Emerging Test

New Studies Support Viability of Reliable COVID-19 Lateral Flow-Based Home Testing Device

As deaths and case rates fall, the focus of COVID-19 testing will continue to shift from diagnosing patients to screening the asymptomatic. This will fuel the demand for products that can deliver results accurately, quickly and at the point of care. The fly in the ointment is that current SARS-CoV-2 antigen tests that meet these requirements are nowhere near as accurate as the tests used for diagnosis applications. However, new research suggests that an alternative technology support the viability of a more accurate rapid testing solution: lateral flow assays.

The Diagnostic Challenge

 Polymerase chain reaction (PCR) tests that detect SARS-CoV-2 nucleic acids from the virus’ RNA were the first tests used to identify patients with COVID-19. And they remain the gold standard in accuracy with false negative rates ranging less then 5 percent, depending primarily on the sampling site, sample type and stage of infection). The downside of PCR tests is that the RNA from the sample must be amplified and converted into DNA for testing, operations that must be performed at a CLIA-certified laboratory off the site.

Rapid antigen tests use antibodies that the body produces to fight the SARS-CoV-2 virus to detect specific parts of the viral particle itself. Antigen tests are the Yin to PCR tests’ Yang: They deliver rapid results at the point of care but they are relatively lacking in accuracy. The biggest problem with antigen tests is their susceptibility to false negatives. Using them for screening purposes thus entails the risk that asymptomatic individuals with infections will be allowed to enter schools, workplaces, airplanes, ballgames and other settings where they may spread the virus to others.

The optimal solution for screening would be to somehow combine the scalability and mobility of antigen tests with something approaching the accuracy of PCR testing. Such a solution would also be useful as the opening stage in the diagnosis and treatment process, much like current home pregnancy tests where users who test positive would call their physicians for confirmatory tests and initiate precautionary measures like self-isolation.

The Potential of Lateral Flow Technology for COVID-19 Detection

Lateral flow tests (LFTs) are simple devices that use immunoassay technology to detect the presence of a target substance in a urine, blood, saliva or other liquid sample. LFTs operate along the same principles as current enzyme-linked immunosorbent assays (ELISA). The tests run the liquid sample along the surface of a pad with reactive molecules that show a visual positive or negative result. The pads are based on a series of capillary beds, each of which pads the capacity to transport fluid spontaneously.

Because they do not rely on specialized and costly equipment, LFTs are well suited for home use. One of the most common applications of LFT technology for medical use is home pregnancy testing capable of detecting hormones in urine that are associated with pregnancy in the range of five to 30 minutes.

Can LFT Be Trusted for COVID-19?

But while LFT technology is cheap and fast, its capability for use in reliably detecting COVID-19 remains unproven. The lack of test sensitivity makes LTFs prone to produce false negative results. Last September, the World Health Organization warned that “very few” LFTs had undergone “stringent” regulatory procedures. In a mass-testing pilot carried out in the UK at the end of 2020 in Liverpool, tests made by Innova Medical Group missed 60 percent of asymptomatic cases.

Identifying the Cause of False Negatives: The King’s College Study

The good news is that recent research suggests that it is possible to cost-effectively produce more sensitive LFTs for use in COVID-19 testing. One notable example is a new study published in the journal ACS Materials and Interfaces that explains why LFTs produce such large numbers of false negatives and what modifications could be made to improve accuracy.

Researchers from King’s College London used X-ray fluorescence imaging from Diamond Light Source Trust, a national science facility to image how the virus interacts with the tests. They found that the underlying technology of many LFTs is highly accurate and theoretically capable of detecting trace amounts of the SARS-CoV-2 virus. The problems, they concluded, stem not from the test technology but limitations in the technology used to communicate the result of the test, i.e., the read-out. They then lay out a series of relatively simple technical modifications that could be made to potentially improve the performance of LFTs.

Improving LFT Sensitivity: The Berkeley Lab Study

And now a new study from Lawrence Berkeley National Laboratory (Berkeley Lab) suggests that it is possible to develop a highly sensitive LFT for COVID-19. The assay would be done on mucus samples taken from the nose or throat using a swab, which would be dipped in a tube containing a solution to dilute the sample, and then placed at one end of a porous strip in a test cartridge. As the sample is pulled along the strip via capillary action it would draw pairs of rigid antibodies designed to recognize and bind onto SARS-CoV-2 antigens. As with a home pregnancy test, a colored band would appear on the strip if the test subject has a COVID-19 infection in 15 minutes.

The researchers, led by Michael Hammel and Curtis D. Hodge, used small angle X-ray scattering (SAXS) performed at Berkeley Lab’s Advanced Light Source (ALS) to examine about 20 antibody-antigen interactions. They found that a particular pair of monoclonal antibodies bound to the nucleocapsid protein very strongly, in part due to the antibodies’ rigidity. “The combination of the two rigid antibodies was also observed to increase networking—a process in which multiple antibodies bound to the same antigen at different sites form larger clumps or ‘networks,’” Hodge explained.

It has long been understood that antibody networking and high binding stability improve LFT sensitivity. But studying the physical dynamics of antibody-antigen pairs to find the most effective antibodies is very difficult with traditional imaging techniques, which require the molecules to be stabilized or crystallized. The SAXS technique developed by Hammel and his colleagues allows scientists to examine antibodies and antigens in their natural state, i.e., when moving freely in a liquid.

“We showed that we can rapidly identify new antibody-antigen pairs that result in a more sensitive detection assay,” said Hammel. “This technique could be applied to hundreds of antibodies in a short amount of time to identify the most suitable antibodies to achieve as-of-yet unattained sensitivity of antibody-based diagnostics, which are key for early diagnosis of SARS-CoV-2 as well as other pathogens.”

Takeaway

While LFTs offer significant advantages in costs, ease of use and speed, many in the scientific community have warned that they lack the sensitivity necessary for COVID-19 screening. And this may be true. However, many powerful actors, including the British government, have made LFT devices modeled after home pregnancy tests a centerpiece of their COVID-19 response strategy. And now scientific evidence is emerging to suggest that this might prove to be a very wise decision.

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