Monkeypox Outbreak Strain Has Far More Mutations Than Expected

Monkeypox Outbreak Strain Has Far More Mutations Than Expected

June 24, 2022 0 By Jennifer Walker

The strain of monkeypox involved in the current global outbreak differs from its parent strain by about 50 single nucleotide polymorphisms (SNPs) — far more than would be expected for an orthopoxvirus, researchers reported.

There’s also evidence of continued evolution and adaptation during human-to-human transmission that’s occurring faster than expected, which may account for its apparently increased transmissibility, João Paulo Gomes, PhD, of Portugal’s National Institute of Health in Lisbon, and colleagues reported in Nature Medicine.

“Considering the genome characteristics of this type of virus, no more than one or two mutations are likely to emerge each year,” Gomes told MedPage Today via email. “However, considering that this 2022 [strain] is likely a descendant of one in the 2017 Nigeria outbreak, one would expect no more than five to 10 additional mutations instead of the observed about 50 mutations.”

Many of the mutations “affect proteins that interact with the immune system, which, hypothetically, may yield some kind of immune evasion,” Gomes added. “We hope that specialized groups will now investigate the role of these multiple mutations on transmission.”

Grant McFadden, PhD, a monkeypox expert at Arizona State University, who was not involved with the paper, noted that it’s “hard to say” whether any of the mutations have changed viral behavior.

“I don’t know how quickly we will know whether or not the fundamentals of the disease have changed, but the disease characteristics look a little milder than what we saw in West Africa, in terms of the number of lesions and the way they’re distributed,” McFadden told MedPage Today.

“The changes in nucleotides may just be a collection of mutations that have arisen over a longer time than we would have predicted,” he added. “And now that it’s in a new host, the selection pressures are a bit different on the virus than they were in rodents, and that may be exerting a selective pressure to acquire more alleles. But we don’t know what the functional significance of any of the changes are.”

Nonetheless, he said, it will be important to do that work.

For their study, Gomes and colleagues analyzed the first monkeypox sequence publicly released on May 20, 2022 by Portugal, along with additional sequences released before May 27, totaling 15 sequences, most of which were from Portugal.

They confirmed that the new variant belonged in clade 3, which is within the less lethal West African clade (compared with the deadlier Central African clade), and found that all of the strains tightly clustered together, suggesting a single origin for the ongoing outbreak.

The current outbreak strain is divergent but descends from a branch associated with exported cases of monkeypox from Nigeria to the U.K., Israel, and Singapore in 2018-2019, and has genetic links to a large outbreak in Nigeria in 2017-2018, they reported.

Thus, they say it’s likely that the current outbreak indicates there were one or more importations of the virus from a single origin and that there was “continuous circulation and evolution” of the virus involved in the 2017-2018 outbreak in Nigeria. Superspreader events — such as “saunas used for sexual encounters” — and international travel “likely trigger[ed] the rapid worldwide dissemination” of the virus, they wrote.

The researchers noted that they can’t exclude the hypothesis of prolonged cryptic disseminations in humans or in animals in a non-endemic country, but silent human-to-human transmission seems less likely given the disease characteristics of the affected individuals, they wrote. Cryptic animal transmission plus recent spillovers would be even less likely, they said.

What’s responsible for the 50-SNP gap between the parent virus and the one involved in the current outbreak? A certain enzyme family involved in viral genome editing may play a role, they reported: apolipoprotein B mRNA-editing catalytic polypeptide-like 3 (APOBEC3).

These enzymes can be upregulated in response to viral infection, as they can inhibit a wide range of viruses by introducing mutations. In some circumstances, the researchers said, APOBEC3-mediating mutations may not completely disrupt the virus, boosting the chances of creating hyper-mutated but viable variants.

Gomes and colleagues also found evidence of ongoing evolution and adaptation, with 15 SNPs discovered with human-to-human transmission in the ongoing outbreak.

“[M]ultiple mutations that we are seeing during the 2022 person-to-person transmission affect proteins associated with the human immune system, so it might mean a process of adaptation to humans,” Gomes said via email. “And, yes, it seems to occur in a faster rate than expected, which is in line with the also unexpected observation of the excess of mutations of the 2022 [strain] when compared with its ancestor.”

Stephen Goldstein, PhD, an evolutionary virologist at the University of Utah in Salt Lake City, who wasn’t involved with the paper, told MedPage Today that the continued adaptive changes are still speculative.

“Without understanding the functional relevance of any of these mutations, it’s pretty difficult to make that argument,” Goldstein said.

“We know so little about the transmission of these viruses,” he continued. “We have not observed smallpox transmission in the era of modern genomics, and we don’t have much more with respect to monkeypox. I just don’t think we understand enough about the transmission of these viruses to link any kind of genetic changes to different transmission dynamics.”

Gomes said the characteristics described in their paper indicate that “we are definitely dealing with a different virus from what could be expected,” though he noted that increased transmissibility is not yet confirmed.

“Even if this 2022 [strain] is more transmissible than previous versions … the strategy must be the block of transmission chains,” he wrote.

“So, public health authorities must concert their efforts in the epidemiological aspects of the outbreak, and the mostly affected community (MSM — men who have sex with men) must be aware that the close physical contact is unquestionably the trigger for the infection numbers that we are seeing now worldwide,” Gomes added. “Prevention measures must also be taken by the affected persons and close contacts, besides the guidelines of the health authorities.”

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    Kristina Fiore leads MedPage’s enterprise & investigative reporting team. She’s been a medical journalist for more than a decade and her work has been recognized by Barlett & Steele, AHCJ, SABEW, and others. Send story tips to [email protected] Follow

Disclosures

Gomes disclosed no relevant conflicts of interest.