To influenza and beyond

Awaking to find that you have a cough or runny nose over the last two and a half years, it’s been sensible to assume that SARS-CoV-2 may have caught up with you. However, for many people, both rapid antigen and PCR tests will have stubbornly refused to return a positive result for SARS-CoV-2. Fantastic that you didn’t have COVID-19, but what did you have that left you feeling unwell?

While diagnostic tests are generally used to determine the infecting agent for severe illnesses that require hospitalization, in reality, for most cases with cold and flu symptoms, the virus responsible is never identified. Indeed, despite many decades of research on respiratory viruses, we still have a surprisingly shallow understanding of which viruses are circulating in a community at a given time, when and where they transmit from person to person, why the symptoms they cause are severe in some but mild in others, or how they evolve over time.

Genomic sequencing has become a powerful tool with which to deepen our understanding of respiratory viruses and begin to answer some of these questions. This has been ably demonstrated during the pandemic, where more than 14 million SARS-CoV-2 genomes have been sequenced globally and used to understand the evolution and spread of variants of concern in community and institutional settings. The UK alone has sequenced more than 3 million SARS-CoV-2 genomes, with the Wellcome Sanger Institute having a pivotal role, both as a sequencing and analysis hub for the COVID-19 Genomics UK (COG-UK) consortium and more recently in partnership with the UK Health Security Agency (UKHSA). During this work, more than 300 Sanger staff have received and handled more than 30 million samples, sequencing up to 60,000 SARS-CoV-2 genomes per week.

With the launch of the ‘Respiratory Virus and Microbiome Initiative’, the Sanger Institute is now aiming to take what we have learned through COVID-19 and establish the groundwork for large scale genomic surveillance of other respiratory viruses, such as influenza virus and respiratory syncytial virus (RSV), and to survey for as yet unknown pathogens.

The Sanger Institute is uniquely placed to undertake this work in large part owing to the infrastructure and operational experience gained in sequencing diagnostic swab samples at scale during the COVID-19 pandemic. The team will initially seek to establish a baseline picture of the dynamics of a range of common respiratory viruses in the UK through targeted sequencing for specific viruses. They will also develop the tools and approaches needed to use shotgun metagenomics – sampling all genes and organisms present –  for untargeted surveys of the species of virus, bacteria and fungi present in respiratory samples.

Co-infection and secondary infections caused by bacterial and fungal pathogens are common in severe respiratory viral infections, including for SARS-CoV-2, RSV, and pandemic influenza. As such, using metagenomics to understand how the respiratory microbiota changes during infection may help to explain variability in the severity of illness between individuals and identify opportunities to intervene earlier to prevent or blunt a respiratory pathogen.

Metagenomics also has the potential to allow tracking of antimicrobial resistance (AMR) in the respiratory microbiome, which will be increasingly important in the years to come as our arsenal of effective antimicrobial dwindles. Understanding and tracking the epidemiology of AMR pathogens such methicillin resistant Staphylococcus aureus (MRSA) and multi-drug resistant Mycobacterium tuberculosis will be vital for informing infection control and antibiotic stewardship measures.

The initiative will be led by Dr Ewan Harrison, previously a Career Development Fellow at the Sanger Institute and University of Cambridge and also a Deputy Director of COG-UK.

“The systems we develop are intended to be the canary in the coal-mine,” says Ewan. Often, new viruses are first identified in intensive care once an outbreak is already well underway. By using genomic surveillance to monitor all the respiratory viruses present in a population, the hope is that we can get an earlier warning of a potential threat.

In addition to looking for new viruses, the metagenomic approaches the team develop will allow researchers to better understand the transmission and evolution of respiratory viruses that are already well established.

“Many countries monitor and track flu, as well as COVID, and we know a lot about their epidemiology. But for other viruses this isn’t the case. We’ve got an opportunity here to study the evolution of a whole range of pathogens,” says Ewan.

The idea behind the initiative owes much to Dr Harrison’s track record in seeking to couple his academic research with delivering actionable insights to improve public health. Whether as a leading figure in COG-UK, or in his on-going work to understand the biological basis of persistent nasal colonization by Staphylococcus aureus, Ewan has sought to apply microbial genome sequencing to large patient cohorts and integrate microbiology with host genetic and electronic health data. Taking this multidisciplinary approach means that in addition to generating new understanding of the biology underpinning host-microbe interactions and how this causes disease, the data can be used to inform best practices in infection control and clinical care.

Reflecting these dual aims, the initiative will sit within the Sanger Institute’s Parasites and Microbes programme, but also work closely with the Sanger teams responsible for surveillance operations, as well as partners at UKHSA. These connections will enable Ewan’s team to build on the considerable experience using genome sequencing for pathogen surveillance at Sanger and the UKHSA, as well linking in ongoing nasal microbiome studies in healthy people, and studies of the gut microbiome in the Lawley research group, and an extensive global network of faculty, fellows and research partners.

If successful, in the longer term the platforms and technologies developed will be scaled up and transferred to the UKHSA, and other public health partners, to be incorporated into their pathogen surveillance programmes.