Image created by Dr. Michael J. Miller
The COVID-19 pandemic is seared into the collective consciousness, but fewer people remember the other pandemics—SARS, H1N1 influenza—and epidemics— MERS, Ebola, and Zika—that have struck over just the past 20 years. Now, the risk of another pandemic is set to triple over the coming decades due to climate change and increased global connectivity. Pandemics are most likely to arise from pathogens that are new to the human population, making it crucial to catch them early. “We need to be able to detect the next emerging threat when it’s still a small outbreak, before it becomes a pandemic-level threat,” says Jessica Kubicek-Sutherland, a molecular biologist at the Lab.
Five years ago, Kubicek-Sutherland and her team began their work on FEVER (Fast Evaluation of Viral Emerging Risks), a software that designs molecular probes for rapid viral detection. It could enable the development of revolutionary diagnostic tests with broad enough coverage and high enough sensitivity to keep future outbreaks at bay.
Effective viral detection methods must be rapid, accurate, and capable of monitoring multiple viruses. Unfortunately, few methods currently check all boxes. Take the testing options available for COVID-19: an at-home test with quick but untrustworthy results, or a more reliable PCR test with several days of wait time. Neither is fast nor accurate enough to mitigate an outbreak, and both fail to effectively monitor exactly which viruses or strains are present in the population. “This is one of the main problems with diagnostics right now,” says Kubicek-Sutherland. “These tests are like pregnancy tests—all they can tell you is ‘yes’ or ‘no.’ If you’re sick but test negative, it might take multiple tests to find out what you have.” FEVER could change this. In the long term, it could be used to create a single, rapid at-home test that could check for multiple viruses—for example, COVID, RSV, and influenza—all at once.
An illustration showing a new approach to viral detection that finds viral spike proteins:
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| The more mismatches that exist between a probe and viral target sequence, the less effective the probe will be at detecting the target virus. Here, probe 1 matches its target exactly, and the virus is detected. Probe 2, however, contains too many mismatches for the probe to bind, so the virus is not detected. FEVER solves this problem through the use of a “probe cocktail,” which contains multiple low-mismatch probes and increases the likelihood of a virus being detected, even after having genetically mutated. |
FEVER uses multiple molecular probes designed to strike a balance between broad coverage and high sensitivity. Tests must contain enough different probes to cover every strain of a virus and account for mutations, but not so many that they lose accuracy. Molecular probes work by binding to specific regions of a pathogen’s gene sequence. The trouble is that RNA viruses, like those responsible for COVID, RSV, and influenza, mutate quickly, causing small genetic differences that can prevent a probe from binding to its target. If a probe fails to bind, the virus won’t be detected. FEVER addresses this by combining multiple probes into its assays, increasing the likelihood that every strain of the virus, including those with mutations, will be detected. Too many probes, however, can dilute the detector’s signal, so the number of probes used in each assay must still be limited. To do this, FEVER finds the lowest number of probes that will cover the widest variety of strains of a virus. It starts by scanning a dataset of genetic sequences from every known strain of that virus and identifying regions of the genome with the least variability between strains. It then designs a probe matching the sequence appearing in the highest number of strains and removes all strains covered by that probe from the dataset. This process is repeated with the remaining strains, eliminating matched sequences from the dataset until every strain has been covered.
For each virus FEVER has been tested on so far, every strain of the virus was covered with just four different probes. But it doesn’t have to stop at viruses—one day, FEVER’s capabilities could be extended to any pathogen, making it easier to both diagnose disease and manage future outbreaks.
Source: Los Alamos National Laboratory