Poxviruses' Genetic Evolution Unveiled

Poxviruses have for quite a long been a reason for fear as well as curiosity for humankind. One particularly infamous poxvirus, smallpox, alone may have killed over 500 million people in the last century.

Smallpox didn't discriminate between rich, poor, young, and old, and killed nearly 33% of the people whom it infected. The turning point came with evidence of the efficacy of the smallpox vaccine. Thus followed a concerted effort worldwide to administer the vaccine and eventually eradicate the dead disease. This feat has stood as a testament to the power of sustained global public health initiatives.

Mpox

Another pox virus, mpox, was in the headlines after a rapidly expanding global outbreak in 2022-2023. The virus was previously called 'monkeypox' after a spillover event in a research facility including monkeys in 1958; the name is considered both wrong and inappropriate today: since then, researchers have identified mpox in many sporadic outbreaks among humans. They have also found multiple mpox lineages have been circulating in humans, adapting by accumulating mutations modulated largely by the APOBEC proteins.

But, it was only after 2022 that the disease became widely known, thanks to outbreaks in more than 118 countries and the World Health Organisation (WHO) quickly declaring it a public health emergency. Until now, this outbreak has infected almost 100,000 people. Based on WHO data, infections have a mortality rate of 1-10%.

The outbreak was due to one clade (strains of the virus descended from a common ancestor) — called IIb — having grown very high human-to-human transmission through close contact and spread through the sexual route. While the rate of new infections has been dropping, mpox continues to circulate among unvaccinated people around the world. This increases the chance that a more virulent and transmissible strain might emerge and become endemic somewhere.

Expanding, contracting as required

Mpox, similar to all poxviruses, are DNA viruses. The mpox genome has around 197 kilobases (kb). The core genes are those closely conserved (for example preserved during evolution) by various poxviruses plus two sections around 6.4 kb long, one at each end of the genome. Researchers don't yet know what function these sections serve but suspect they influence how well the poxviruses can infect different hosts.

The mpox genome also has a sequence of bases repeating in evolution, which researchers believe plays a role in the virus's evolution.

The mpox family of viruses is also known to be able to evade selective evolutionary pressures. It does this by duplicating genes and/ or potentially accumulating mutations and expanding its genome significantly or contracting its genome by deleting gene stretches or inactivating them. Such rhythmic expansions and contractions are called genomic accordions.

Track down the accordion

In a study published by Nature Communications, researchers at the Icahn School of Medicine in New York and multiple institutions in Spain extensively sequenced the genome of the mpox virus implicated in the 2022 outbreak. They used advanced genome sequencing technologies to piece together a comprehensive genome of the mpox virus from scratch.

They found that the 6.4-kb-long sections of the virus strongly influenced the virus's human-to-human transmissibility. They also reported that variations in three genes, in particular, could affect the virus advancement. Importantly, 6.4-kb-long sections, which researchers had previously considered to be not all that informative, were found to be the virus's genomic accordions.

All mpox genomes can be divided into two distinct yet broad clades: I and II. Clade I is thought to have a higher mortality. Each clade has sub-clades, or lineage, defined by specific evolutionary processes. Researchers have also tracked down evidence of significantly different mpox virulence in animal models. The new study, like others like it, further the idea that the 2022 outbreak largely involved a new lineage of the virus, clade IIb, that was even better adapted to human-to-human transmission than clades I or IIa.

The outbreak in the DRC

Between September 2023 and February 2024, health workers detected a large mpox outbreak detected in the Democratic Republic of the Congo (DRC), centered on a mining village and rapidly spreading to various regions within the country. This outbreak was associated with a significantly large spread as well as mortality. Researchers soon confirmed mpox clade I was responsible.

This outbreak differed from earlier ones, which were sporadic and self-contained spillover events, by spreading through human-to-human contact and affecting young adults instead of children. A preprint paper, uploaded by researchers from Belgium, Canada, the DRC, France, Ghana, Nigeria, South Africa, and the U.S. describes the genomes of virus samples obtained from 241 people suspected to have been infected during the outbreak.

The genomic data suggest a distinct lineage of clade I being associated with human-to-human transmission. The researchers also found evidence in fragments of the genome that closely resembled viruses isolated and sequenced in recent years of the hypothesis that this lineage emerged from a very zoonotic spillover.

One eye on the genome

As with any viral infection, without urgent intervention, the outbreak can spread quickly across national, and even continental, boundaries, and emerge as another global outbreak.

To prevent such an outcome, genome sequences from before and during the mpox outbreak have provided a sufficient glimpse of the evolutionary dynamic the virus uses to invent new ways to move between and survive in different populations of animals and people.

Thus, through rigorous genomic investigations and coordinated public health efforts, we can mitigate the threat of emerging pathogens and the world's health security.