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Harvard Team Develops Blood-Based SARS-CoV-2 Antigen Test on Quanterix Platform

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NEW YORK — A team led by researchers at Harvard University and Brigham and Women's Hospital has developed an assay capable of detecting SARS-CoV-2 antigens in patient blood.

Described in a paper published this week in Clinical Chemistry, the assay uses Quanterix's Simoa high-sensitivity immunoassay technology to detect SARS-CoV-2 spike, S1 subunit, and nucleocapsid proteins in blood and could prove useful for detecting patients at risk of severe disease, said Harvard Professor David Walt, senior author on the study and one of the developers of the Simoa technology.

According to the authors, the assay is the first to directly detect SARS-CoV-2 proteins in patient blood. Walt said that he did not envision that the test would compete with molecular or rapid antigen tests for diagnosing infections, but he said that he believed it might help with more rapid identification and better management of severe cases.

He suggested this was because the presence of viral antigen in the bloodstream, as opposed to the saliva and nasal swab samples commonly used for diagnosing the virus, might indicate the presence of tissue damage caused by infection.

"The presence of antigen in saliva just indicates that there is virus present," Walt said.

Antigen in the blood, on the other hand, could be due to leakage of molecules from damaged tissue, he said. "We think that as a consequence of the infection, there is damage to the lungs, and that in more severe forms of the disease the endothelial lining of the lungs is getting damaged and becoming leaky… and antigen from the virus is leaking into the bloodstream."

In the study, Walt and his colleagues used Simoa assays to measure levels of the spike, S1 subunit, and nucleocapsid proteins in 64 COVID-19-positive patients, finding that they could detect the S1 and nucleocapsid proteins in 41 of them. In these patients, they found a correlation between the levels of these antigens detected and the time to ICU admission and intubation.

Levels of S1 were particularly correlated, with 30 percent of patients with undetectable levels of the protein ultimately being admitted to the ICU versus 52 percent of patients with low levels and 77 percent of patients with high levels.

Based on these findings, the researchers hope to develop the assay to monitor patients for progression to more severe infection, Walt said.

"For individuals who get diagnosed with a SARS-CoV-2 infection with either the conventional molecular PCR test or an antigen test, you could imagine that those individuals could then start to get blood tests for these antigens," he said. "And if the antigen begins to appear in their bloodstream, then what that would signify is that there is some damage to the lungs… and that perhaps intervention at an earlier stage could prevent them from progressing to extremely severe stages of disease."

The researchers also looked at patient antibodies against SARS-CoV-2 proteins using a Simoa-based serology test developed by Walt's lab and licensed in May by Quanterix. Using that assay in combination with their blood-based antigen test, they looked at how the production of anti-SARS-CoV-2 antibodies correlated with the clearance of viral antigens, finding that full clearance of antigens typically occurred around five days after seroconversion.

While Walt was the scientific co-founder of Quanterix and is on the firm's board of directors, his lab's work, including the SARS-CoV-2 antigen study, is separate from the company, he said.

Walt noted that the samples used in the study were collected during the initial wave of cases seen in the Boston area this past winter and spring and added that they were all from patients visiting hospital emergency departments, meaning they tended towards more severe cases.

He said he and his colleagues are now collecting samples from a wider range of cases including individuals with milder or asymptomatic infections with the goal of correlating levels of viral antigen and anti-viral antibodies at different timepoints to disease progression and outcomes.

"I think as we begin to look at [a broader range of] COVID-positive individuals we will probably get a much better read on the real utility of the antigen test for being able to predict disease progression and severity, at least with respect to the respiratory aspects of the disease," Walt said.

He noted that his lab has run the assays in asymptomatic individuals and those with mild infections and found that they are able to detect SARS-CoV-2 antigens in the blood of these patients, but he said that they still need to collect additional samples before they analyze any correlations to disease severity or other outcomes.

The Clinical Chemistry study also identified 12 patients without detectable levels of antigen in their blood who nonetheless were admitted to the ICU and intubated during their hospitalizations.

The authors suggested that these patients could have already seroconverted and cleared the antigen from their blood but still suffered significant lung damage that required intubation. Walt added that these patients might also have experienced different manifestations of the infection that were less focused on the lungs.

"The disease is highly heterogeneous," he said. "Some individuals have neurological manifestations, some have gastrointestinal manifestations."

Walt noted that the ultimate usefulness of the test will also, of course, depend on what interventions are available to doctors treating COVID-19 patients.

"It's one thing to be able to detect and predict severity," he said. "It's an entirely different story trying to prevent that progression. I think it's really going to be a question of, if we end up with a large number of patients in a second surge, I think we will probably be able to deploy this in a way that gives [doctors] another credible piece of information they can use to decide how they want to proceed with certain individuals, but that's going to be up to the clinicians and how they want to use this."