Since the world eradicated smallpox in 1980, scientists have known that the battle against poxviruses was far from over. Of the multiple types that exist, scientists have been wary of one in particular: mpox. In fact, one of the points in the World Health Assembly’s post-eradication policies was the “continuation of monkeypox surveillance in West and Central Africa, at least until 1985”.
In the 2022-2023, the World Health Organisation (WHO) declared the then global outbreak of mpox a ‘public health emergency of international concern’. In August this year, the WHO declared mpox to be a public health emergency for the second time in two years.
(Note: In 2022, the WHO designated “mpox” as a preferred synonym for “monkeypox” disease. The virus is still called “monkeypox” according to the International Committee on the Taxonomy of Viruses. For uniformity’s sake, this article will use “mpox” to refer to both the disease and the virus clades.)
New cause for worry
The declaration ensured multiple countries would pledge vaccines to the 15 African nations affected by the outbreak, six of which had never reported a single case of mpox before. But the paucity of doses has forced countries to prioritise their campaigns. Barely two months since these countries started their targeted vaccinations, scientists have a new cause for worry. A preprint paper uploaded on Virologica, a scientists’ discussion forum online, on October 24 reported evidence that yet another strain of the mpox virus appeared to have achieved human-to-human transmission.
There are two clades of mpox: I and II. Clade I viruses have been shown to cause more severe disease in the mouse model, but that doesn’t mean the same may be true for humans. Both clades are classified into two subclades, making a total of four known variants: Ia, Ib, IIa, and IIb. Of these, clade IIb was responsible for the 2022 outbreak, which is still continuing in certain parts of Africa.
Clade Ib, discovered towards the end of 2023, is the primary cause of infection in central Africa.
Researchers believed these two clades to be the primary contributors of the present mpox problem. They know very little about clade IIa except that it causes infections in western Africa.
When viruses make ‘mistakes’
Clade Ia, on the other hand, is the oldest known variant of the mpox virus. It has been known to cause sporadic infections in humans, mostly children, since 1970. But these infections were always limited to a few families or communities and the transmission was always from animals to humans. There was no proof of sustained human to human transmission — until recently.
The preprint posted on Virologica reported evidence that the DNA of clade Ia viruses sequenced from the present outbreak bears clear signs of human-to-human transmission.
Viruses evolve by introducing changes to their genetic material. Each time a virus infects a new host, an enzyme known as a polymerase makes multiple copies of the virus’s genetic material (DNA or RNA), which is then packed into new viruses. But sometimes the polymerases make a mistake. These mistakes, called mutations, could have a positive, negative or no impact on the virus, meaning the virus can get better or worse or be the same at its job.
The rate at which the polymerases make mutations is different for different viruses. Generally, viruses that have RNA as their genetic material, such as the human immunodeficiency virus (HIV) and influenza, make mistakes much more frequently than those that have DNA, like the human papillomavirus (HPV) and adenoviruses.
This error rate is even lower in some DNA viruses, like the members of the pox family, which also have an error-correction mechanism built into them. This mechanism, called proof-reading, ensures few mistakes are made: around one mistake every three years in a circulating viral strain.
The APOBEC family
However, viral polymerases are not the only source of mistakes in a virus’s genetic material.
The immune system also has a mechanism to introduce random changes in foreign DNA. A family of proteins called APOBEC — short for ‘apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like’ — can introduce changes to the viral DNA while it is being copied in the cells.
By doing so, APOBEC proteins force mistakes, some of which can be lethal to the virus. Importantly, of the four bases that DNA is made of, namely adenine, guanine, cytosine, and thymine, viral DNA polymerases can make a mistake anywhere, but APOBEC’s activity is usually limited to changing a cytosine to a thymine.
In a 2023 paper that appeared in Science, researchers showed that since the mutations made by APOBEC are more numerous than those by the viral polymerase, a sudden surge in the prevalence of mutations in circulating mpox viral DNA can be attributed to the activity of APOBEC. That is, the virus came from human cells and APOBEC must have acted on it. Otherwise those mutations couldn’t have arisen so quickly.
The researchers also estimated that on average, APOBEC activity would introduce around six mutations every year. Based on how many mutations the researchers observed, and the nature of those mutations, they predicted mpox clade IIb had been circulating in Africa from humans to humans since 2016.
The new study described in the preprint used the same method to show clade Ia viruses have achieved human to human transmission as well. This is because 63% of mutations they observed in the clade Ia infections were consistent with changes that could be introduced by APOBEC.
Viruses’ responses to antivirals
The news that clade Ia viruses can spread from humans to humans is not likely to affect the vaccination strategies of the affected countries. However, it is certainly cause for worry because researchers know that the different mpox clades respond differently to certain antiviral drugs used to treat them.
For now, Africa has pinned its hopes on the few doses of vaccines it has and is hoping against odds that its targeted campaign will suffice to stem the rising tide of mpox cases.
Arun Panchapakesan is an assistant professor at the Y.R. Gaithonde Centre for AIDS Research and Education, Chennai.
Published – November 11, 2024 05:30 am IST
