For the diagnostic testing industry, the pandemic has been a bonanza.
The Food and Drug Administration has so far approved emergency use of 349 COVID-19 tests, and counting. Although the bungled rollout of diagnostic testing a year ago allowed infections to explode undetected for weeks, current testing capacity is vast and turnaround is generally fast. Quest Diagnostics alone can do 280,000 molecular diagnostic tests a day, providing results within 48 hours. Quest and other big companies — including LabCorp, Roche, Abbott, and Quidel — have seen their profits soar during the global health crisis.
And yet we still don’t have the one thing that, coupled with vaccinations, could conquer the coronavirus: a reliable screening test that yields an answer quickly.
Such a test could be used anytime, anywhere to check people with no symptoms, who account for about 40% of infections and can unwittingly spread the virus. The test would be simple, cheap, and provide rapid results, so it could be repeated every few days.
Last week, the FDA took action to fill the void by allowing two previously authorized rapid antigen tests made by Abbott and Quidel to be sold, without a prescription, to screen asymptomatic individuals on a routine basis.
In its news release, the FDA said the tests “will give schools, workplaces, communities and others several options for serial screening tests that are accurate and reliable.”
That, at least, is the hope. The reality is that some experts have championed screening with rapid antigen tests — and some countries including the United States have invested in it — but it hasn’t succeeded so far, partly because the tests have not been accurate and reliable for asymptomatic people.
COVID-19 screening tests that use “biosensor” technology are being developed by labs around the world, including one at the University of Pennsylvania.
But the challenges hampering screening are more than just technological. Michael Mina, a Harvard University scientist who has emerged as an antigen screening test guru, says testing is “where science, policy, and regulation collide.”
“Thus far, we really have not devised any actual strategy around one of the most crucial tools: knowing who is positive and who is negative for COVID-19,” Mina said last month during a presentation now posted on YouTube. “That continues to be surprising and frustrating.”
Tests and tribulations
COVID-19 testing has come a very long way from a year ago.
Molecular, or PCR, tests remain the gold standard for diagnosis because they’re the most accurate. The disastrous early months of PCR testing — crippled by regulatory mistakes and shortages of virtually everything — have given way to a workable testing network, shaped mostly by commercial forces. Patients also have more options. Many of the 248 authorized PCR tests now require just a home-collected, front-of-the-nostrils swab — not a deep nose dive at a drive-through collection site.
Antibody tests, meanwhile, have found a smaller niche than experts hoped for. These blood tests look for disease-fighting proteins called antibodies, a sign of immune response to infection. In theory, the tests could identify people with immunity who could safely go back to work, as well as track the spread of the pandemic. In reality, test results are often wrong, and the strength and longevity of natural immunity remain uncertain. However, antibody tests have become important tools for studying those questions, and for understanding the scope of coronavirus exposure in populations.
Antigen tests, in contrast, can signal a new infection even before it causes symptoms, by detecting a protein the virus starts making soon after it invades the body. A nasal swab is placed directly into chemicals that break open and react with the virus if it is present, giving results in as little as 15 minutes.
Many coronavirus antigen devices and kits are almost as easy to use as a more familiar antigen detector — a pregnancy test.
In September, the Trump administration got a flood of favorable press for its plan to supply the states with 150 million Abbott coronavirus antigen tests, each $5. Some experts hailed the move as a “game-changer.”
But it wasn’t.
Using antigen tests effectively requires careful deployment strategies, and standardized rules for reporting and classifying the data — things that were sorely missing, as the Washington Post reported.
Antigen testing also posed that pesky problem of unreliability.
How good is good enough?
Makers of coronavirus antigen tests often tout near-perfect accuracy, but that is based on validation using known samples in a laboratory. In the real world, there are many unknowns and variables, including whether the test is done according to the manufacturer’s directions.
Last week, Cochrane, an international organization that reviews published medical studies, concluded that even the best antigen tests are not good enough to screen asymptomatic people.
The Cochrane panel reviewed 48 studies of 16 brands of antigen tests. None of the studies evaluated self-testing or repeated testing.
Based on results for the most sensitive brand (made by SD Biosensor Inc.), the panel calculated how it would perform in 10,000 asymptomatic people if 50 of them really had COVID-19: The test would be positive for 125 people, but 90 of them (72%) would be false alarms. The test would be negative for 9,875 people, including 15 (.2%) who were actually infected.
“Some antigen tests are accurate enough to replace PCR when used in people with symptoms,” wrote the panel, co-led by Jon Deeks, a biostatistician at the University of Birmingham in England. “We need more evidence on rapid testing in people without symptoms … testing in settings such as schools (including self-testing), and direct comparisons of test brands.”
Mina, the Harvard epidemiologist, disagrees.
Even before the first antigen test was authorized by the FDA in August, Mina argued that doing rapid antigen testing every two or three days would offset any inaccuracy. Molecular tests, he points out, can be too sensitive, giving positive results days after a person is no longer spreading infectious virus. Antigen tests, in contrast, work only during that early transmission period, when the coronavirus’ telltale protein surges and then plummets.
Both Deeks and Mina see dangers if their views are not heeded.
Deeks coauthored an opinion piece in BMJ in January calling on the British government to “urgently rethink” its plan for national COVID-19 screening using Innova’s saliva-based antigen test. The program “may cause serious harm” including outbreaks, unnecessary quarantines, and added burdens on teachers, nursing homes, and more. (The test is currently being offered to asymptomatic people in various community settings, according to the United Kingdom’s National Health Service.)
Mina and colleagues fired back in the Lancet, criticizing “uncorroborated” reports of Innova’s poor accuracy as well as the debate over the United Kingdom’s program. “The debate … risks confusing policymakers internationally and potentially stalling” screening with antigen tests in other countries.
Betting on biosensors
Cesar de la Fuente, a microbiologist and immunologist at the University of Pennsylvania, believes biosensor technology could make COVID-19 screening practical.
A biosensor basically converts one form of energy — say, a chemical reaction — into another form of energy, often electrical, that can be readily measured. The field got started in 1962 with a glucose biosensor for checking blood sugar levels in diabetes. Now, the technology is used in food processing, environmental monitoring, drug discovery, as well as health care.
De la Fuente’s lab developed a biosensor that captures the chemical information generated when the coronavirus’ spike protein binds to its natural receptors in human cells. Saliva or a nasal swab is put on a strip of cardboard imprinted with an electrode. The strip gets inserted into an energy-converting device that plugs into a smartphone, providing results on an app in five minutes.
The electrode strip is cheap to make, “so developing countries could use them,” said de la Fuente, who has begun a study of saliva samples from 400 volunteers. “And it enables high-frequency testing, which I believe is the key to preventing the spread” of infection.
Many researchers echo that view. In a recent article in the journal Biosensor and Bioelectronics, Spanish and American scientists wrote: “It is expected that biosensor technologies will be employed not only for rapid coronavirus infection diagnosis in humans, but also as a global screening tool for surveillance, prevention, and preparedness in the event of future outbreaks.”