Mpox virus: why its rapid mutation remains a concern

University of Hull Virologist Dr Cheryl Walter explains the concerns relating to the spread of mpox.

In 2022, as the world was slowly beginning to recover from the worst of the COVID-19 pandemic, an outbreak of mpox – then still called monkeypox – began spreading at an alarming rate in many countries worldwide. Confirmed cases were cropping up in places where the disease wasn’t normally present (endemic) – and it was spreading quickly among certain groups.

Global mpox infections have fallen significantly since the height of this outbreak. But a recent paper, which has not yet been peer reviewed, has renewed concerns about the potential for mpox to cause another global outbreak like that seen in 2022.

The researchers, who analysed mpox samples from patients in the Democratic Republic of the Congo (DRC), discovered a new cluster of mpox variants. This cluster is genetically distinct from the variants that were circulating in 2022 – and alarmingly, this variant has evolved rapidly.

However, this is just one example of the way mpox has continued to evolve since the 2022 outbreak.

Mpox virus, as the name suggests, is a pox virus. It’s related to smallpox, cowpox and other animal pox viruses. Notably, it’s not related to chickenpox, although there are some shared symptoms.

Mpox symptoms include rash, fever, sore throat and swollen lymph nodes. The rash, which is often the first symptom people notice, can develop into liquid-filled blisters. However, some people exhibit no symptoms.

The virus is transmitted between people through close contact, respiratory droplets or direct contact with open blisters. The case fatality rate varies – and can be as high as 10% in some instances.

Mpox was first discovered in laboratory monkeys in the 1950s. The first human case was reported in 1970 in the DRC. Since then, outbreaks of mpox have been small and traceable to a single person – typically someone who had recently returned from a country where the virus is endemic – such as west and central Africa.

The 2022 outbreak was unlike any previously seen outside of Africa. Infections were reported in 117 countries – with 95,226 cases and 185 deaths confirmed since the height of the outbreak.

Mpox’s genetic evolution

Mpox is a large virus. Its particles are often described as being “brick-shaped”. To match its clunky appearance, it also has a very large genome for a virus. The genome contains all the information the virus needs to produce new virus particles. Because of mpox’s large DNA genome, it tends to evolve more slowly than viruses with smaller genomes – such as SARS-CoV-2, which causes COVID.

A virus can be clustered into categories based on differences in their genome sequence – referred to as clades. Clades are like the leafy branches of a tree. The more leaves you have on a branch (the clade), the more genetic variants you have in that particular clustering.

The number of branches and leaves on the tree vary for a number of reasons – such as how quickly a virus mutates and how many people are infected. Sometimes, these clades will branch even further into sub-clades.

Using genetic sequencing, scientists can wind back the molecular clock and work out how old a variant is. This is important for establishing an outbreak timeline, working out the virus’ mutation rate and where a particular variant fits on the tree branch.

Before 2022, mpox could be clustered into two distinct clades. Clade I was typically found in the Congo basin of central Africa, while clade II isolates were found in west Africa.

Clade I was associated with severe disease and a higher case fatality rate. Clade II tended to be associated with less severe disease. But around 2016, variants from clade II started readily spreading between people in Nigeria. This means the genome changed, potentially allowing it to be more transmissible.

Scientists also used genetic sequencing to work out the timelines of the 2022 global mpox outbreak. Importantly, they were able to analyse what had changed in new samples compared to older virus samples.

A string of tell-tale mutations in these mpox samples confirmed the virus was spreading from person-to-person at a rapid rate. Previously, mpox outbreaks tended to originate almost entirely via animal-to-human transmission. Furthermore, a new clade – clade IIb – had formed.

There’s still many questions we can’t answer about the 2022 outbreak – including about what events led to the sustained transmission that happened between people. Yet, based on the low case fatality rate during the outbreak and subsequent research in mice, clade IIb appears to have reduced virulence compared to other clade I. Less virulence means it’s less fatal – which might contribute to the virus being able to spread more easily between people.

This recent pre-print paper, which used samples from the 2023 mpox outbreak in the DRC, has now identified a new offshoot from clade I – clade Ib. This shows mpox is continuing to adapt and becoming more genetically diverse.

This is indeed concerning, especially considering mpox from clade I was associated with more severe disease and a higher case fatality rate. We still don’t fully understand why mpox is becoming more genetically diverse within such a short period of time.

Mpox can be a dangerous infection for the very young and those that have weakened immune function. We also don’t have a vaccine for mpox yet, so rely on cross-immunity from often limited stocks of the smallpox vaccine. Treatments for mpox infections are also limited.

It’s important scientists and doctors continue to monitor new cases worldwide so we can understand how the virus is evolving – and hopefully get closer to breaking the cycle of human-to-human transmission.

This article by Dr Cheryl Walter, Senior Lecturer in Biomedical Science, at the University of Hull was originally published on The Conversation. The views or opinions expressed by individuals do not necessarily reflect those of the University.