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Clade I Mpox virus genomic diversity in the Democratic Republic of the Congo, 2018 - 2024: Predominance of Zoonotic Transmission
Posted August 22, 2024.
View ORCID ProfileEddy Kinganda-Lusamaki, View ORCID ProfileAdrienne Amuri-Aziza, View ORCID ProfileNicolas Fernandez, View ORCID ProfileJean-Claude Makangara-Cigolo, View ORCID ProfileCatherine Pratt, View ORCID ProfileEmmanuel Hasivirwe Vakaniaki, View ORCID ProfileNicole A. Hoff, Gradi Luakanda, Prince Akil-Bandali, View ORCID ProfileSabin Sabiti Nundu, Noella Mulopo-Mukanya, Michel Ngimba, Brigitte Modadra-Madakpa, Ruth Diavita, Princesse Paku, Elisabeth Pukuta-Simbu, View ORCID ProfileSydney Merritt, Áine O’Toole, View ORCID ProfileNicola Low, Antoine Nkuba-Ndaye, View ORCID ProfileHugo Kavunga-Membo, Robert Shongo, View ORCID ProfileLaurens Liesenborghs, View ORCID ProfileTony Wawina-Bokalanga, View ORCID ProfileKoen Vercauteren, View ORCID ProfileDaniel Mukadi-Bamuleka, View ORCID ProfileLorenzo Subissi, View ORCID ProfileJean-Jacques Muyembe, View ORCID ProfileJason Kindrachuk, Ahidjo Ayouba, Andrew Rambaut, View ORCID ProfileEric Delaporte, View ORCID ProfileSofonias Tessema, View ORCID ProfileEric D’Ortenzio, View ORCID ProfileAnne W. Rimoin, View ORCID ProfileLisa E. Hensley, View ORCID ProfilePlacide Mbala-Kingebeni, View ORCID ProfileMartine Peeters, Steve Ahuka-Mundeke
doi: https://doi.org/10.1101/2024.08.13.24311951
This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.
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.
...
DISCUSSION
In this report we have characterized the diversity of MPXV in DRC from 2018 to early 2024 and provide insight into the potential drivers underlying the increasing mpox cases. This study generated a total of 348 near-complete (> 90% genome coverage) MPXV genomes from 337 individuals and 14 out of 26 provinces. Almost all (95%) of the new strains belong to clade Ia, in which high genetic diversity is observed. Most new clade Ia strains were in the previously described group II, followed by group III and IV. We also identified new clusters representing potential new groups and sub-groups (Berthet et al, 2021; Nakazawa et al, 2015). In contrast, the new clade Ib strains, all from South Kivu province in 2024, cluster in the single lineage recently described in the South Kivu and North Kivu provinces, with little diversity (Masirika et al, 2024; Vakaniaki et al, 2024, INRB, 2024). Our study highlights two patterns of transmission contributing to the source of human cases: the traditional paradigm of zoonotic spillover with interspecies transmission events and the more recently observed sustained human-to-human transmission driven by sexual contact with an enrichment of APOBEC3-type mutations. The low number of APOBEC3 mutations observed in Clade Ia suggests that most mpox cases have resulted from independent zoonotic introductions into the human population. We also showed that genetically diverse MPXV lineages can co-circulate in small geographic areas during the same outbreak, suggesting multiple zoonotic introductions over a short time span from one or multiple reservoir species. The observation of some clusters from endemic areas with slightly increased numbers of APOBEC3 mutations in MPXV, suggest that there might also be some sustained human transmission in these areas from potential transmission chains that were missed.
The increasing numbers of mpox cases reported from provinces in DRC around the Congo river and its tributaries highlight the potential links between viral spread and human activities around these rivers and reflects possible widespread presence of the animal reservoir for these variants. Human activities could have potentiated MPXV introductions to new health zones and urban areas as illustrated by the introduction of multiple lineages in Kinshasa linked to MPXV strains originating from endemic areas in 2023. These events should be closely monitored as they represent a major threat for additional regional and international dissemination in densely populated areas. This is of particular concern given the increased disease severity associated with clade I MPXV as compared to clade II (Americo et al, 2010; Hutson et al, 2010).
