All newly generated MPXV sequences belonged to clade I, among which 17 were clade Ib strains, all from patients infected in 2024 in the South-Kivu province. The large majority (>95%) of the new strains fall within previously described clade Ia groups and potential new groups have also been observed. The low number of APOBEC3 mutations found among clade Ia suggests that most human mpox cases are probably linked to zoonotic transmissions. Genetically diverse MPXV lineages co-circulate in small geographic areas during the same outbreak suggesting multiple zoonotic introductions over a short period from one or multiple reservoir species. Recent identification of mpox cases in Kinshasa shows that multiple lineages circulate in a large urban center, indicating separate introduction events.Conclusion The mpox epidemic in the DRC exhibits two distinct patterns. In traditional endemic regions, the epidemic is predominated by zoonotic spill-over events involving clade Ia. Conversely, in the eastern part of the country, the clade Ib outbreak is driven by human-to-human transmission highlighting the need for a coordinated response effort at the national, regional and international levels.

RR\ID Evidence Scale rating by reviewer:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

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Review: Kinganda-Lusamaki et al. performed a comprehensive genomic analysis, sequencing the genomes of 603 mpox specimens collected from 581 individuals between 2018 and 2024 in the Democratic Republic of Congo (DRC). Their investigation revealed the concurrent circulation of both clade Ia and Ib in DRC. >95% of the MPXV sequences were attributed to clade Ia, with only 17 to clade Ib. Furthermore, they deduced that the clade Ia outbreak in the traditionally endemic regions, was largely the result of zoonotic spillover events in contrast to the clade Ib outbreak in the eastern region, which appears to be transmitted among human population. These findings are crucial for preventing the occurrence of mpox outbreaks and for curbing the escalation of mpox epidemics. The paper will be an important contribution to the field. I only have some minor suggestions that the authors should consider to address before the publication.

  1. Based on the phylogenetic analysis, the Yakusu Health zone (as depicted in Figure 3B) appears to have experienced two separate outbreaks between 15th December 2022 and 1st January 2023 (represented by green dots), and between 10th December 2022 and 2nd January 2023 (indicated by blue dots). However, in both the outbreaks, it seems that clade Ia has established limited human-to-human transmission, leading to the formation of clusters among the collected sequences. This suggests that while there may be discrete outbreaks, they are characterized by some degree of transmission within human populations, which is reflected in the clustering observed in the genetic sequences. Figure 3A-D could be consolidated into a single illustrative representation, with branches colored or strap-like annotations added to reflect both the timing and the geographical origins of the samples. 

  2. Is it feasible to deduce the transmission pathways of the virus across various regions? Is the data on human mobility available? Given the prevalence of multiple clade Ia variants in Kinshasa, it is essential to discern whether this diversity is due to potential human-to-human transmission of clade Ia variants, drawing them to Kinshasa, or if it is a result of multiple zoonotic spillover events occurring in the area. If the former is the case, then investigating human mobility and the data on transmission chains become highly significant. This has significant implications for the conclusions. If the aggregation of multiple clade Ia variants in Kinshasa is indeed due to human mobility, it serves as a warning sign for the potential stealth transmission of clade Ia among human populations and the associated risk of triggering large-scale outbreaks.

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