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Sanger Institute-led Respiratory and Microbiome Initiative to Develop Genomic Surveillance Methods

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NEW YORK – The Wellcome Sanger Institute this week announced a new initiative that will develop new methods and workflows for the routine genomic surveillance of respiratory pathogens.

The five-year Respiratory Virus & Microbiome Initiative (RVI) is fully funded by the Wellcome Trust, though a funding amount has not been announced. A spokesperson for the institute said the funding would be drawn from the Sanger's core budget and that it is unclear how much will be invested, noting that the project is focused on reducing the costs of genomic surveillance.

According to the organizers, RVI will expand on the expertise gained through the use of genomic sequencing during the ongoing COVID-19 pandemic, applying it to other respiratory pathogens.

Ewan Harrison, head of the new endeavor and a group leader at Sanger, said in a call with journalists earlier this week that the initiative will build on work in pathogen genomics around SARS-CoV-2 undertaken at the institute, within the UK, and globally.

"Pathogen genomics arguably enabled us to mount a rapid and successful response to COVID-19," Harrison commented, noting that the initial pathogen was identified via genome sequencing in January 2020. This, in turn, enabled the quick development of diagnostics and vaccines.

It also allowed investigators at the Sanger and elsewhere to hone low-cost microbial genome sequencing methods that have been employed throughout the pandemic for a variety of reasons. "We have done a huge amount of COVID-19 sequencing, which has allowed us to track SARS-CoV-2 globally," Harrison said. It has also allowed researchers to better understand transmission and infection, to track emerging variants, and to gain, in Harrison's words, "huge insights" into fundamental biology.

Not only has all of this genome sequencing provided an "unprecedented understanding of a respiratory pathogen," it has also enabled large-scale genomics to influence policymakers, providing them with up-to-date information to better react to a pandemic.

"That is a profound change in science and health policy, and something we now think we should build upon," he said.

There are a few ways that the initiative will expand beyond what has already been done for SARS-CoV-2. The first and most obvious one is by investigating other common respiratory viruses, including influenza A and B, parainfluenza, human metapneumovirus, adenovirus, rhinovirus, and respiratory syncytial virus (RSV), as well as other coronaviruses.

Harrison noted that while some viruses, such as the flu virus, are currently tracked by epidemiologists, others are not, or at least not to the extent that SARS-CoV-2 has been. "The initiative really hopes to address this and to develop routine sequencing for these [viruses] as a part of public health as well as, eventually, the healthcare system."

Beyond broadening the number of respiratory viruses of interest, the new initiative also foresees significant technology development. Rather than relying on the amplicon sequencing that was employed heavily during the COVID-19 pandemic for SARS-CoV-2, the Sanger's new initiative is interested in developing a metagenomic approach, so that it can look at more viruses across the same sample.

According to Harrison, RVI will rely on bait-capture metagenomics, where one generates a sequence library of all DNA molecules contained in the sample and then probes the library using baits to capture specific sequences. Once captured, these can be sequenced, providing a rich amount of information on the pathogens of interest.

"You don't have to target just one particular species, you can target multiple species within a single assay," said Harrison. "It's incredibly useful because you can see all the species there, including bacteria and other viruses."

Indeed, looking at the microbiome of the respiratory tract, including bacteria and fungi, and monitoring its interaction with viruses and perhaps impact on disease severity, is another goal of RVI. Harrison said that RVI has access to millions of samples collected during the COVID-19 pandemic. These will be used to develop and validate its metagenomics approach, comparing its ability to detect SARS-CoV-2, for example, against standard methods.

That approach, however, is still in development and will be rolled out in time. Harrison noted that RVI is liaising with other academic teams in the UK — the UK Health and Security Agency is also a partner — to develop the approach it will ultimately deploy routinely through the RVI. By late spring, RVI hopes to have a "first-pass assay up and running" that will use the stored COVID-19 samples to conduct pilot sequencing at scale.

Using its envisioned assay in real time, though, on incoming samples from patients with various respiratory viruses is still "a little way off, but we are aiming to get there as soon as we can," he said.

The longer-term goal is not only to have methods that work cheaply and effectively for RVI and in the UK but also to make them available elsewhere. Harrison said that RVI plans to make its sequencing methods, software, computational methods, and all sequencing data publicly available. Ideally, such low-cost sequencing methods could be used by "someone with a laptop and a nanopore sequencing machine" eventually, he said.

"We do hope that we can contribute to ensuring that genomic surveillance that was built during the pandemic is continued," said Harrison.

For its own work, Harrison said in an email that RVI will be using Illumina sequencing platforms, but he stressed that the initiative is "technology agnostic" and aims to develop methods that "as much as possible are capable of being used on any sequencing platform."

Judith Breuer, a professor of virology at University College London who also participated in the call with Harrison, said that RVI is an "amazingly important initiative" that will provide policymakers with data necessary to manage ongoing and future outbreaks.

She said in an email that UKHSA could potentially contribute data on the geographical location of cases, as well as hospital or community location, the date of sample collection, and the age of the patient that could be combined with RVI's genomic data.

Harrison confirmed via email that certain limited anonymous data fields, such as age groups and geographic locations, will be made available via UKHSA.

"This will allow us to investigate, for example, how different viruses spread geographically through England during a winter, [whether there] are multiple introductions, how much movement there is between different geographic areas," said Harrison. "We will also be interested to see how viruses circulating hospitals relate to those in the local community," he added.

UKHSA also maintains data on clinical disease as well as underlying patient characteristics or comorbidities that the agency could combine with genomics data to conduct epidemiological analysis, Harrison noted. "Further analysis like this will need to be carried out within secure UKHSA systems as part of the RVI collaboration," he said.

Breuer's lab at UCL is focused on using whole-pathogen genome sequencing, and she is also a co-investigator in the COVID-19 Genomics UK Consortium.

According to Breuer, the methods being developed by the RVI should support similar efforts to expand genomic surveillance in other countries, continuing on from previous investments made during the COVID-19 pandemic.

"There is a huge amount of know-how and expertise in pathogen sequencing all over the world now, and I think that standardizing simple protocols, and having expertise around to help troubleshoot issues, will [offer] really powerful incentives to get sequencing up and running in other places," Breuer said on the call.

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