Genomic Pathogen Surveillance in the Spotlight

The COVID-19 pandemic has really highlighted the need for effective genomic pathogen surveillance and allowed researchers around the world to hone their skills and technology. While these advances are not in doubt, whether they are maintained and used to help prevent new pandemics and fight global threats such as antimicrobial resistance remains to be seen.

Over the last decade, huge advances in technology have made genomic sequencing cheaper and more accessible, facilitating the tracking of bacteria, viruses, and other pathogens. According to Sharon Peacock, Professor of Public Health and Microbiology at the University of Cambridge and Executive Director and Chair of the COVID-19 Genomics consortium, this kind of pathogen surveillance really started in earnest 10 years ago.

“That’s when people had access to instruments; the price, the availability and the ease of use that changed in the 2012–2014 period was a pivot point,” she told Inside Precision Medicine.

This was also the time that the intention to complete the 100,000 Genomes Project was announced by then U.K. Prime Minister David Cameron. Infectious diseases was one of the three focus areas for the project and Peacock was asked to head up this working group.

“I chaired the pathogen genome sequencing committee to decide what the priorities were. I think that for the U.K., at least, that was the turning point for us, because we then reached a conclusion that number one was tuberculosis… we also suggested that deep sequencing of HIV was really important to look for rare variants that were resistant to antiretroviral therapy.”

While the initial focus of fledgling genomic pathogen surveillance groups was more on pathogens such as Mycobacterium tuberculosis, events in the following few years helped highlight shortcomings and develop this area.

In late 2013 there was an outbreak of lethal haemorrhagic fever epidemic in Guinea. By the time it was found to be Ebola, it had spread to three more African countries, with sporadic cases in Europe and the U.S, and had become the largest Ebola outbreak on record. Similarly, the Zika virus outbreak of 2015–2016 was not picked up by surveillance systems until it had spread across South America causing microcephaly in infants and other neurological conditions.

A number of researchers started using sequencing to track and trace infections during the Ebola epidemic, for example, using the portable MinION sequencing machine developed by Oxford Nanopore Technologies.

“I think the Ebola outbreak showed the potential that this could be done,” commented Pablo Tsukayama, an assistant professor at Universidad Peruana Cayetano Heredia in Lima, Peru, who specializes in pathogen surveillance.

However, despite earlier calls for a ‘genomics-informed, real-time, global pathogen surveillance system’ to improve pandemic preparedness, many places remained relatively unprepared for the COVID-19 pandemic when it began in late 2019. Despite this, researchers, healthcare professionals and public health systems around the world have seized the opportunity to showcase the power of science, developing vaccines, treatments, and a range of diagnostics, and also demonstrating how improving genomic pathogen surveillance can have dramatic lifesaving effects.

“I think that SARS-CoV-2 was a fantastic example of why you need it. I mean, you couldn’t get a better case study than that,” emphasized Peacock.

It is tempting to speculate that the sheer scale of the SARS-CoV-2 pandemic will have long lasting, and hopefully beneficial, effects on genomic pathogen surveillance. For example, this March the World Health Organization (WHO) released a 10-year strategy for genomic surveillance of pathogens. But whether the energy of scientific endeavour in this area will continue long-term and in what form remains to be seen.

Tracking COVID-19: a task of mammoth proportions

The U.K. has a strong history of genomic sequencing innovation and research and was one of the first places to implement a system for sequencing SARS-CoV-2 after the COVID-19 pandemic began, something Peacock was instrumental in setting up.

The COVID-19 Genomics UK (COG-UK) consortium was formed in March 2020. “I pulled together a group of scientists in the Wellcome building on Euston Road… We put together a blueprint over the course of the day and wrote an application. It went to Patrick Vallance, chief scientific adviser to the U.K. Government, and it was funded by the first of April,” explained Peacock.

