Mpox returns: Global health emergency declared anew after 15 months

Just 15 months after lifting the global alert status for the previous mpox outbreak, the WHO again declared the recent upsurge of mpox a public health emergency of international concern (PHEIC) on 14 August 2024.

This was following the emergence of new strains of the virus, denoted as clade Ib, which appear to cause more severe disease than clade IIb, which figured in the previous multicountry outbreak.

The clade Ib strains have spread rapidly in the eastern Democratic Republic of the Congo (DR Congo). Moreover, four neighbouring African countries, where mpox had not been reported previously, recorded a total of >100 laboratory-confirmed cases of these strains in July 2024.

Meanwhile, on the day following the PHEIC declaration, Sweden became the first country outside Africa to confirm an mpox clade Ib case in an individual with a travel history to Central Africa. A week later, Thailand confirmed its first clade Ib case in a European who had recently travelled from Africa.

“On top of outbreaks of other mpox clades in DR Congo and other countries in Africa, it’s clear that a coordinated international response is needed to stop these outbreaks and save lives,” said WHO Director-General Dr Tedros Adhanom Ghebreyesus.

Second time PHEIC was declared but different triggers

Mpox (the preferred nomenclature for the former monkeypox) is not new to the PHEIC list; the WHO issued its highest level of alert for the multicountry mpox outbreak for the first time on 23 July 2022. After a 10-month–long global alert, the WHO declared that mpox was no longer a PHEIC on 11 May 2023, citing a significant decline in confirmed cases.

During the last global outbreak, more than 87,000 cases and 140 deaths from 111 countries were reported to the WHO.

Under the spotlight this time is the novel clade Ib lineage of the monkeypox virus (MPXV), a designation first proposed 2 months ago. [Nat Med 2024;doi:10.1038/s41591-024-03130-3]

MPXV has two genetically distinct known clades.

During the previous multicountry outbreak, clade I was largely restricted to three countries in Central Africa: DR Congo, Cameroon, and the Central African Republic (CAR). It appeared only sporadically in other border-sharing countries.

On the other hand, the 2022 global outbreak was driven by the MPXV subclade IIb; however, it causes less severe illness and has a lower mortality rate than clade I, and has largely subsided.

“Clade” is a well-established system to group viruses derived from a common ancestor and its lineal descendants. As an illustration, the strain of the virus detected in Sweden is denoted as hMpxV/Sweden/PHAS-11304/2024 and is grouped within subclade Ib (termed clade Ib) through genomic sequencing, due to its shared common ancestor with strains from Central Africa.

What is currently known about clade Ib?

Based on genomic analysis of MPXV from 22 patients during a recent outbreak investigation in DR Congo, clade Ib exhibits distinct phylogenetic divergence from clade I. The new lineage increases the known genomic diversity of clade I by an additional 54 percent.

It was first suspected as a new sublineage due to the predominance of APOBEC3-type mutations in the MPXV sequence, which serves as a hallmark sign of the zoonotic virus’ potential for human-to-human transmission.

The previously described clade I was subsequently renamed clade Ia.

Of the six sequences analyzed in a separate investigation in DR Congo, the novel sublineage was observed to share a deletion at the US Centers for Disease Control and Prevention-recommended target for clade I-specific real-time polymerase chain reaction (PCR). As a result, certain rapid PCR surveillance tools designed to identify clade I infections would fail to detect the novel MPXV clade Ib. [Euro Surveill 2024;29:2400106]

Clade Ib- (2024) vs clade IIb-associated (2022) outbreaks

According to recent information released by the WHO, the outbreak associated with clade Ib in DR Congo primarily affects adults. It is spreading rapidly and has been largely sustained, though not exclusively, by transmission linked to sexual contact, particularly in networks associated with commercial sex and sex workers.

Specifically, among the 108 PCR-confirmed mpox cases reviewed in the recent outbreak investigation in DR Congo, a slight majority were female (51.9 percent), and the median age was 22 years. Self-identified sex workers comprised 28.7 percent of the confirmed cases. Only 6.5 percent of the suspected cases with known HIV status were HIV-positive. The in-hospital case fatality rate was 1.4 percent.