A strength of this study is that we obtained sequences from most of the provinces within DRC that are endemic for mpox with the highest number of mpox cases and provinces, such as South-Kivu with more recent reports of mpox cases. There are also limitations. First, the global picture of MPXV diversity remains incomplete as the 348 MPXV genomes with >90% coverage represent a minority of the suspected mpox cases and only from symptomatic patients seeking health care. More large-scale studies, including genomic surveillance and serosurveys with accompanying epidemiological and clinical data are needed to characterize the extent of the mpox epidemic in humans and the genetic diversity of MPXV strains involved. Secondly, the samples collected and shipped for confirmatory tests were not always from the primary cases (Kinganda-Lusamaki et al, 2022). Thus, more studies are needed for investigating primary cases and a better understanding of viral introduction into the human population.
Our study provides important new information about the genetic diversity of MPXV circulating in DRC. Mpox in DRC is caused predominantly by clade Ia, traditionally associated with zoonotic transmission events. It is thus urgent to better document the nature and extent of animal reservoirs to understand whether the increasing number of cases results from increased direct contacts with putative natural reservoirs, an increase in prevalence of the infection in the animal reservoir, an increase in animal reservoir populations, or a combination of those. The newly described clade Ib was found only in samples from South-Kivu and the limited genetic diversity is compatible with its emergence in 2023 (Vakaniaki et al, 2024). More information is needed about the clinical presentations of mpox caused by different clades and subclades. In the multi-country outbreak of clade IIb, pauci- or asymptomatic cases were documented (Rosenthal, 2024; Debaetselier et al 2022). The clinical presentation of mpox can also differ according to transmission modes, as shown in South-Kivu and North Kivu versus endemic regions in DRC (Vakaniaki et al,2024). The long-term impact of mpox on clinical sequelae, viral dynamics in animal reservoirs and human-to-human transmission, host-immune responses, and persistence of humoral and/or cellular immunity over time need also to be documented.
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https://www.medrxiv.org/content/10.1101/2024.08.13.24311951v2.full-text
Posted August 22, 2024.
View ORCID ProfileEddy Kinganda-Lusamaki, View ORCID ProfileAdrienne Amuri-Aziza, View ORCID ProfileNicolas Fernandez, View ORCID ProfileJean-Claude Makangara-Cigolo, View ORCID ProfileCatherine Pratt, View ORCID ProfileEmmanuel Hasivirwe Vakaniaki, View ORCID ProfileNicole A. Hoff, Gradi Luakanda, Prince Akil-Bandali, View ORCID ProfileSabin Sabiti Nundu, Noella Mulopo-Mukanya, Michel Ngimba, Brigitte Modadra-Madakpa, Ruth Diavita, Princesse Paku, Elisabeth Pukuta-Simbu, View ORCID ProfileSydney Merritt, Áine O’Toole, View ORCID ProfileNicola Low, Antoine Nkuba-Ndaye, View ORCID ProfileHugo Kavunga-Membo, Robert Shongo, View ORCID ProfileLaurens Liesenborghs, View ORCID ProfileTony Wawina-Bokalanga, View ORCID ProfileKoen Vercauteren, View ORCID ProfileDaniel Mukadi-Bamuleka, View ORCID ProfileLorenzo Subissi, View ORCID ProfileJean-Jacques Muyembe, View ORCID ProfileJason Kindrachuk, Ahidjo Ayouba, Andrew Rambaut, View ORCID ProfileEric Delaporte, View ORCID ProfileSofonias Tessema, View ORCID ProfileEric D’Ortenzio, View ORCID ProfileAnne W. Rimoin, View ORCID ProfileLisa E. Hensley, View ORCID ProfilePlacide Mbala-Kingebeni, View ORCID ProfileMartine Peeters, Steve Ahuka-Mundeke
doi: https://doi.org/10.1101/2024.08.13.24311951
This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.
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.
...