“We had 21 different sequencing sites… we just contacted everyone who we thought could do it. They had the instruments, the capability, the willingness to do it. We had 16 academic institutions across the country, four public health agencies, and the Wellcome Sanger Institute. We were at the starting blocks very early.”

Catalina Lopez-Correa is currently Chief Scientific Officer of Genome Canada, a government funded non-profit research organization using genomics to find answers to problems of national interest such as health, the environment, and sustainable resources.

After the COVID-19 pandemic began she helped found and was executive director of the Canadian COVID-19 Genomics Network (CanCOGeN). An initial aim of the group was to sequence 150,000 viral samples from people testing positive for COVID-19, as part of the VirusSeq project.

“We more than doubled the target. And that illustrates why this is important, because really, it allows us to have a whole different level of understanding of infectious diseases by using genomics,” Lopez-Correa told Inside Precision Medicine.

“This is quite unique from a scientific perspective to have the opportunity to really see a pandemic real time… To see how the virus is evolving, see the new mutations that are being generated, the distribution of the virus, the distribution of those variants.”

Both Peacock and Lopez-Correa recognise that the UK and Canada were well set up from a research and financial point of view to carry out extensive genomic surveillance during the pandemic.

“The UK has been leading the way,” said Lopez-Correa. “The U.S., I think, was interesting, because they had such an immense capacity. But they were very fragmented, they didn’t really coordinate with a single initiative, whereas Canada in that sense, with CAN-COGEN, was not perfect, but we were able to coordinate our efforts in a very strategic way.”

Western countries were not the only ones to shine when it comes to genomic surveillance. “South Africa, in particular, I think, should really be mentioned,” emphasized Lopez-Correa, noting that they were the first country to report the Omicron variant. “They did a lot of training, a lot of data sharing, and they helped set up the African Pathogen Genomics Initiative, which I think is a critical effort.”

South American researchers also stepped up to help track SARS-CoV-2. Tsukayama, who also has an association with the Wellcome Sanger Institute in the U.K., was well placed to help lead efforts in Peru.

“I was looking at bacterial pathogens that are relevant to Peru, mostly antibiotic-resistant infections in hospitals, tuberculosis, which is a big deal here, and some other minor pathogens. But then when COVID struck, we had all the tools, we had the knowledge, so it was easy to study these new emerging pathogens,” he explained.

“It was very clear at that point that this was what we should be doing and our lab was in a good position to do so.” Noting the difference in resources between Peru and a country like the U.K. he added “at the time, there was probably 5–10 sequencing instruments in the entire country. We needed funds, so the Peruvian government openened up an emergency call for related projects. By mid-April 2020 we were already setting everything up.”

Despite having small amounts of resources compared with other places, Tsukayama and colleagues identified a new variant known as Lambda during the pandemic, which subsequently spread to around 40 countries, but did not dominate the variant scene.

Returning to bacterial origins

Although COVID-19 has dominated headlines since early 2020, it is important to remember that many other disease-causing microbes exist. One expanding area of genomic pathogen surveillance is in tracking food-borne illnesses such as those caused by pathogenic Escherichia coli, Salmonella, and Listeria monocytogenes bacteria.

In May 2019, two patients in North West England died from infection with L. monocytogenes bacteria. After it was revealed that they were both in hospital when they were infected and had been exposed to the same food sources, an investigation was launched.

“Public Health England was sequencing listeria routinely. And they got a match for two isolates, by chance,” explained Peacock. “They were from patients in hospitals that were completely geographically separate, but in time, were quite linked… In terms of the number of cases, it hadn’t exceeded anything. It didn’t flag as an exceedance in numbers, but they were identical. And that, by chance, would be very unlikely.”

The investigation found listeria in the sandwiches that were given to patients in the hospitals and resulted in the closure of a factory providing sandwiches to a group of NHS hospitals. “It’s a really nice case example of how you can use sequencing to detect an outbreak before anyone spots that the cases are linked,” notes Peacock.

