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The first COVID-19 test that diagnoses an active infection by detecting proteins from SARS-CoV-2 is now available in the US, but it’s not clear how much information such antigen tests will add as health professionals try to track a pandemic that shows little sign of slowing down.
Quidel, a San Diego–based company that specializes in diagnostic testing, earned an Emergency Use Authorization (EUA) from the US Food and Drug Administration on May 8 for its Sofia 2 SARS antigen test. Scott Gottlieb, the former head of the FDA, called the announcement that an antigen test was available a “gamechanger” during a television appearance shortly after the authorization. Besides the Quidel test, several companies are working on antigen tests for use in the US, and multiple antigen tests are already available outside the US.
Gottlieb and others have said that the availability of antigen tests would speed up efforts to test large numbers of people for COVID-19 because the diagnostics are cheaper and faster to perform than the more widely used molecular test that detects the RNA from SARS-CoV-2, the coronavirus that causes COVID-19.
But not everyone is rushing to start antigen detection. Neither Quest Diagnostics nor ARUP, two of the largest testing providers in the US, are immediately planning to offer the tests, company officials tell C&EN. Antigen tests may be fast, says Patricia Slev, the medical director of ARUP, and they may be cheap, but they just aren’t as reliable as the molecular tests that providers in the US have been using since the pandemic started.
“Molecular assays, in general, are the preferred method,” she says. “They’re very specific. In some cases, they are also more sensitive.” In diagnostic tests, specificity refers to the rate of false positives a test produces and sensitivity indicates the rate of false negatives. Both statistics define how trustworthy the results from a diagnostic can be.
Quidel notes that its test cannot distinguish between a person who is infected with SARS-CoV-2 or its cousin, SARS-CoV, another coronavirus that caused outbreaks of severe acute respiratory syndrome (SARS) in 2002–3. Fortunately, SARS has since died off across the globe and that virus is unlikely to be circulating now. The FDA notes that antigen tests, as compared with RNA tests, have a higher chance of false negatives, so a person who receives a negative test result might still be infected.
A typical antigen test starts with collecting a patient sample. In the case of Quidel’s test, this sample is a swab from the nose or the back of the nose and throat. Some antigen tests, such as those used to diagnose Ebola or HIV infection, use blood. In Quidel’s test, according to documentation submitted to the FDA, the patient sample is added to a solution that breaks up the virus, freeing its proteins for recognition by the test.
The resulting solution is added to a test strip. If the solution contains viral proteins, they travel along the strip and eventually get trapped by a single type of antibody, called a monoclonal antibody, which recognizes a specific segment of the SARS-CoV nucleocapsid protein. This antibody is also expected to bind to the same segment of the SARS-CoV-2 nucleocapsid protein because the proteins are 90.5% identical in their amino acid sequences.
The test results are read by a device that measures fluorescence signals. It’s not clear how the Quidel test creates this fluorescence signal—a company spokesperson did not respond to requests for information. But similar antigen tests typically use a second antibody with a fluorescent molecule attached to it. This second antibody binds to the antigen-antibody complex.
Other tests use what are called polyclonal antibodies, Slev says. These antibodies have the potential to recognize a target viral protein in more than one spot, increasing the likelihood of a positive test. But, compared with monoclonal antibodies, they also run a higher risk of cross-reactivity, which is when an antibody binds something other than its target antigen because that off-target protein has a similar amino acid sequence that the antibody recognizes. This cross reactivity could lead to false positives, or perhaps inconclusive results because the signal that the test gives off is not clear.
Quidel reports that the test is 100% specific and 80% sensitive. In 143 patient samples, there were zero false positives and 12 false negatives.
One concern that experts have about antigen tests is that levels of the virus in some patients might be too low to detect, leading to false negatives. Quidel tested swabs with a range of viral levels and could detect the virus in all of them, but it’s not clear if these levels indicate that these people have recovered from an infection with SARS-CoV-2.
Quidel isn’t the only company that has developed an antigen test. Sino Biological claims to be the first company in the world to have produced an antigen test. And OraSure Technologies, which has developed an antigen test for Ebola, told Science that it is developing one for SARS-CoV-2.
Slev says that like a rapid Ebola test, an antigen test for COVID-19 might be best suited for resource-limited areas, where the molecular test is harder to perform due to lack of access to the proper machines to run it. This family of tests now completes the trifecta of infectious disease testing—antigen tests, antibody tests, and tests that detect DNA or RNA, which will be helpful in tracking the spread of COVID-19.