COVID-19 testing: A brief history
According to some sources, the novel coronavirus was wreaking havoc in China as early as November, 2019, although the current official line from the World Health Organization is that the disease caused by the novel coronavirus was identified on Dec. 30 following the collection of three bronchoalveolar lavage samples from a patient with pneumonia of unknown etiology at a hospital in Wuhan. Researchers used Illumina and nanopore sequencing to acquire the whole genome sequence of the virus and analyzed it to identify its lineage. Virus isolation was achieved using human airway epithelial cells, crown-like particles were observed under transmission electron microscope, mice and monkeys exposed to the virus developed a type of pneumonia, and, QED, the world had a new disease, COVID-19.
Testing has emerged as one of the key worldwide measures to slow and hopefully stop the spread of COVID-19. Testing leads to quick identification of cases and is critical for this pandemic as people can have the disease—and spread it far and wide—for two weeks before showing symptoms. Fast testing is credited with slowing the spread of the virus in places such as South Korea, and continued testing can help better allocate resources, save time and equipment in hospitals, and provide helpful data.
Three kinds of tests: Some need approval, some don’t
The breadth and scope of testing has progressed rapidly in recent weeks; as of April 13 the US Food and Drug Administration’s list of approved tests included 117 tests using PCR, serological or isothermal amplification technologies. Most tests need to file for Emergency Use Authorization approval before they can be used on patients; some can move ahead on notification only while antibody-based serology tests from commercial manufacturers or high-complexity labs do not need to submit an EUA application at all. Here’s more about those three types of tests:
Serological tests: These measure the amount of antibodies or proteins present in blood; less effective than other tests, these tests may not detect antibodies when the body’s immune system building a response to the virus, but they can help health professionals identify those who have become immune to the disease.
Isothermal nucleic acid amplification tests: Rapid and simple—and likely less expensive—this family of tests extracts viral RNA and amplifies it; a Cas12 protein and a guide RNA that slots into it are paired. “If Cas12 and its guide find a match in the RNA, Cas12 binds to that matched RNA, which activates Cas12 to cut it and go on to cut any other short RNA or DNA strands in the vicinity, including copies of a strand designed to liberate color-changing molecules when Cas12 cuts them free,” explains Science. “The upshot can be a simple color change on a test strip.”
Polymerase chain reaction (PCR) tests: Fast, specific, and sensitive, these “gold standard” tests detect specific genetic material within the virus to make a match. Here, viral RNA are extracted from a patient sample and converted to DNA, which is replicated to make it easier to detect.
The WHO lists two COVID-19 diagnostic tests for emergency use—they are both the slower nucleic acid tests which require a swab to detect the RNA virus. They are the Z-path test from Primerdesign in the U.K. (suitable for labs with moderate sample testing ability) and the cobas SARS-CoV-2 qualitative assay for use on the cobas 6800/8800 Systems from Roche, which is a closed system assay best for larger labs.
Among the first tests to gain wide use was one from Chinese Company BGI Group, which won approval from the Chinese National Medical Products Administration in late January and later was awarded European Conformity CE mark approval for its real-time fluorescent RT-PCR test, which produced results in three hours; the company went on to export tests to dozens of countries, reported China Daily.
Faulty tests came from three continents
As COVID-19 cases swept in a wave west from China across Europe, European officials turned to Chinese manufacturers for tests to quickly identify hotspots, often with unsatisfying results. Slovakia, Czech Republic, Turkey, and Spain each returned thousands of faulty tests they purchased from China; those tests, according to the Los Angeles Times, were antigen and antibody tests which use blood samples to look for the virus.
“But both kinds of testing are relatively new and not replacements for the nucleic acid tests — notably the antibody test, which is fast and can catch mild or asymptomatic cases in people who’ve already recovered from the coronavirus, but cannot determine whether a person currently has the coronavirus,” the Times explained, adding that the PCR nucleic acid tests are considered by WHO to be “gold standard” tests.
Other countries that had trouble with tests were Georgia and Malaysia, which later decided to go with rapid test kits from a South Korean company. Spain, too, wound up with faulty tests it procured from Shenzhen Bioeasy; that company was not an authorized test supplier, even though the go-between who facilitated the sale apparently vouched that the company had the go-ahead from European regulators.
Testing has not always gone smoothly in the UK, either. News reports on March 31 stated that tests headed there from a test maker in Luxembourg, Eurofins, were contaminated with the virus. A separate order of 3.5 million antibody tests was placed with two Chinese companies, Guangzhou Wondfo Biotech Co and Hangzhou AllTest Biotech Co, though only Wondfo was on the Chinese National Medical Product Administration’s list of authorized test kits.
In the United States, testing got off to a rough start. The first tests were provided by the US Centers for Disease Control and Prevention under an Emergency Use Authorization, but they were later found to provide inconclusive results.