Gemma Langridge is a group leader at the Quadram Institute in Norwich, affiliated with the University of East Anglia, and has a focus on bacterial pathogen monitoring and research. She highlighted the importance of genomic pathogen surveillance for monitoring antimicrobial resistance (AMR) in different bacterial strains, something the WHO are encouraging countries, regions, and organizations to set up.

“We need to understand what reservoirs of AMR are present in the environment and in the food chain, because it’s impacting on animal husbandry practices, but also how we treat in the clinic. Knowing what sort of background resistance there might be, or reduced susceptibility to certain treatments is important,” she emphasized.

One of the pathogens Langridge works with is Salmonella species that carry AMR genes. “With Salmonella typhi we’re now seeing extensive drug resistance, which was first identified in Pakistan… global travel means that this is now being identified in people coming back from these regions,” she explained.

“Places like the U.K. Health Security Agency have started to flag that these are coming into the country. We need to have clinical guidance and protocols in place so that we can deal with them, even though they’re not endemic here, that can recognize that these are organisms that we are coming into contact with and know how to treat them appropriately.”

Pandemic take-home messages

Out of necessity, a huge amount of time, effort, and money has been poured into genomic pathogen surveillance during the pandemic, but the experts have learned a lot during this time. Peacock hopes one thing that will come out of the pandemic is evidence to show that genomic pathogen sequencing is cost effective to allow it to become more devolved and accessible.

“The next level of maturity, I think, for using sequencing is actually starting to roll it out into other places. If we’d centralized sequencing during the pandemic, it would have been very slow. You can get the turnaround times right down if you devolve the sequencing and get it done locally.”

She also highlights that currently sequencing can actually cost more in low- and middle-income countries than in high income countries like the U.K. “You start to deal with intermediaries who have their own costs, so to sequence in a low-income country will cost you much more than to sequence in the U.K., which is the other way around to what it should be.”

Tsukayama agrees and adds that simple logistics can also get in the way. “Nanopore is great. And I’ve been trying to push for the adoption of the technology, but just getting the reagents and machines adds a layer of problems here because I think you have to buy directly from the manufacturer and importing is difficult. Whereas Illumina is very well established in the region. There’s distributors and it’s easy to get reagents from them.”

He also says it is important to invest in research and monitoring systems in areas where new infection risk is high. “Many studies and predictions and models keep saying that the Amazon rainforest is a hotspot for zoonosis and likely a place where something new might jump into humans, so I’ve been pushing this idea that the region in general has to be prepared for this and have the tools, the protocols, the trained personnel and laboratory capacities, to do this sampling,” he emphasized.

“I think they have to put the resources where these things are likely to emerge. It’s great that you have all these setups in the United States, in the U.K, or in Europe, but it is likely to emerge elsewhere. And it’s in everyone’s best interest to fund these things.”

Lopez-Correa agrees about logistics, for example, ensuring everyone can sequence and access the tools they need, when they need them; but says data sharing and data analytics were also highlighted as areas needing more attention during the pandemic. “We have plenty of technologies to do good and fast sequencing so that was not the bottleneck in itself,” she explained. Genome Canada worked with a local health tech company, DNAstack to help improve data analytics and safe data sharing during the pandemic. The company has since been recognized for its work by the World Economic Forum.

“We now understand the importance of genomic pathogen surveillance in general. But it’s not enough to just sequence the data. You have to share it in real time,” Mark Fiume, DNAstack CEO, told Inside Precision Medicine.

“We think that the best approach to sharing data is using a federated model. And what we mean by federated is kind of like the Internet where you don’t bring all the data into one database with one custodian. It’s rather a sort of mesh, an internet of genomics and health data.”

Fiume and colleagues provided valuable data sharing and data analytics services to researchers and public health authorities during the pandemic with the help of their internal bioinformatics capability and their federated machine learning platform. As a result of their success, the company has now tripled in size and is now working to provide access to this kind of service to different countries and regions around the world including lower- and middle-income areas.

