Nine months into the pandemic, population-scale COVID testing remains elusive, but signs suggest we may be reaching a stage in which testing of tens of millions of people in the U.S. on a regular basis may become feasible.
According to data from The COVID Tracking Project, U.S. COVID testing hit an all-time high over the last two weeks with an average of 1.7 million tests performed per day, including a record 2.1 million tests reported on November 27.
Rising COVID-19 cases numbers and the Thanksgiving holiday drove the increase, which further challenged the country's already strained testing capacity. News outlets reported people waiting in hours-long lines for SARS-CoV-2 testing around the country.
On November 24, Quest Diagnostics reported that turnaround times for its SARS-CoV-2 molecular testing had risen to an average of two to three days for patients overall and around two days for priority patients. This followed a warning earlier in the month from the American Clinical Laboratory Association, which represents Quest and a number of other large lab firms, that the increase in demand could lead to shortages of important testing supplies and longer turnaround times.
Even at these record testing volumes, however, the country still fell short of the numbers required for various mass testing programs various researchers and organizations have proposed as way of controlling the pandemic. Since the spring, figures like Harvard epidemiologist Michael Mina, New York University economist Paul Romer, and non-profit organization the Rockefeller Foundation have called for regular population scale testing for the virus as a means of stopping its spread.
In interviews, Romer has suggested around 23 million tests per day would be needed under the plan. Mina has similarly called for in the range of 10 million to 20 million tests per day, while the Rockefeller proposal calls for a somewhat more modest 30 million tests per week. However, even that number significantly outstrips current testing capacity.
There is reason to think, though, that the nation's COVID testing capacity is on the brink of a dramatic expansion, particularly on the antigen testing side.
A number of in vitro diagnostic firms have launched both instrument-based and instrument-free point-of-care rapid antigen tests in recent months. In August, Abbott received Food and Drug Administration Emergency Use Authorization for an antigen test that costs $5 and returns results in 15 minutes. The company said it can produce tens of millions of these tests per month. Roche has an antigen test under consideration for EUA that it has said it will also be able to produce at levels of tens of millions per month.
Meanwhile, firms including Quidel and BD have been selling instrument-based rapid antigen tests since the summer. On Quidel's recent earnings call, Quidel CEO Douglas Bryant said the company is currently producing around 2.1 million rapid antigen tests per week.
While rapid antigen tests aren't as accurate as PCR-based tests, any population-scale testing would rely on such tests because of their faster time to results and lower costs.
Such antigen tests have significantly expanded testing capacity beyond what was possible relying only on lab-based nucleic acid assays, and an explosion in antigen testing capacity is coming in the first quarter of next year, said Ted Meigs is cofounder, president, and CEO of Kinematic Automation.
The Twain Harte, California-based firm makes the automated manufacturing systems used to produce medical equipment including the sort of point-of-care assays used to test for COVID. Meigs said that based on the orders and delivery timelines he and others in the business were seeing, he expected test capacity to expand by roughly tenfold in the first quarter of next year. Such an expansion would be more than enough to hit the numbers required by the Rockefeller plan and could even approach the capacity called for by figures like Mina and Romer.
Mara Aspinall, professor of practice, biomedical diagnostics at Arizona State University as well as the former president of CEO of Ventana Medical Systems, coauthored Rockefeller's National COVID-19 National Testing & Contact Tracing Action Plan. Like Meigs, she is anticipating a large expansion of antigen testing capacity in Q1 2021.
"I believe there will be a sea change at the beginning of 2021," she said, adding that she expects to see a quadrupling of volume.
Capacity is only one part of the challenge, though. Another key question mass testing efforts face is how to most effectively deploy that capacity.
Aspinall said that she sees antigen testing as breaking down into three basic categories: home tests, point-of-care test, and lab-based tests.
This latter category has received heightened attention recently as companies like Ortho Clinical Diagnostics and DiaSorin have announced plans to offer lab-based COVID antigen tests. Most of the discussion of rapid antigen testing has focused on its point-of-care and home applications. However, Chockalingam Palaniappan, chief innovation officer at Ortho Clinical Diagnostics, said that lab-based antigen testing could provide a faster, higher-throughput alternative to molecular testing and could potentially be used to test large numbers of people in a way that is less feasible with point-of-care antigen testing, where the per test processing time makes it impractical to test large numbers of people given that samples must be run serially as opposed to in batches.
"Say you go to a university campus with 20,000 to 30,000 students, you give them all a swab, get them collected, by the next morning, all of those test [results] will be available," he said. "Our machines are located in many central laboratories, and each machine can process around 3,000 tests per day. So ten machines, that is about 30,000 tests."
Aspinall likewise highlighted the potential of lab-based antigen testing.