US testing accelerates
The CDC’s faulty tests were remedied with the qualification of a batch of primers and probes produced by Integrated DNA Technologies for use in the CDC test protocol. As of March 9, IDT had sent primers and probes sufficient to enable 1 million CDC tests and manufactured primers and probes sufficient to enable more than 700,000 CDC tests every day by March 16.
“We are honored to be the first company in the nation to have our primer and probe kits approved by the CDC for use as a key component of the CDC EUA testing protocol for the diagnosis and detection of COVID-19,” said IDT President Trey Martin.
By mid-March, Becton Dickinson had sought approval of a two-hour test from the FDA; that test had been used in China originally and the U.S. would piggyback on Becton Dickinson’s broad existing network of respiratory illness testing machines and platforms.
On March 13, BioReference Laboratories opened the East Coast’s first drive-through testing facility; it was in early epicenter community New Rochelle, NY That same day, Thermo Fisher announced plans to produce up to 5 million tests.
Barely a week later, Cepheid unveiled a new diagnostic test which returned results in just 45 minutes. Cepheid said it would produce a million of the tests over the course of the spring; its tests are run in a machine processing one test at a time, which speeds up delivery. There are already 5,000 Cepheid devices in the US and more than 23,000 around the world.
New tests yield results in minutes—perhaps even at home
On April 2, the FDA approved the first test which looks for antibodies in the blood rather than hunting for the virus in the nose or throat. Created by Cellex, the test requires healthcare workers to draw blood from a patient in a certified lab—not any old doctor’s office—and results come in 15–20 minutes. Coris BioConcept also announced an antigen test which could deliver results in 15 minutes, while Abbott Laboratories claims to have cut the detection time to just five minutes and which said it would deliver 50,000 tests a day. A test from Becton Dickinson announced on April 1 delivers results in 15 minutes; it looks for the proteins produced by the virus’ genetic material and while it produces the results quickly, the device that renders a diagnosis can only process a handful of tests per hour—it would work well in a smaller setting such as a doctor’s office, noted Time.
“When someone is infected with a virus for the first time, their immune system begins producing antibodies specific to that virus,” notes The Verge. “Checking to see if someone has coronavirus-specific antibodies is good evidence that they’ve been infected. However, the body doesn’t start to make these immediately, and they might not appear until someone’s illness has run its course. As a result, antibody-based tests can tell doctors whether someone has already had COVID-19, but they’re not as good at testing if the patient currently has it.”
In late March, Scanwell Health, an at-home test company, licensed the rights to an antibody test developed by Innovita, a Chinese company, for a rapid at-home test. The Innovita test was approved by China’s Centers for Disease Control but the test was only used by doctors and health officials in that country. Scanwell requested emergency authorization from the FDA, which could be granted by June. The Scanwell test would hinge first on answers to questions submitted through an app as a means of pre-qualification; doctors from telehealth company Lemonaid would review the answers and prescribe the test as needed. Once the test arrives by mail, patients put a single drop of blood and two drops of solution into a test kit and wait 15 minutes; like a pregnancy test, the results appear as lines on a testing stick. Patients then take a picture of the results and submit it via the app, where Lemonaid doctors interpret the result and return advice on what to do next.
The first at-home test to gain Emergency Use Authorization was unveiled not by Scanwell but instead by LabCorp, whose Pixel test is part of a line of at-home tests already developed for colorectal cancer, diabetes, and cardiac lipid conditions. The company said that tests will first go to healthcare workers and first responders and will be available to consumers in coming weeks. LabCorp said the test can be purchased online after completing a short risk questionnaire. The $119 test arrives via FedEx, patients self-swab, and the results are mailed back to the company for analysis. Results can be accessed online.
Testing advancements continued to come quickly through the first part of April. On April 10, the FDA granted emergency use authorization to Rutgers Clinical Genomics Laboratory for a test originally developed by Thermo Fisher Scientific but which can use saliva. It can be run on “the Applied Biosystems 7500 Fast Dx Real-Time PCR instrument or other authorized instruments, and later received expanded EUA for manual sample extraction using the MagMax viral/pathogen nucleic acid isolation kit, the Applied Biosystems 7500 Fast real-time PCR system that utilizes DCS versions 1.5.1 and 2.3, and the Applied Biosystems COVID-19 interpretative software v1.1,” notes GenomeWeb.
Other test approvals granted by the FDA on April 10 included one from Orig3n, which detects two regions in the virus’ nucleocapsid gene, and one from Specialty Diagnostic Laboratories, which is meant for the qualitative detection of a region in the virus’ ORF 1a/b gene in throat and nose swabs. An additional test approval went to a test from the University of North Carolina which is designed to detect the viral envelope gene in respiratory specimens.
Scientists still don’t know everything about how COVID-19 is transmitted or how prevalent it is—good testing, with fast, reliable results—can help answer those questions. Expect more tests to continue to arrive on the market.