“Every single night we reprocessed raw genetic sequence data, regardless of what format it was in, into some very consistent kind of variant calling assembly lineage assignment,” explained Fiume. “We did the things that we thought that the community would need as a resource to really create an immaculate dataset of genomic information on SARS-CoV-2.”

This kind of service is very important, particularly in areas where expert bioinformaticians and high-powered computers are in short supply. “We don’t have great training in bioinformatics,” says Tsukayama. “The fact that a lot of folks that do are putting free, web based, very easy to follow black boxes online that will analyze data… that’s a huge plus and makes things a lot easier.”

According to the experts, increasingly people working in genomic pathogen surveillance are using a hybrid sequencing model of both short (normally Illumina) and long read (normally Oxford Nanopore) sequencing to encompass a wider range of pathogens with both long and shorter genomes and also a range of different mutations.

Langridge has been working with a local biotech company to help make the longer read pathogen sequencing that she and her team are doing easier. RevoluGen has pioneered a method to extract longer sections of DNA from samples using their quick and easy Fire Monkey High Molecular Weight DNA extraction system, which works like a standard spin column kit.

“Any other spin column kit will extract DNA with an average of between 30,000 to 40,000 base pairs, where the fire monkey spin column kit goes between 100,000-120,000 base pairs on average.

So, there’s a real difference,” explained RevoluGen CSO Georgios Patsos. “It just happens that this kind of average is also a ‘sweet spot’ for nanopore sequencing.”

The company has worked with Langridge and other researchers during the pandemic to automate their system to allow much higher throughput and speed at the same quality.

Pandemic preparedness 2.0

The big question on everyone’s lips right now is how to use the knowledge gained during the COVID-19 pandemic to try and prevent or at least better control the next pandemic. Also, can pathogen monitoring and research momentum be maintained amid waning cases, funding, and interest?

Lopez-Correa and her Canadian colleagues are looking at how to use the information and experience they gained over the last two years to help prevent future pandemics. “We are now creating a national alliance for pathogen surveillance for Canada… we are starting to have the meetings and it is going to be with all the public health labs and academic institutions. It’s a bit of a transformation of our network.”

COG-UK is actively trying to pass on the knowledge they learned during the pandemic by running a number of online courses using distributed classrooms. Peacock thinks collaboration and working as a team, as well as with international colleagues, can really help drive pandemic preparedness and management.

“The genome data is the starting point. In the U.K., that was very joined up [during the pandemic]. There was a viral genotype to phenotype consortium led by Wendy Barclay. There was an immunology consortium led by Paul Moss. And then of course, we had the Office for National Statistics surveys, where the sequencing could kind of support that. But team science was really key and collaboration and interdisciplinarity were fundamental to the success of the science in the U.K.”

Fiume and his colleagues at DNAstack are also working to promote teamwork and collaboration around the world. “We want to democratize access to technology to low- and middle-income countries as much as we empowered Canada. We want to make sure that everyone has access to this technology so that we’re all working together on these kinds of things.”

Like many other organizations and public health authorities in the U.S. and around the world, CanCOGeN is using pooled wastewater testing to continue monitoring in a cheaper and less invasive way and to check for other pathogens. “Instead of looking just for SARS-CoV-2, we are using these tools and thinking about pathogen surveillance in a much broader way. We have monkey pox, we have influenza, we have other pathogens that we should be also worried about,” says Lopez-Correa.

Langridge agrees and adds “some of the surveillance mechanisms that have started because of COVID, things like wastewater surveillance, mean we don’t just have to focus on what’s coming out of hospitals, we can look in the environment, we can look in food. That’s something that we’ve been doing on a research level for a while, but to get that recognition more widely, I think, is a positive.”

 

Helen Albert is senior editor at Inside Precision Medicine and a freelance science journalist. She has academic degrees in genetics and anthropology.