"I think that a central lab antigen test which is a batch system where you can load a thousand tests and get answers very quickly is absolutely critical to fighting the next stage of the pandemic where we need to be doing fast and frequent tests," she said.
Aspinall noted that even the fastest lab-based molecular tests take at least two hours with most taking significantly longer. A lab-based antigen test, on the other hand, can be done in under 30 minutes.
"So we have the ability to get results out much faster than PCR," she said.
The other obvious path to mass testing is widespread home testing. Mina, in particular, has advocated strongly for regular home testing using inexpensive tests like lateral flow assays that people could perhaps buy in packages containing multiple tests. Such tests would likely be less sensitive than molecular tests, and antigen tests have run into performance issues with, for instance, the FDA issuing a letter last month warning about the potential for false positive results from COVID rapid antigen test. Mina and other advocates argue, however, that such performance issues can be accounted for by serial testing; hence the need for these tests to be inexpensive and widely available in large numbers.
The problem is that no such tests exist as of yet. A number of companies including OraSure Technologies and E25Bio are developing home antigen tests while others like Mammoth Biosciences and UbiDx are working on home molecular tests. In November, FDA granted the first EUA for a start-to-finish home-based COVID-19 test – to Lucira Health's Lucira COVID-19 All-in-One home test, which uses real-time loop-mediated isothermal amplification to detect SARS-CoV-2 RNA, though that test will be relatively expensive at around $50 and will not be available nationwide until spring of 2021.
Aspinall is on the board of OraSure, which is developing a COVID rapid antigen test for three different EUA submissions — for use by a medical professional, for use by patients who are prescribed a test by a medical professional, and as an over-the-counter product. The company plans to make an EUA submission in the first quarter of 2021. It originally planned to submit this fall but has pushed back its development timeline.
Aspinall said that developing a home test with data that ensures accurate and reproducible results is a substantial challenge and one that takes time.
She also noted that FDA has "appropriately" high performance standards for home tests, calling for 80% sensitivity and 99% specificity for home tests available by prescription and for 90% sensitivity and 99% specificity for over-the-counter tests.
Advocates of home testing like Mina have criticized these requirements, arguing that lower-performance home tests that returned results rapidly and could be used frequently could still be effective at preventing spread of the virus. Previously, an FDA official told 360Dx on background that these benchmarks are not hard-and-fast cutoffs that tests must hit in order to receive EUA. The official said that the agency was open to considering a variety of SARS-CoV-2 testing approaches including lower sensitivity rapid tests that could be used at home in a serial manner. They highlighted Abbott's ID Now SARS-CoV-2 test as an example of the agency's willingness to consider trade-offs between test performance and convenience and turnaround time. While the Abbott test has shown relatively high levels of false negatives in some studies, the fact that it works at the point-of-care and provides rapid results adds value that compensates for lower sensitivity, the official suggested.
On a September call for labs and test developers, Timothy Stenzel, director of the Office of In Vitro Diagnostics and Radiological Health at the FDA's Center for Devices and Radiological Health, entertained a serial testing scenario much like those proposed by Mina.
"Where our recommended levels of sensitivity may not be achieved with a single test result in a home situation, maybe with the paper strip test, strategies utilizing serial testing, for less sensitive tests, could be deployed," he said, noting that in the case of a test with, for instance, 70% sensitivity, "perhaps with a two-pack, two test results you can achieve a greater sensitivity together."
Aspinall noted that while the FDA guidelines call for 99% specificity, data published by Lucira on its home test show 98% specificity, indicating that the agency may be flexible on its stated performance requirements.
Several lab-based molecular tests have received EUA for asymptomatic testing. No rapid antigen tests have received EUA for asymptomatic testing, though many are being used for that purpose.
Were a plan like Mina's to prove tractable from the capacity and regulatory standpoints, another challenge would remain — ensuring that people use the tests correctly and modify their behavior appropriately in response to the results.
This is an issue for any testing regime, but it is particularly so for a mass testing approach that relies on frequent serial testing to counter relatively low test performance. As organizations ranging from the National Football League to the White House have discovered, access to testing can only do so much to prevent spread of the virus in the absence of close adherence to other practices like physical distancing and mask wearing.
"We need to think about how to make sure people understand both the benefits and limitations of these tests," said Brandon Marshall, an epidemiologist at Brown University who has worked with the Rockefeller Foundation to develop communications materials to help public health experts educate people about asymptomatic COVID-19 testing.
"No test is 100% accurate, so it's never going to be a panacea," he said. "It's got to be one tool in the toolbox that includes consistent masking, social distancing, and so forth."
This story first appeared in our sister publication, 360Dx, which provides in-depth coverage of in vitro diagnostics and the clinical lab market.
