In brief

Whole-genome sequencing of SARS-CoV-2 samples from immunocompromised patients with infections over 90 days revealed therapeutic escape mutations in spike protein genes, highlighting the potential role of bedside genomics in pathogen surveillance.

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Keeping pace with evasive viruses

19 Sep 2023

With near-real-time genomic monitoring, researchers catch emergent, treatment-evading SARS-CoV-2 mutations in immunocompromised patients with chronic infections.

Viruses like SARS-CoV-2 are natural escape artists. Faced with bodily defences and medical treatments designed to stamp them out, viruses can mutate their genetic blueprints to help them dodge these threats—as long as small groups of them persist out of sight.

Most healthy immune systems clear out viral particles from the body within days after an infection. However, in an immunocompromised person—like a patient with cancer—active viral particles can linger and replicate for months. This gives them more time to acquire escape mutations that make existing vaccines or antiviral drugs ineffective, forming new, more dangerous viral variants.

To support both patient care and public health efforts, experts like Karrie Ko say it’s critical to actively monitor persistent infections like these for signs of new escape mutations, especially when viruses of global concern like SARS-CoV-2 are involved.

“With today’s sequencing technologies, we can study how viruses evolve over a chronic infection’s course in a hospital setting,” said Ko, a PhD student at A*STAR’s Genome Institute of Singapore (GIS) and consultant pathologist at Singapore General Hospital (SGH).

In the early days of the COVID-19 pandemic, Ko and GIS Scientist, Chayaporn Suphavilai, teamed up with clinicians and researchers from SGH and Thailand’s Chiang Mai University to establish a robust microbial genomic surveillance programme of SGH patients, aiming to track dangerous SARS-CoV-2 escape mutations.

Among the patients monitored in the programme were two immunocompromised individuals with COVID-19 infections that lasted over 90 days. The team performed whole-genome sequencing (WGS) on remnant nasopharyngeal samples taken from both patients over the course of their active infections.

As suspected, the team found that SARS-CoV-2 from both patients gradually acquired clusters of mutations in genes encoding the spike (S) protein’s receptor binding domain, which is a frequent target for antibody treatments such as REGN-COV2.

“Over the course of these infections, the virus evolved with both a permissive environment—a compromised immune system—and selection pressure from the various therapies used to treat both patients,” Ko explained.

These findings underscore the importance of genomic monitoring and special infection control measures for the immunocompromised. “The study supported changes in hospital policy,” Ko elaborated. “It became standard practice for these vulnerable patients to receive additional sensitive diagnostic tests and be cared for in isolated rooms.”

Moreover, the study demonstrated how cutting-edge sequencing technologies and close collaboration between scientists and clinicians can improve early warning systems for viral outbreaks. “Bringing fast, easy and applicable microbial genomics tools to the bedside makes sense not just for pandemic preparedness, but for hospital pathogen surveillance that protects individual patients and public health,” said Ko.

The A*STAR-affiliated researchers contributing to this research are from the Genome Institute of Singapore (GIS).

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Ko, K.K.K., Yingtaweesittikul, H., Tan, T.T., Wijaya, L., Cao, D.Y., et al. Emergence of SARS-CoV-2 spike mutations during prolonged infection in immunocompromised hosts. Microbiology Spectrum 10 (3), e0079122 (2022). | article

About the Researchers

Karrie Ko is a Consultant Pathologist in the Department of Microbiology and the Department of Molecular Pathology in Singapore General Hospital (SGH). She is also the Director of Genomics for the Pathology Academic Clinical Programme (ACP) at Duke-NUS Medical School. Her work involves clinical diagnostics in bacteriology and molecular diagnostics for infectious diseases. Karrie is also a National Medical Research Council (NMRC) fellowship awardee and is currently working on her PhD under the supervision of Niranjan Nagarajan in the Laboratory of Metagenomic Technologies and Microbial Systems in the Genome Institute of Singapore (GIS).
Chayaporn Suphavilai is a Scientist at the Laboratory of Metagenomic Technologies and Microbial Systems in the Genome Institute of Singapore (GIS), A*STAR. She holds a PhD in Computer Science from the National University of Singapore where her thesis focused on machine learning models for precision medicine. Currently, she leads a multidisciplinary team in developing a microbial genomic analytics platform specifically designed for infectious disease diagnostics and surveillance.

This article was made for A*STAR Research by Wildtype Media Group