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Birx and others have touted another option: antigen tests, which detect the presence of viral proteins in a biological sample, such as saliva or tissue swabbed from the nasal cavity. Antigen tests are typically cheap, return results in minutes, and, like the genetic tests, reveal an active infection. They already exist for strep throat, influenza, tuberculosis, HIV, and other infectious diseases. But so far, only one antigen test for SARS-CoV-2, the coronavirus that causes COVID-19, has received emergency use authorization from the U.S. Food and Drug Administration (FDA). Can it or other antigen-based methods solve the testing problem? Some scientists are optimistic, whereasothers remain skeptical, noting that such tests can be far less accurate than nucleic acid tests and may not be as easy to scale up as proponents claim. What everyone wants is for a test to be cheap, accurate, and fast, says Geoffrey Baird, a laboratory medicine specialist at the University of Washington, Seattle. You can only ever have two of those. Developing an antigen test is not that easy to do, says Werner Kroll, senior vice president for research and development at Quidel, a California-based company that received the greenlight from FDA for its test earlier this month. Rather than performing all the analytical steps inside an expensive dedicated machine at a lab or a doctors office, as is done with tests for the DNA or RNA of virus, antigen tests build most, if not all, those steps into a paperlike strip that returns a simple yes or no answer, much like pregnancy tests. Its a lab on a swab, says Stephen Tang, president and CEO of Orasure, a diagnostics company developing its own antigen test for SARS-CoV-2. With most setups, a sample of bodily fluid is collected using a nasal swab or related procedure, then mixed with a few milliliters of a liquid, typically a sterile buffer solution. A few drops are spotted on one end of a test strip. Capillary forces pull the liquid over copies of two different antibodies specific for the same viral protein. If both antibodies spot their targeta positive testthe strip generates a signal, often a color change. This signal is generally read out by a person visually, although some setups use small readers to improve the accuracy. What triggers the signal can differin some tests the antibody bindings set off a chemical reaction or expose a fluorescent marker joined to one antibody. Another test in contention for FDA approval produces an electrical readout after antibodies on an electrochemical sensor bind to their target antigen. The challenge is finding the right antibodies, says Lee Gehrke, a virologist at the Massachusetts Institute of Technology, who has developed an antigen test for SARS-CoV-2 that E25Bio, a company he co-founded, is now evaluating. Both antibodies must bind to a single viral protein, such as the spike protein SARS-CoV-2 uses to enter cells, but at separate sites. You have to find two antibodies that dont interfere with each other, Gehrke says. Those same antibodies also cant cross react to proteins from other coronavirusesall of which have their own spikes, for exampleor anything else. Antibodies often stick to other things nonspecifically, Baird says. Another challenge is weak signals. Genetic tests use the polymerase chain reaction (PCR) to amplify tagged DNA or RNA sequences, making it easy to reliably identify just a few copies of a virus. That gives PCR tests for the SARS-CoV-2 virus about a 98% sensitivity and near perfect selectivity, meaning almost every active infection is detected and only in very rare cases does someone uninfected receive a positive test. (Many false negatives, a result indicating an infected person is free of the virus, result not from the tests deficiencies, but from poor samples, which can be difficult to collect with nasal swabs.) Antigen tests dont amplify their protein signal, so they are inherently less sensitive. To make matters worse, that signal gets diluted when samples are mixed with the liquid needed to enable the material to flow across test strips. As a result, most antigen tests have a sensitivity of anywhere between 50% and 90%in other words, one in two infected people might incorrectly be told they dont have the virus. Last month, Spanish health authorities returned thousands of SARS-CoV-2 antigen tests to the Chinese firm Shengzhen Bioeasy Biotechnology after finding the tests correctly identified infected people only 30% of the time, according to a report by the Spanish newspaperEl Pais. Quidel executives say the companys initial SARS-CoV-2 test meets FDAs minimum of 80% sensitivity. (That means it could still generate false negative results 20% of the time.)A revised sample preparation protocol that doesnt require dilution of the nasal swab is expected to boost that figure to nearly 90%, but thats still below the 98% sensitivity of state-of-the-art PCR tests.