DISCUSSION
In this report we have characterized the diversity of MPXV in DRC from 2018 to early 2024 and provide insight into the potential drivers underlying the increasing mpox cases. This study generated a total of 348 near-complete (> 90% genome coverage) MPXV genomes from 337 individuals and 14 out of 26 provinces. Almost all (95%) of the new strains belong to clade Ia, in which high genetic diversity is observed. Most new clade Ia strains were in the previously described group II, followed by group III and IV. We also identified new clusters representing potential new groups and sub-groups (Berthet et al, 2021; Nakazawa et al, 2015). In contrast, the new clade Ib strains, all from South Kivu province in 2024, cluster in the single lineage recently described in the South Kivu and North Kivu provinces, with little diversity (Masirika et al, 2024; Vakaniaki et al, 2024, INRB, 2024). Our study highlights two patterns of transmission contributing to the source of human cases: the traditional paradigm of zoonotic spillover with interspecies transmission events and the more recently observed sustained human-to-human transmission driven by sexual contact with an enrichment of APOBEC3-type mutations. The low number of APOBEC3 mutations observed in Clade Ia suggests that most mpox cases have resulted from independent zoonotic introductions into the human population. We also showed that genetically diverse MPXV lineages can co-circulate in small geographic areas during the same outbreak, suggesting multiple zoonotic introductions over a short time span from one or multiple reservoir species. The observation of some clusters from endemic areas with slightly increased numbers of APOBEC3 mutations in MPXV, suggest that there might also be some sustained human transmission in these areas from potential transmission chains that were missed.
The increasing numbers of mpox cases reported from provinces in DRC around the Congo river and its tributaries highlight the potential links between viral spread and human activities around these rivers and reflects possible widespread presence of the animal reservoir for these variants. Human activities could have potentiated MPXV introductions to new health zones and urban areas as illustrated by the introduction of multiple lineages in Kinshasa linked to MPXV strains originating from endemic areas in 2023. These events should be closely monitored as they represent a major threat for additional regional and international dissemination in densely populated areas. This is of particular concern given the increased disease severity associated with clade I MPXV as compared to clade II (Americo et al, 2010; Hutson et al, 2010).
A strength of this study is that we obtained sequences from most of the provinces within DRC that are endemic for mpox with the highest number of mpox cases and provinces, such as South-Kivu with more recent reports of mpox cases. There are also limitations. First, the global picture of MPXV diversity remains incomplete as the 348 MPXV genomes with >90% coverage represent a minority of the suspected mpox cases and only from symptomatic patients seeking health care. More large-scale studies, including genomic surveillance and serosurveys with accompanying epidemiological and clinical data are needed to characterize the extent of the mpox epidemic in humans and the genetic diversity of MPXV strains involved. Secondly, the samples collected and shipped for confirmatory tests were not always from the primary cases (Kinganda-Lusamaki et al, 2022). Thus, more studies are needed for investigating primary cases and a better understanding of viral introduction into the human population.
Our study provides important new information about the genetic diversity of MPXV circulating in DRC. Mpox in DRC is caused predominantly by clade Ia, traditionally associated with zoonotic transmission events. It is thus urgent to better document the nature and extent of animal reservoirs to understand whether the increasing number of cases results from increased direct contacts with putative natural reservoirs, an increase in prevalence of the infection in the animal reservoir, an increase in animal reservoir populations, or a combination of those. The newly described clade Ib was found only in samples from South-Kivu and the limited genetic diversity is compatible with its emergence in 2023 (Vakaniaki et al, 2024). More information is needed about the clinical presentations of mpox caused by different clades and subclades. In the multi-country outbreak of clade IIb, pauci- or asymptomatic cases were documented (Rosenthal, 2024; Debaetselier et al 2022). The clinical presentation of mpox can also differ according to transmission modes, as shown in South-Kivu and North Kivu versus endemic regions in DRC (Vakaniaki et al,2024). The long-term impact of mpox on clinical sequelae, viral dynamics in animal reservoirs and human-to-human transmission, host-immune responses, and persistence of humoral and/or cellular immunity over time need also to be documented.
...
https://www.medrxiv.org/content/10.1101/2024.08.13.24311951v2.full-text