#17,949
Clade I Mpox (formerly Monkeypox) - which is endemic to central Africa (see map at top of post) - is far more severe than the Clade IIb Mpox virus which began its world tour in 2022. It appears more transmissible, can produce more disfiguring lesions, and is associated with a much higher fatality rate.
While we've seen no indication of international spread of the Clade I Mpox virus, last year's discovery of two clusters of sexually transmitted Mpox (in MSM and sex workers) (see WHO Reports 1st Confirmed Cluster Of Sexually Transmitted MPXV Clade 1 in the DRC) - has raised concerns that - like Clade IIb - this more aggressive strain could eventually turn up outside of Africa.
Since then we've looked at several reports and risk assessments, including:
CDC HAN Advisory #00501: Mpox Caused by H-2-H Transmission with Geographic Spread in the Democratic Republic of the Congo
ECDC Risk Assessment On Transmission & Spread of Clade I Mpox From The DRC
CDC EID Journal: Clade I–Associated Mpox Cases Associated with Sexual Contact, the Democratic Republic of the CongoLike all viruses, Mpox continues to evolve and diversify, as was discussed in the 2014 EID Journal article Genomic Variability of Monkeypox Virus among Humans, Democratic Republic of the Congo, where the authors cautioned:
Small genetic changes could favor adaptation to a human host, and this potential is greatest for pathogens with moderate transmission rates (such as MPXV) (40). The ability to spread rapidly and efficiently from human to human could enhance spread by travelers to new regions.
Today we have a the first report on a genomic analysis of samples from a recent outbreak in a previously unaffected region of the DRC, which reveals a novel clade I sub-linage has emerged - most likely from a zoonotic spillover - that may render current CDC tests unreliable.
First some excerpts from the Eurosurveillance report (follow the link to read it in its entirety), after which I'll return with a postscript.
Rapid communication Open Access
Ongoing Mpox Outbreak in Kamituga, South Kivu province, associated with Monkeypox virus of a novel Clade I sub-lineage, Democratic Republic of the Congo, 2024Leandre Murhula Masirika1,2 , Jean Claude Udahemuka3,4 , Leonard Schuele5 , Pacifique Ndishimye4,6,7 , Saria Otani8 , Justin Bengehya Mbiribindi9 , Jean M. Marekani10 , Léandre Mutimbwa Mambo11 , Nadine Malyamungu Bubala9 , Marjan Boter5 , David F. Nieuwenhuijse5 , Trudie Lang12 , Ernest Balyahamwabo Kalalizi2 , Jean Pierre Musabyimana4,13 , Frank M. Aarestrup8 , Marion Koopmans5 , Bas B. Oude Munnink5,* , Freddy Belesi Siangoli14,*https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2024.29.11.2400106
In the Democratic Republic of the Congo (DRC), the numbers of people with suspected infection with monkeypox virus (MPXV), the virus that causes mpox, have increased since the start of 2023. A total of 12,569 suspected mpox cases have been reported up to 12 November, the highest number of annual cases ever recorded [1]. The case fatality rate has been estimated at 4.6% [1]; moreover, new cases have occurred in geographical areas of the country where the disease was previously not observed, such as Kinshasa and South Kivu province [1,2].
Despite this concerning situation, there is only limited genomic information available on the circulating viruses, which suggests that they belong to Clade I [3]. To gain more insight into the characteristics of the strains causing the epidemic, as well as assurance that current and commonly used molecular assays to diagnose MPXV infections can detect these strains, we sequenced monkeypox viral genomes from recently diagnosed cases in South Kivu, DRC.
Case definitions and patient characteristics
A case was listed as ‘suspect’ if presenting with an acute illness with fever, intense headache, myalgia, and back pain, followed by 1 to 3 days of a progressively developing rash often starting on the face and spreading on the body. A confirmed mpox case had a monkeypox virus infection which was laboratory-confirmed by PCR. A case was listed as ‘probable’ when satisfying the clinical definition of a suspected case and having an epidemiological link to a confirmed or probable case; a probable case was not laboratory-confirmed [4].
