Can Global Genomic Surveillance Forecast the Next Pandemic?

COVID took the world by stunned surprise – but, to quote an old Who song, we won’t be fooled again.

That’s thanks to accelerated genome sequencing technologies, expanded laboratory capabilities, and interacting infrastructure on a global level. These factors are converging to enable both identification of novel infectious diseases as well as microbial resistance, before these threats can impact public health, write a team from the European Society for Clinical Microbiology and Infectious Diseases in Frontiers in Science.

The “One Health” Paradigm

Their suggestions in “Real-time Genomic Surveillance for Enhanced Control of Infectious Diseases and Antimicrobial Resistance” lie within a “one health” framework of the World Health Organization.

The concept of a coordinated, global response to infectious disease dates back to the 1800s, originally based on recognition of the relationship of diseases of humans compared to those of other animal species. One Health is “an integrated, unifying approach that recognizes that the health of humans, domestic and wild animals, plants, and the wider environment (including ecosystems) are closely linked and interdependent.”

Today’s ability to rapidly sequence and compare whole viral and bacterial genomes takes the One Health concept to a new level, fueling real-time monitoring of the emergence of novel pathogens, their patterns of spread, infection rate, and perhaps most importantly, how they evolve. A One Health approach requires sharing of surveillance and sequencing databases among all nations, and building up the infrastructure and expertise to do so, to prevent, detect, prepare, respond to, and manage unfolding pandemics.

COVID clearly caught us off guard. Had we grown complacent in a world freed from a list of once-deadly infectious diseases, thanks largely to vaccines and other public health measures? How soon will it be until the anti-vax movement opens up ecological niches for once-vanquished pathogens? It’s already starting, apparently, with a return of measles.

The COVID years are beginning to feel like a bit of a blur, a blip in time that’s perhaps best forgotten. But I think about that time often, and the warning that it sounded. Many of the links below are to some of the 100+ DNA Science posts that I wrote during the pandemic.

A Novel Virus Appears

In retrospect, everything unfolded with astonishing speed.

A few days after New Years, 2020, I heard BBC News report the first cases, in China. Two weeks later, Nancy Messonnier, director of CDC’s National Center for Immunization and Respiratory Diseases, rolled the date back at a press briefing:

“On December 30th, China reported an outbreak of respiratory disease in Wuhan City, a major transportation hub about 700 miles south of Beijing with a population of more than 11 million people.”

I’ve long thought that SARS-CoV-2, or an immediate viral predecessor, emerged years before 2019 – at least as far back as 2013. The evidence for an earlier origin lies in viral genome sequences, specifically bat coronavirus RaTG13.

Might investigators have brought a sample of RaTG13, in bat dung from the cave where it was discovered, to a lab in Wuhan? Did it there either recombine with another virus on its own, or inspire a manipulation of another virus of a key part of the spike gene, seeding the pandemic through a “lab leak?” I explained why I think this is the most likely explanation in 3 Possible Origins of COVID: Lab Escapee, Evolution, or Mutator Genes? from April 15, 2021:

“A leap from the RaTG13 virus found in the bat muck of the abandoned mine in 2013 to the emergence of SARS-CoV-2 in 2019 is like reading the first and last chapters of a novel: there’s not enough of a plot to reconstruct a story. But as more chapters are being revealed, it’s looking like SARS-CoV-2 arose from a poop soup of viruses – and continues to evolve.”

Recently, the US Department of Health and Human Services finally suspending funding for the organization that connected the genetic dots between bat cave viruses and something else, spawning SARS-CoV-2.

Whenever and wherever the virus emerged, CDC officially alerted clinicians to the new, deadly respiratory illness on January 8, 2020. But the proverbial cat was already out of the bag.

Zhang Yongzhen, of the Shanghai Public Health Clinical Center and School of Public Health at Fudan University, had sequenced the new potential pathogen’s genome by January 5, publishing it online January 10. He announced it online on January 15, apparently without state approval – a move that is coming back to bite him now. The government recently evicted him from his lab, part of the crackdown on anything having to do with the “lab leak” hypothesis.

As soon as the initial RNA genome sequence of the pathogen that would be named SARS-CoV-2 was published, CDC and other organizations began developing diagnostic tests. Work on vaccines ensued too.

The first US case came to a physician’s attention on January 21.

Monitoring Viral Genomes

An online clearinghouse at WHO for genome sequences of influenza viruses was quickly refitted to handle the new coronavirus: GISAID, for Global Initiative on Sharing All Influenza Data (GISAID.org).

At the beginning, I clicked on GISAID daily, sometimes even more frequently, as the numbers climbed, like the Stock Exchange on a good day. As the number of mutations mounted, geneticists began to group them into viral variants (see How Viral Variants Arise).

“The sharing of SARS-CoV-2 sequence data via the GISAID database enabled countries around the world to understand which variants were emerging and circulating nationally and internationally. This allowed for early responses to mitigate the transmission of novel variants across borders, and for the amendment of testing and sequencing procedures to detect new variants. And so variants alpha, delta, omicron emerged,” write the authors of the Frontiers in Science paper.

