As companies and regulators grapple with the accuracy of serological tests that detect past exposure to the novel coronavirus, another type of immunoassay aimed at spotting presymptomatic infections is poised to go from zero to sixty in the coming weeks.
Although more than 100 COVID-19 serological tests are already commercialized around the world, questions about their accuracy, and about the hands-off approach taken by regulators, still loom large. Though the tests are not used for diagnosis, the stakes are arguably just as high, with governments viewing them as key for guiding the allocation of resources and determining who can go back to work (see “Wild West of COVID-19 Antibody Tests”).
On Wednesday, separate presentations from FDA and from medical device trade organization AdvaMed highlighted next steps in the scramble to validate COVID-19 serological tests: the imminent release of a template to help manufacturers apply for FDA Emergency Use Authorization (EUA), and updates from a serological test validation program led by NIH’s National Cancer Institute (see “NCI Leads Serological Test Validation”).
The presentations also pointed to growing momentum for viral antigen tests that could rapidly identify infected individuals at the point of care, before symptoms appear.
Though antigen tests are not yet on the market, millions could become available within the coming weeks.
In a press call, AdvaMed President and CEO Scott Whitaker said antigen tests will be an “important component” of the road to recovery from the COVID-19 crisis. AdvaMedDx Executive Director Susan Van Meter said that though antigen tests are not yet on the market, millions could become available within the coming weeks.
And in FDA’s latest virtual town hall on COVID-19 diagnostic development, Timothy Stenzel said viral antigen tests had made “significant progress” and were his team’s “next priority.” Stenzel is director of FDA’s Office of In Vitro Diagnostics and Radiological Health.
Wednesday also saw Roche (SIX:ROG; OTCQX:RHHBY) make a bid to dominate the serological testing market. In an investor call, the company said its high-throughput serological assay, set to launch in May, will be among the most accurate on the market, though it declined to release sensitivity and specificity data before the launch (see “Roche to Scale Up Serological Tests”).
While Roche is exploring rapid point-of-care tests, including viral antigen tests, it thinks the fast turnarounds and distributed access they provide come with accuracy trade-offs. “With a point-of-care test, specifically with a strip test, you will never get the same performance as with the lab,” said Thomas Schinecker, CEO of the pharma’s Roche Diagnostics unit.
Roche CEO Severin Schwan was blunt about the pharma’s internal assessment of other marketed serological tests, echoing reports out of University of Oxford (see “Assays don’t Meet Performance Criteria”).
“We looked at the performance of these antibodies, and I can tell you it’s a disaster,” Schwan said.
Antigen tests use the same underlying technology as serological tests, but share the goals of molecular diagnostics based on reverse transcription polymerase chain reaction (RT-PCR).
Both serological and antigen tests are immunoassays, meaning they rely on tool antibodies to detect their targets. They can both can be done via laboratory tests that return results on the order of hours, or via point-of-care dipstick tests that flow samples across cellulose strips and read out in minutes (see “COVID-19 Diagnostic Tech Tableau”).
But while serological tests detect whether an individual has generated antibodies against a pathogen at some point in the past, antigen tests detect the virus itself, and could therefore be used to diagnose active infections and determine whether someone is contagious.
Moreover, serological tests are run on patient blood or plasma samples, while antigen tests are likely to be run on swabs from respiratory tissues.
In these two ways, antigen tests are similar to RT-PCR tests. The difference is that RT-PCR detects viral nucleic acids via sequence-specific primers, while antigen tests detect proteins or lipids on viral cell surfaces via tool antibodies.
The former’s advantage is the relative ease with which a test can be developed, since virus-specific PCR primers are more straightforward to optimize than virus-specific antibodies.
Yet the latter offers a more established path to a rapid, point-of-care test that can be scaled rapidly. While dipstick immunoassays have a long history as diagnostics, rapid point-of-care nucleic acid tests are newer; for some, the COVID-19 crisis is likely to be their debut (see “Crisis Spurs Rapid Diagnostic Tech”).
Van Meter said that although lab-based molecular diagnostics will remain the gold standard, viral antigen tests could be more economical and widely accessible, which could enable routine monitoring.
FDA’s Stenzel invited manufacturers to engage in discussions with the agency about viral antigen tests, and said such assays would ideally have accuracy metrics on par with similar tests designed to detect influenza.
FDA officials provided updates on serological testing validation resources that are on the way.
Stenzel said an EUA application template specific for serological tests could soon become available.
The template is the U.S. government’s latest tool to encourage FDA review of serological tests, despite the agency’s March 16 guidance letting manufacturers off the hook (see “New Policies Complicate Regulatory Calculus”).
More than 90 manufacturers have brought serological tests to market without FDA review; in contrast, only four serological tests have received EUA. In a press conference Tuesday, FDA Commissioner Stephen Hahn said 140 serological test developers have EUAs in progress.
Hahn also said there soon will be updates from the serological test validation initiative involving researchers from NCI, FDA and CDC. “We expect to hear more information this week about that, and we will provide that information in a transparent manner,” he said, adding that independent labs around the country have also been doing their own validation studies.
Stenzel said FDA is looking at ways to make the results of the validation initiative known, including offering a “streamlined approach to EUA” for tests that pass a certain performance bar, which would make their performance metrics public.
He said that even if validation studies show a serological test has impressive specificity metrics, because of the low prevalence of SARS-CoV-2 exposure in the population, the test could still yield an unacceptable rate of false positives, giving people a false sense of security that could put them in danger.
But Stenzel said the false positive rate goes down dramatically if someone is deemed seropositive by two separate tests that detect different antigens. “Confirmatory serology testing may be important,” he said.