Benefits of pathogen sequencing for human health - Sharon Peacock
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Benefits of pathogen sequencing for human health

Benefits of pathogen sequencing for human health

The COVID-19 pandemic has demonstrated how rapid SARS-CoV-2 sequencing can provide actionable information towards the public health response. But more needs to be done to establish global sequencing capacity for SARS-CoV-2 and other pathogens, supported by equitable and ethical systems that aggregate and analyse datasets for the benefit of all.

Responding to an urgent need

Viruses evolve through random mutations (‘typos’) in their genetic code. Mutations that alter the virus biology in ways that result in a fitness advantage may then become selected out from the wider population of that pathogen. In real-world terms, this means that variants with such a mutation (or combination of mutations) will become more prevalent under the right circumstances. This reflects the well-described process of natural selection.

Early in the COVID-19 pandemic, we were faced with the question of whether (and if so, when) SARS-CoV-2 variants with one or a combination of mutations would emerge that changed viral behaviour for the worse (for humans). In short, we were concerned about variants with increased transmissibility, the potential to evade natural or vaccine-induced immunity, increased severity or course of clinical infection, or any combination of these. 

Early in the COVID-19 pandemic, scientists around the world recognised the potential value that could be gained from rapid and large-scale genome sequencing of the SARS-CoV-2 virus, so that genetic changes could be detected and tracked over time and geography. This technology has since been used extensively to provide actionable information for public health responses and vaccine development.

A need for speed

In the UK, we raced to establish the COVID-19 Genomics UK Consortium (COG-UK) in March 2020. Our aim was to generate high-volume SARS-CoV-2 genomes for public health agencies to use in identifying and monitoring genetic changes in the virus over time. Data were also used to examine transmission of the virus across borders, and in settings such as hospitals, care homes and universities.

In setting up COG-UK, we aimed to be inclusive of people and groups who could deliver sequencing as soon as possible. The result was a consortium that brought together numerous universities, the four public health agencies of the United Kingdom, and the Wellcome Sanger Institute. This became networked with more than a hundred NHS hospital labs, and the high-throughput national testing laboratories. The operations and logistics were managed by a team in Cambridge. We were fortunate in having access to CLIMB, the UKs Cloud Infrastructure for Microbial Bioinformatics. This housed a custom data management system and was further developed to contain the necessary software and analysis tools to support large-scale genomic efforts. This proved pivotal to our success.

This national effort has enabled the UK to sequence more than 1 million SARS-CoV-2 genomes. Sequence data provided vital information to vaccine developers and vaccine trials. It also provided the means to detect and track variants of concern across the UK, including the Alpha and Delta variants. Around 600 consortium members have contributed to these efforts, many of whom volunteered their time and expertise. They also became adept at reacting to an evolving situation at speed and develop sequencing at pace, demonstrating huge flexibility and ingenuity around how this was achieved.

Underpinning our activities have been values of transparency and open access data release. We have shared our genome data with others as soon as possible, through the global database GISAID, and through the European Nucleotide Archive.

We were not alone in standing up sequencing activity – many other countries have developed similar capabilities.

A response built on past activity and learning

Pathogen sequencing is not new to public health. Prior to the pandemic, pathogen genomes were already generated as routine by wealthy nations for a variety of use cases. For example, sequencing of pathogens associated with foodborne associated outbreaks, such as Salmonella and Listeria, has become the standard in many countries to detect and investigate outbreaks. This is essential if outbreaks are to be rapidly detected, particularly when this involves foods with a highly complex food distribution.

Sequencing is also increasingly used for TB. This can rapidly predict the presence of multidrug resistance in the causative organism (Mycobacterium tuberculosis) and can lead to more rapid administration of effective treatment. Sequencing is also established for the treatment of people with HIV, to detect the presence of changes in the virus that indicate resistance to antiretroviral drugs. It is also used during the treatment of other viral infectious diseases, including Hepatitis C.

Sequencing has been used to investigate past outbreaks, including SARS, MERS, Zika and Ebola. Extensive research has also been undertaken on how sequencing could inform hospital infection control, as well as replacing a myriad of microbiological methods in the laboratory (such as pathogen typing, and detection of genes encoding drug resistance).

In a recent technical report, the ECDC (European Center for Disease Prevention and Control) provided a comprehensive list of use cases for pathogen sequencing, combined with the status of integration of molecular and genomic typing into European surveillance and multi-country outbreak investigations [1]. This reflects the breadth of current and future uses, and represents core capabilities in dealing with numerous other infectious threats to health beyond COVID-19.

Sequencing during present and future pandemics

Sequencing of SARS-CoV-2 will be required for as long as the virus causes symptomatic infection, to keep close tabs on genetic changes (and associated biology) that could be of concern, and that require careful observation and appropriate public health measures.

We will also use sequencing to detect and better understand the next novel virus that emerges and crosses over into the human population. Sequencing will once again prove crucial in vaccine development and monitoring for pathogen evolution, and evasion from vaccines and drugs. One potential scenario is that sequencing becomes increasingly used to examine samples from patients with a severe respiratory infection of unknown cause. Rapid and early detection of a new virus with pandemic potential could lead to control measures that aim to ring-fence and control the infection as soon as humanly possible.

