Monkeypox genomic surveillance will challenge lessons learned from SARS-CoV-2

The emergence of a series of epidemiologically connected monkeypox virus infections around the world, with ongoing human-to-human transmission (as of June 15, 2022, 2103 confirmed cases, one probable case, and one death have been reported to WHO from 42 countries), raises concerns of a long-apprehended comeback of a human-adapted orthopoxvirus related to variola virus, the aetiological agent of smallpox. Since variola virus had no natural reservoir other than humans, the eradication of the virus by use of highly effective vaccines against orthopoxviruses was irreversible.¹ However, other orthopoxviruses have reservoirs in wildlife, such as cowpox virus (in voles), taterapox virus (in African gerbils), and monkeypox virus (in small mammals), do have the potential to spill into the human population and facilitate a restart of the genetic adaptation of the virus to the human host, which once resulted in variola virus.² This adaptation is possible by the unique genomic make up of orthopoxviruses and their ability to jumpstart evolution by use of gene loss,³ rather than by progressive mutation as seen in SARS-CoV-2.

Within orthopoxviruses, a genetic core of about 120 000 base pairs is highly conserved and thought to code for basic viral functions; however, towards the termini the orthopoxvirus genome is plastic, and large regions can be readily deleted (appendix). These regions contain genes related to host adaption. Orthopoxviruses like variola virus that have adapted to a specific host species tend to lose many terminal host-restriction genes during adaptation (appendix), allowing them to spread more easily or cause more severe disease. This loss could optimise both the spread (eg, by droplet-related transmission) via enhanced systemic infection and disease severity.

Circulating monkeypox virus might be undergoing adaption for the human host, so we must keep its genetic changes under tight surveillance so as to be prepared when sudden epidemiological changes and prevent the emergence of a variola virus epigone. This surveillance, however, will require a conceptual shift from observing lone single nucleotide polymorphisms, as with SARS-CoV-2 variants, towards watching closely for the integrity and stability of the monkeypox virus genomic termini. Therefore, the constant sequencing of full monkeypox virus genomes is of utmost importance to detect not only single nucleotide polymorphisms but any intragenic frameshifts or premature stop codons, that might indicate initial signals of gene loss. This surveillance, however, requires the highest-quality genomic data and careful annotation. Currently many sequences from the ongoing outbreak are erroneous or do not have annotation, which makes it difficult to establish useful genomic characterisation.

For WHO's monkeypox outbreak situation update see https://www.who.int/emergencies/disease-outbreak-news/item/2022-DON393