Sequencing monkeypox

Over the weekend the WHO declared the monkeypox outbreak a “public health emergency of international concern” (PHEIC). Monkeypox (MPX) is typically found in western and central Africa. In the rest of the world only a handful of cases have been diagnosed in people who travelled from these countries, or were linked to animal trafficking. However, as of early May 2022, growing numbers of cases have been detected around the globe. As of 25 July, there have been 16,016 confirmed cases in 74 countries, of which over 11,000 are in Europe and over 3,700 from the Americas. While MPX can cause rare complications and death in 1-10% of cases, depending on the strain, no deaths have been reported by previously unaffected countries.

Containment of MPX outbreaks relies on a strategy of educating people about the disease and finding cases early to reduce the chance of transmission. There are vaccines which can prevent disease even if used up to four days after a person is exposed to the virus. Track and trace procedures to identify close contacts of people with MPX can identify people who could receive these vaccines. Some countries are also offering the vaccine to at risk populations.

This outbreak is exposing gaps in our knowledge about the disease. MPX is not highly transmissible, but its continued circulation is a concern. One complication is that the extent of asymptomatic infection is unknown and complicate control efforts as well as delay testing.

The use of sequencing

Sequencing of the MPX virus to read its genetic code has an important part to play in understanding the outbreak, allowing researchers to piece together transmission networks, and give clues as to how the virus spreads from person to person as well as reveal if any genetic changes that might make it more pathogenic or transmissible.

Right now, the world is particularly well placed to implement genomic epidemiology measures, which have been established and widely used during the COVID-19 pandemic. Genomic sequencing centres that analyse COVID-19 samples have been redeployed to sequence MPX, and sequencing of wastewater is being used to understand how widespread the outbreak is.

The true burden of MPX in countries where it is endemic, and the diversity and extent of the animal reservoir, is poorly understood, but it is critical for prevention and control of future outbreaks as well as understand the current one. Animal reservoirs can lead to animal-to-human infections, which is the main cause of outbreaks in endemic countries. Understanding what genetic changes that have occurred between the virus circulating in animal reservoirs could provide clues as to the human-to-human transmission that is occurring in this outbreak. Supporting these countries to be able to investigate these concerns should be a priority.

The MPX genome is complex

MPX is a DNA virus and its genome structure poses some challenges for sequencing. It is large – around 200,000 DNA letters long, about seven times the size of SARS-CoV-2.

The first full draft sequence from the current outbreak, covering 92% of the MPX reference genome, was released by a Portuguese team in May 2022. This genomic information was refined and updated as more sequencing was done.

Despite some gaps, this draft has helped scientists identify some important features in the early stages of the outbreak. Such as, the strain of MPX virus in the current outbreak closely resembles a West African strain carried by travellers from Nigeria to Singapore, Israel, and the UK in 2018-19. The West African strain has a fatality rate of around 1-3.5%, less severe than the 10% fatality rate of the Congo strain. Knowing which strain is circulating and causing an outbreak can be vital in determining the urgency of any public health response.

The virus changes

Changes in the viral genome can affect its biology – e.g. making it more or less infectious – and also provide scientists with a tool to track the evolution of the virus and compare current and past outbreaks. The MPX virus has a slow evolutionary rate – around one genetic letter change per year – making it more difficult to study over short time periods. However, sequences from the current outbreak have up to 50 changes when it is compared to the 2018 MPX viruses. This is an unexpectedly high number, no more than five to ten changes in that time frame would normally be expected. The explanation for these differences is not yet clear, however further sequencing, including sequencing of archived MPX samples from endemic countries, many provide further insight, including a more accurate evolutionary rate.

For now, the implications of these changes for disease severity or transmissibility are unclear. Initially some scientists speculated that a new, more transmissible form of MPX might have emerged, but the genomic sequence data does not appear to support this. Some now think that sustained onward transmission might explain the current outbreak rather than increased transmissibility. One possible reason could be the time it takes for symptoms to appear, leading to continued transmission before someone realises they are infected. What is clear is that a threshold has been crossed that is allowing for human-to-human transmission. Scientists hope that further sequencing will help address these uncertainties, as well as clarify exactly when and how the outbreak began.

Sequencing data from MPX virus in the UK shows a similar number of mutations, 48, compared to the 2018 strain. These mutations are distributed across the genome and three are classified as high priority since they occur in genes coding for proteins that are involved in virus transmission, virulence or interaction with antiviral drugs. More work is needed to assess their exact impact.

Data sharing

As of 20 July, 429 sequences from 24 countries have been uploaded onto the database NCBI Virus GenBank. As has been demonstrated during the COVID-19 pandemic, sharing of virus sequence information in public databases enables real-time accurate comparisons of sequences, supporting faster insights into the spread of the disease, and development of appropriate public health interventions. It is hoped that as the outbreak progresses, further sequences will become available in public databases and help answer many remaining questions about the MPX virus.

Going forward

With the WHO declaring the MPX outbreak a PHEIC, it is likely that it will lead to greater international cooperation on research and vaccines to battle the outbreak. The MPX outbreak illustrates how vital it is to monitor viruses that have the potential to cause a major health crisis. Every new outbreak is a chance for us to refine surveillance, including use of genetic epidemiology to monitor and understand pathogens, so that we can be better prepared to prevent future outbreaks.