Sequencing will also be used in vital research studies to examine reservoirs of novel viruses in the animal kingdom, including in bats, so that we can better understand future risk from currently unknown viruses.

Sequencing has become a vital tool to detect, treat and contain outbreaks, both now and in the future. We have broken through a glass ceiling in wealthy nations where the value of pathogen sequencing has been fully realised and embraced by policy makers, politicians, and the public.

But there are challenges to the effective use of sequencing.

Inequity in access to sequencing

Something that the COVID-19 pandemic has demonstrated clearly is the troubling inequity in access to modalities that can protect the health of nations. The prime example is vaccines. But the same is true for sequencing, so that a country may have no or limited knowledge about the variants that are circulating.

This is of concern for several reasons.

First, this situation is unethical. It is only fair that everyone has equal access to an understanding of what lineage is causing COVID-19 infection. This will become especially important if variants of concern emerge that can increasingly dodge our immunity.

Second, this represents a large chink in the armour of global control of COVID-19. If new variants of concern are to emerge, they are likely to do so in places with high rates of infection and transmission. With our inter-connected world, we have seen repeatedly that it takes a very short time for a variant to travel the globe many times over and infect people across the planet.

It is not possible to predict what happens next with variants of concern. But for a new variant of concern to emerge and become prominent as a cause of infection, or even dominate and replace other variants, it will need to be ‘fitter’ than the Delta variant – which is already highly transmissible and partially evades the immune response. So, it is reasonable to postulate that a new variant of concern that can out-compete Delta will be even more transmissible, or have greater immune evasive properties, or both. However, with low or no sequencing coverage for positive cases being the norm in many countries, its early emergence and spread may go entirely unnoticed for some time.

Only through the international generation of large-scale sequencing data will we be able to comprehensively monitor for variants whose increasing prevalence suggest cause for concern.

Furthermore, we need to strengthen the science pathways that connect genomics with modelling and laboratory experiments, to determine whether a variant under investigation should be classified as a variant of concern and prioritised for a suitable response. This means strengthening in sequencing, virology and immunology.

Are there reasons to hope?

We are not where we need to be, but there is some reason for hope. There are numerous efforts worldwide to deliver pathogen sequencing in a geographic distribution that does not only align with wealth.

Many contributors are contributing to sequencing in low and middle-income countries. Africa CDC is playing a key role in this effort. A new initiative between the Africa CDC, the WHO, Bill and Melinda Gates Foundation and US CDC (the Africa Pathogen Genomics Initiative) promises an expansion in sustainable sequencing capacity. There are numerous other contributors who are expanding sequencing capacity, training and knowledge worldwide.

Team science is also creating new ways of working across borders and countries on a scale that is unprecedented in my experience of genomics.  One exemplary example of team science is a recent study published in the journal Science. This described SARS-CoV-2 variants over one year across Africa and was achieved through the involvement of more than 300 authors and 137 affiliations [2].

This and other efforts represent a climate of positive action from the ground up, arising from the efforts of motivated individuals and teams. These efforts can make an important and tangible difference now.

But in the longer term, there is a need for an integrated, trusted international system, whereby member states can work with the WHO and regional health organisations to generate and analyse genomic data for microbial pathogens causing the current and future pandemics. Issues such as standard methods and protocols and data sharing agreements should be fully embedded in these efforts. This could draw together bottom-up and national efforts so that aggregated global data becomes greater than the sum of the parts.

The funding and development of the WHO Hub for Pandemic and Epidemic Intelligence based in Berlin will strengthen intelligence specifically for pandemics and epidemics by striving for better data, better analytics, and better decisions. Sequence data will make an important contribution to their suite of capabilities. In addition, a global pandemic radar was announced by the UK prime Minister in May 2021, at the start of the UK G7 presidency.

Declarations of intent are an important starting point – every initiative needs to start with an idea supported by a strategy, from which operational planning and implementation flow. But time is pressing, and urgent action is required from leaders and institutions who have the mandate and responsibility to scale up sequencing. Data will require aggregation, analysis, and application in a way that achieves public health benefit as well as garnering political and public trust.

Making a lasting difference

We live in a time when technological innovations have made a real and tangible difference to the way that we detect and control pandemics. These are required both now, and for the health of future generations. But access to such technologies reveals a gulf of inequalities.

As a global community there is a great deal to do to change this situation. There is no time to lose in facing up to such challenges and finding ways to overcome them.

This blog contains the contents of a speech given by Sharon Peacock at the World Health Summit October 2021 (Session PD (panel discussion) 17 – Genomic Data for Global Human Health), with further editing and text additions.

References

  1. ECDC strategic framework for the integration of molecular and genomic typing into European surveillance and multi-country outbreak investigations 2019–2021.
  2. Wilkinson E et al. A year of genomic surveillance reveals how the SARS-CoV-2 pandemic unfolded in Africa. Science 2021;Vol 374: Issue 6566: pp 423-431. DOI: 10.1126/science.abj4336