Intriguingly, cases of mpox linked to clade IIb, the strains that had spread globally, have not been reported in DR Congo, the current epicentre. Limited information constrains comparisons of whether the symptoms associated with MPXV clade Ib differ from those of clade IIb and makes it difficult to address questions regarding its relative danger and transmissibility.

To further complicate the situation, the WHO learned little about either clade I from the previous outbreak. Out of 1,619 MPXV genomic sequences collated over 9 months encompassing the time before and after the prior PHEIC declaration, only four sequences classified as then-clade I (0.2 percent) were documented, all originating from DR Congo. [Lancet Glob Health 2023;11:e1012-e1023]

Known mpox presentation

Based on analyses conducted primarily on clade IIb-associated cases, mpox symptoms consist of a characteristic vesiculopustular rash. Skin or mucosal lesions, particularly in the oral and genital regions, were frequently reported. Fever and headache are the most common noncutaneous, nonmucosal symptoms. The presence of lymphadenopathy is useful for distinguishing mpox from other rash-causing diseases. [New Microbes New Infect 2023:53:101154]

Among 85,473 confirmed cases of mpox (median age 34 years, 96.4 percent male) collected by the WHO during the previous global outbreak, self-identified men who have sex with men (86.9 percent) were disproportionately involved, as widely reported. Among those with known HIV status, 48 percent were HIV-positive.

Hospitalizations occurred in 7.3 percent of the cases. With 89 mpox-related deaths reported to the WHO during the period, the crude case fatality rate was 0.1 percent.

While infection through occupational exposure was initially a significant concern, only 5.3 percent of the cases reported to the WHO involved health workers. Among cases with more information available, only 10.1 percent of the health worker cases were linked to occupational exposure.

The evident differences vs the limited available information about the ongoing outbreak in DR Congo may be attributed to surveillance biases, viral factors, and the fact that cases reported from Central Africa tend to be generally younger and have a more even sex distribution.

Vaccines and therapeutics

There have been no groundbreaking advancements in interventions for mpox since the prior outbreak, which still primarily rely on prevention with the modified vaccinia Ankara vaccine (MVA-BN) and treatment with tecovirimat for patients requiring more than supportive care in countries where these are available. Brincidofovir, along with its parent drug cidofovir, is also utilized. Vaccinia immunoglobulin is typically reserved for complicated infections, but its availability is limited to a few countries. Topical trifluridine can be considered for ocular manifestations.

However, additional evidence supporting these interventions has emerged. In case-control studies, the effectiveness of MVA-BN was estimated to be at least 66 percent with full vaccination and 35.8 percent with partial vaccination. [MMWR Morb Mortal Wkly Rep 2023;72:553-558; N Engl J Med 2023;388:2434-2443]

One of the major pieces of research supporting tecovirimat since then was its protocolized use in CAR, where clade I is endemic, under expanded access. After a 14-day course of tecovirimat, 12 of the 14 patients (85.7 percent) were discharged with negative PCR and no active lesions, with a median time of 5 days from treatment initiation to the absence of active lesions. [N Engl J Med 2022;387:2294-2295]

However, the announcement that tecovirimat did not meet the primary endpoint in the preliminary analysis of the PALM 007 trial dealt a blow to the promising findings. In the randomized trial conducted in DR Congo, tecovirimat did not lead to a statistically significant improvement in the time to lesion resolution within 28 days vs placebo.

Although the findings have yet to be published, the announcement of the topline results suggested that the improvement was meaningful in subgroups of patients receiving tecovirimat within 7 days of symptom onset and those with severe disease (≥100 skin lesions). Additional randomized trials investigating the potential benefit of tecovirimat, with varying trial designs, patient populations, predominant clades, or other factors, are ongoing.

Not “the new COVID”

“Mpox is not the new COVID,” said Dr Hans Kluge, WHO Regional Director for Europe. “Regardless of whether it’s mpox clade I or mpox clade II, we know how to control mpox ... and the steps needed to eliminate its transmission.”