The study involved patients from South Kivu province in the territory of Mwenga, who were hospitalised in the Kamituga hospital, which is in the Kamituga health zone. The first mpox cases in this area were reported from September 2023 onwards.
A total of 10 patients were included in the study. All were young adults in their late teenage up to the age of mid-20 years and five were male and five females. Regarding professions comprised, the majority of the concerned individuals were sex workers. For these patients, admission to the Kamituga Hospital had been based on clinical diagnosis of mpox by hospital staff. According to routines, skin lesion and oropharyngeal swabs collected from the patients had been sent to the national medical research institute of the DRC (Institut National de la Recherche Biomédicale; INRB) in Goma for MPXV infection confirmation by PCR, and all patients had tested positive for the virus.
(SNIP)
The monkeypox virus outbreak strain in South Kivu lacks the target sequence used for identifying Clade I viruses
To check if the strains obtained in the current study could be detected by commonly used molecular assays to diagnose MPXV infections, their sequences were aligned to the closely related Clade I sequence EPI_ISL_13056243. This sequence matches primer and probe sequences recommended by the United States (US) Centers for Disease Control and Prevention (CDC) to diagnose MPXV [15]. The alignment was assessed using an in-house Primer Check Tool (https://viroscience-emc.shinyapps.io/primer-check/ ).
While the generic primers and probe still seem to be functional with only one mutation in the reverse primer, the specific Clade I virus real-time PCR target, recommended by the US CDC, is absent in the genomes of the novel MPXV strains ( Figure 2 and Supplementary Figure 3). The observed deletion is 1,114 nt in size and results in the complete deletion of the OPG032 gene. The coverage of this region ranged between 76× and 941× sequence reads depending on the sample. Due to the deletion, the rapid US CDC method to identify Clade I in newly diagnosed mpox cases is most likely not reliable for detection of the novel sub-lineage identified in the current study.
(SNIP)
Discussion
From the mpox outbreak in Kamituga, South Kivu, six near-to-complete MPXV sequences derived from local patients hospitalised with mpox were obtained. Phylogenetic analyses of these sequences together with those available for other Clade I and II viruses, placed them in a new sub-lineage near the root of Clade I, which suggests that the outbreak in this region results from a new introduction, most likely from a zoonotic reservoir. Although sequences from a small 2023 Kinshasa outbreak are not publicly available, the placement of those sequences in a published phylogenetic tree [3] suggests that the Kamituga outbreak is not related to the outbreak in Kinshasa. Our findings therefore suggest that there are at least two independent outbreaks ongoing in DRC.
Remarkably, a large stretch of sequence in the genomes belonging to the novel MPXV sub-lineage was absent compared to other Clade I genomes, which would lead to failure of the Clade I-specific real-time PCR recommended by the US CDC [15]. A deletion in the same region is also observed in Clade II MPXV, and this was the basis for clade assignment using the CDC PCR.
Therefore, if the viruses from the new lineage were to spread internationally, this molecular surveillance tool can no longer be used to rapidly identify these Clade I virus infections while the global Clade IIb outbreak is ongoing.
Conclusion
Altogether, the findings of this study strongly suggest that whole genome sequencing of a larger subset of MPXV currently causing mpox cases in DRC, as well as public data sharing, are essential to understand the ongoing epidemic. Further studies, sequencing and analyses are ongoing, but in accordance with the above statement we believe that rapid public sharing of all available information is essential to help to better understand and contain the current mpox emergence.
Although many experts voiced surprise when Mpox clade IIb began spreading internationally in the spring of 2022, we'd seen plenty of warning signs over the years, including in PLoS NTD: The Changing Epidemiology of Human Monkeypox—A potential threat?, which had been published just months prior.
Most were ignored.
While there are no guarantees that Clade I Mpox will follow suit, familiar warning signs are flashing once again. And round two may prove more difficult to contain than round one.