Other genomic databases were retooled for the huge datasets that COVID was generating, such as the Cloud Institute for Microbial Bioinformatics, begun in 2014 and rechristened the COVID-19 Genomics UK Consortium (COG-UK). It closed a year ago.

For a time, different facilities handled the mounting genome data differently, complicating efforts to stay ahead of the virus in a tower-of-Babel like scenario. On another front, surveillance had to reach all parts of the environment, from surfaces to aerosols to water supplies. We’re still figuring out exactly how the virus travels from air to human respiratory tract. “Airborne Transmission of SARS-CoV-2: The Contrast between Indoors and Outdoors” appeared recently in the journal Fluids.

Global Genomic Surveillance

Currently the number of SARS-CoV-2 sequences at GISAID is approaching 17 million, as the virus settles into predominant sequences that enable and even fuel its persistence. These viral dynamics display the very essence of natural selection, the most powerful driving force behind evolution.

The opening page of GISAID today features icons of nations, each with an evolutionary tree of the virus festooned with branches displaying its variants (see How Viral Variants Arise). These data are fueling global genomic surveillance.

Tracking the changes in the genome sequence of SARS-CoV-2 has told us a lot about this new pathogen. Keeping ahead of new mutations

• provides compelling clues to the origin of the virus.
• identifies parts of the virus to target to provoke an immune response from a vaccine.
• reveals viral vulnerability to inspire novel treatments.
• offers clues to how the virus might change.

An accompanying news release to the Frontiers in Science paper, “Genomics to head off pandemics,” provides perspective and comments. Said lead author Marc Struelens of the Université libre de Bruxelles, Belgium, “Epidemic-prone infectious diseases cross borders as fast as people and trade goods travel around the world. A local outbreak today may become the world’s next pandemic crisis tomorrow.”

By comparing genome sequences we can also track the origin and rise of antibiotic resistance among novel bacterial species, and decipher the roles of different species in transmission patterns. Struelens explained:

“Pathogen genomic surveillance is a tool that looks at the interplay between antimicrobial selective pressure on populations of microbes and the adaptive evolution of those microbes towards drug resistance. It lets us detect the emergence and disentangle the transmission dynamics of super-fit, multidrug-resistant epidemic clones—’superbugs.’ Genomic surveillance can help track both zoonotic and inter-human transmission of viral variants, strains of bacteria, and signs of drug resistance.”

This information can inform design of vaccines, therapeutics, and public health measures, which can help prevent epidemics from flaring up.

Struelens cites “places where genomic surveillance is already providing crucial protection against the spread of disease … foodborne infections in Europe, North America, and Australia; and epidemic viral diseases like avian influenza across many countries worldwide.”

Three Strategies Have Fueled Sequencing

Three technological advances are fueling genomic surveillance.

• Long-read RNA and DNA sequencing technologies have improved speed and accuracy by analyzing long stretches of the nucleic acids, compared to the small pieces that fueled earlier sequencing methods.

• Ultra-high-throughput (or rapid) DNA and RNA sequencing determine base sequences, identify single-base locations that vary (SNPs), find patterns of repeats, and predict how a sequence folds into three-dimensional forms under certain conditions.

• Single-cell sequencing. This includes spatial transcriptomics, which is determining the mRNAs made in a particular cell within a tissue or organ, juxtaposed with scans to identify and localize activities at a molecular level, but in an anatomical context. (See Looking into a COVID Lung Using Spatial Transcriptomics.)

After sequencing, artificial intelligence adds context to RNA and DNA sequences through comparisons to others.

Not Just Technology, but Infrastructure

The “pan” in “pandemic” means “all,” but nations are unequal in the ability to generate accessible, real-time data on cases and spread.

In the Frontiers in Science article, the authors call for massive investment in assuring appropriate training, expertise, and laboratory capacity among nations. They point out that during COVID, countries with pre-existing access to genomic surveillance expertise and equipment had a leg up in disease surveillance, facilitating testing, taking public health measures, and treating patients. The article provides a framework for the equitable implementation of interconnected global surveillance systems at all income levels.

“To ensure universal participation in collaborative systems of genomic surveillance around the world, our critical challenges are sufficient laboratory and sequencing capacity, the training of an expert workforce, and access to validated genomic data analysis and sharing tools within a comprehensive, secure digital health information infrastructure. Integrating epidemic pathogen genomic information with epidemiological information must happen at scale, from the local to global level,” said Struelens.

In an accompanying editorial, Marion Koopmans from the Erasmus Medical Center in Rotterdam, Netherlands wrote, “The article is a must-read for anyone interested in genomic surveillance as part of epidemic preparedness. The tools and ambition are there—the next step is to build equitable, collaborative surveillance infrastructures for future global health.”

Next time, I think we will be ready.