Ever since it was first reported in humans in 1970, monkeypox virus infections have been largely restricted to countries in Central and Eastern Africa until recently. Early in 2022, multiple cases were identified in Spain and several cases were reported from countries where the disease is not endemic, including regions in Europe and North America, and in patients with no history of travel to endemic regions.
Following a rapid rise in cases, the World Health Organization (WHO) on July 23, 2022 declared the 2022 monkeypox outbreak as a Public Health Emergency of International Concern (PHEIC). As of early August 2022, over 25,000 cases of monkeypox have been reported from 83 countries, 76 of which have never historically reported monkeypox.
Genome sequences
The accelerated use of genomics as a tool to understand outbreaks in the last half decade has left an indelible mark during the ongoing COVID-19 pandemic and has seen a wider deployment of sequencing infrastructure across the world. Genomic surveillance of pathogens could provide unique insights to understand the outbreak better, track the spread of pathogens and provide immense opportunities for public health decision-making as well as for epidemiology.
Researchers from across the world have made available over 650 complete genome sequences of monkeypox isolates to date in public domain databases including GISAID and GenBank. This includes over 600 genomes which were sequenced this year alone from over 35 countries, including genomes of two isolates from India, collected from Kerala.
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Accelerated evolution
The monkeypox virus has a DNA genome of around 2,00,000 base pairs, roughly six times larger than that of SARS-CoV-2. Like other viruses, the monkeypox virus evolves by the accumulation of genetic errors, or mutations, in its genome when it replicates inside a host. Information about mutations occurring in different genome sequences of the monkeypox virus across different regions can, thus, provide essential insights into how the virus is evolving, its genetic diversity and other factors that may be relevant to the development of diagnostic tools.
Being a DNA virus, the monkeypox virus like other poxviruses was believed to have a small rate of accumulating genetic changes compared to viruses with an RNA genome like SARS-CoV-2, which have a much larger rate of mutations. For poxviruses, this rate is estimated to be as low as a couple of genetic changes every year. A recent study, however, revealed that the observed rate of genetic changes in the virus was higher than expected — average of around 50 genetic changes. The higher-than-expected rate of evolution coupled with the rapid rise in monkeypox cases across the world could potentially be due to highly parallel evolution in a large number of individuals simultaneously, as the present outbreak came out of a superspreader event.
APOBEC3 protein
The study also suggests that several mutations that have been identified in the new sequences of the monkeypox virus may have emerged due to interaction between the virus genome and an important family of proteins coded by the human genome known as the Apolipoprotein B Editing Complex (or APOBEC3). These proteins offer protection against certain viral infections by editing the genome sequence of the virus while it replicates in the cell.
Some researchers, therefore, suggest that many of the genetic mutations in the monkeypox genomes from the current outbreak are relics of the effect of APOBEC3 and may not provide a significant evolutionary advantage to the virus.
Monkeypox virus can infect a range of hosts, including non-human primates and rodents which could act as a natural reservoir. Infections in the reservoir could also enable continued transmission and accumulation of mutations before spilling over to cause human infections. Other studies have also suggested a continued evolution of the virus, including deletions involving genes as seen in a few genomes from the present outbreak, which could suggest newer ways in which the virus continues to evolve with sustained human-to-human transmission.
Monkeypox lineages
Clusters of genomes having common and shared mutations and a common origin are referred to as a lineage or clade. In the early 2000s, two different clades of monkeypox virus were defined in Africa where several cases of the disease have been seen — the Central African (Congo Basin) clade and the West African clade, of which the Congo Basin clade has been shown to be more transmissible and cause more severe disease.
Since naming viral lineages using the country or geography of origin could be discriminatory and possibly not in the right spirit, a new system of naming monkeypox lineages has been proposed by researchers recently. Under the new proposed system, the Congo Basin clade is denoted as clade 1, while the West African clade is divided into clade 2 and clade 3. This new system will also describe sub-lineages of the virus, with the original parent lineage being denoted as lineage ‘A’, and its descendants as ‘A.1’, ‘A.1.1’, ‘A.2’, and ‘B.1’. Lineage B.1 denoted the current 2022 outbreak of monkeypox virus infections which is a descendant of the A.1.1 lineage.
2022 outbreak insights
With several genome sequences of the monkeypox virus available in public databases, it is possible today to understand the prevalence of different lineages of the virus across different regions. Over 95% of the recently deposited genome sequences of the virus belong to the B.1 lineage of monkeypox virus and this lineage is epidemiologically linked to the superspreader events in Europe that formed the basis for the current outbreak of monkeypox.
While a majority of the genomes deposited could be linked to the 2022 outbreak of monkeypox, sequences deposited recently in 2022 from the U.S., Thailand and India suggest that there is a second distinct lineage of the monkeypox virus that is currently in active circulation in 2022. These genomes are classified as the A.2 lineage of the monkeypox virus and currently encompass six genome sequences, including two that were collected from Kerala. The earliest genome belonging to this lineage was collected from Texas in 2021 while the two sequences from Kerala collected in 2022 cluster closely with a genome collected from Florida in the same year.
The characterisation of this distinct lineage amid the 2022 outbreak of monkeypox suggests that a previously undetected and cryptic transmission of the virus has been occurring in multiple countries, since at least around 2021, and was probably uncovered due to increasing awareness about the disease and the availability of diagnostic tools.
Genomic surveillance of pathogens provides interesting insights by following a molecular approach for contact tracing and understanding the transmission of the virus across the world. As cases of monkeypox continue to rise, it is therefore important to strengthen the genomic surveillance for the monkeypox virus. Since data from the present outbreak suggest a sustained human-to-human transmission, continuous genomic surveillance is important to understand the evolution and adaptation of the virus, apart from providing useful data to epidemiologists.
With COVID-19 continuing unabated and monkeypox around the corner, the time has never been better, and the need never more acute, to build a sustainable system for genomic surveillance in India.
( The authors are researchers at the CSIR Institute of Genomics and Integrative Biology (CSIR-IGIB) in Delhi. Views expressed are personal)
