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Waters, SISCAPA Assay Technologies Develop Mass Spec Test for SARS-CoV-2

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NEW YORK — Waters and SISCAPA Assay Technologies have developed a mass spectrometry-based antigen test for SARS-CoV-2.

Waters last month began offering the assay as a research tool for studying SARS-CoV-2, but the firm envisions it as a potential clinical test for the virus, said Andy Qiu, general manager of global clinical diagnostics at Waters.

The assay was developed as part of an initiative launched by the UK's National Health Service Test & Trace program that aimed to create high-throughput tests for COVID-19 screening that could serve as an alternative to PCR-based tests.

The Waters test uses SISCAPA Assay Technologies' peptide immuno-enrichment technology to target three SARS-CoV-2 nucleocapsid peptides that are then measured using Waters' Acquity I-Class Plus LC system and its Xevo TQ-XS mass spec instrument. The assay run time is less than two minutes per sample, and it can be automated using liquid handling protocols developed for the Andrew Pipetting Robot using OneLab software.

Scientists have used mass spectrometry extensively to study various aspects of COVID-19, but the technology has seen little to no use for diagnosing infections. While mass spec brings potential advantages like rapid turnaround time and the ability to circumvent PCR supply chain limitations, initial efforts to develop mass spec-based tests for the virus met with little success.

For instance, last year, a team led by researchers at the Technical University of Munich developed a parallel reaction monitoring, or PRM, assay on a Thermo Fisher Scientific Fusion Lumos Tribrid that measured 23 SARS-CoV-2 peptides in nasopharyngeal swab samples from 91 subjects (37 negative and 54 positive by RT-PCR). They found that they were able to identify only 20 percent of the PCR-positive cases with their PRM assay.

More promising was an effort led by Mayo Clinic researchers and published last August as a MedRxiv preprint that combined antibody enrichment of the SARS-CoV-2 nucleocapsid with high-field asymmetric ion mobility spectrometry PRM mass spec on a Thermo Fisher Orbitrap Exploris 480 instrument. Using a machine-learning model to identify COVID-19 positive samples, the researchers were able to identify RT-PCR-positive patients with 98 percent sensitivity and 100 percent specificity.

Leigh Anderson, founder and CEO of SISCAPA Assay Technologies, or SAT, said that his company began exploring the possibility of using its immuno-mass spec workflow to develop a SARS-CoV-2 test last year after discussing with a reference lab client how such a test could be used as a gold standard to measure against PCR results.

SAT was in the middle of developing the antibody reagents needed for such a test when it began discussions with Waters about using the reagents as part of its effort to develop a mass spec COVID-19 test under the NHS' Test & Trace initiative.

From a research perspective, mass spec's multiplexing ability raises the possibility of combining the measurement of the SARS-CoV-2 peptides with other proteins of interest — those related to host response, for instance — to allow scientists to study multiple aspects of the virus at once, Qiu suggested.

Morteza Razavi, vice president, strategy and business development at SAT, likewise suggested the test could be combined with other mass spec measurements to provide a fuller picture of an infection.

"For example, by measuring the viral antigens along with proteins in the patient's inflammation pathways, you can get a measure of infectivity along with the inflammation response," he said.

Qiu also suggested that the test development process provided a road map for the development of mass spec assays for other infectious diseases and added that Waters is exploring the possibility of creating a winter respiratory panel.

"People are thinking about what will happen when winter comes," Qiu said. "And mass spec is a wonderful technology to enable multiplexing."

"Clearly that is an application that the UK government is serious about — a winter panel," said Udit Batra, Waters' president and CEO. "As flu comes in, you already have a SARS-CoV-2 test. Can you take the same workflow and make it multipanel? That is one thing the team is working on."

Batra added that one potential advantage of mass spectrometry is the fact "that LC-MS is present in virtually every hospital for newborn screening. So, if you develop a winter panel that can be used on that existing infrastructure, it has a huge application. I think that is where we see almost immediate potential."

Razavi said that SAT also saw the SARS-CoV-2 test as a step toward the development of additional mass spec tests for infectious disease.

"We are developing the flu equivalent and the RSV equivalent of the COVID test," he said, adding that the company hoped ultimately to develop those assays as in vitro diagnostic kits.

Of course, any such tests will face substantial competition from PCR-based respiratory panels, especially given the significant amount of PCR capacity labs around the world have added over the course of the pandemic.

MALDI mass spec is another potential technology for COVID-19 testing and one that Razavi said was discussed as part of the UK initiative before the decision was made to focus on LC-MS methods. While LC-MS methods can typically reach higher levels of sensitivity than MALDI, MALDI offers a simpler workflow and higher throughput. Additionally, MALDI mass spec has become a widely used technology in the clinical microbiology lab for microbial identification, meaning there is a large preexisting installed base of MALDI instruments in clinical microbiology labs around the world.

While there are questions regarding whether MALDI can achieve the sensitivity needed for an effective SARS-CoV-2 test, the use of immuno-enrichment as in SAT's assays could help a MALDI assay reach the required performance level. Anderson and Razavi have in the past developed MALDI-based SISCAPA assays, and, Razavi noted, "we have no reason to believe that this wouldn't work as part of a MALDI setup."

"If it were to work, it would be a really high-throughput way to do things," Anderson said.

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