NEW YORK – As clinicians and scientists have worked to understand and control the spread and scope of the SARS-CoV-2 pandemic, molecular testing and serology have emerged as important tools for diagnosing and studying the disease.
Protein-based antigen testing has received relatively less attention, but several companies now have such tests in the works with plans to release them for clinical use within the next several months. Given their rapid turnaround time, ease of use, and amenability to large scale production, these tests could prove valuable for addressing the outbreak.
While serology tests measure the host's immune response to a virus, protein antigen tests are conceptually similar to molecular tests, with the former using antibodies to detect the presence of viral proteins in patient samples and the later using PCR to detect viral nucleic acid.
Molecular tests have the advantage of amplification provided by PCR, while protein antigen tests are limited by the sensitivity of the antibodies used. This means molecular tests may be more sensitive and able to diagnose infection earlier in the process than protein tests. On the other hand, protein tests are typically easier to produce at scale and in point-of-care or home use formats. For instance, Bethlehem, Pennsylvania-based diagnostics firm OraSure Technologies, which is developing a SARS-CoV-2 antigen test, sells at-home antibody tests for HIV over-the-counter purchase in national pharmacies like Walgreens and CVS.
And while some rapid antigen viral tests have had a reputation for poor performance, the field has made significant strides in recent years, said Nathan Ledeboer, medical director of the microbiology laboratory at the Medical College of Wisconsin and Froedtert Hospital, noting that in particular, use of better antibodies and a move from manual test reading to instrument-based reading have led to substantial improvements in test sensitivity.
While no antigen tests for SARS-CoV-2 have come to market in the US yet, a number of companies have assays in development. Several are supported by funding from the Biomedical Advanced Research and Development Authority (BARDA), which provided OraSure with $710,310 to support development of its test, as well as $638,000 to Gaithersburg, Maryland-based Hememics Biotechnologies and $569,627 to Emeryville, California-based Nanomix.
Diagnostics firms including Quidel, Roche, and Becton Dickinson have also announced they are developing SARS-CoV-2 antigen tests.
OraSure President and CEO Stephen Tang said the company began considering developing a test as SARS-CoV-2 began spreading in January and February and applied for the BARDA funding in March and received a contract from the agency roughly a week after filing its proposal.
BARDA previously backed OraSure's development of a rapid antigen test for Ebola, awarding the company a grant of up to $10,364,225 in 2015. The test received US Food and Drug Administration Emergency Use Authorization in 2015 and 510(k) clearance in October 2019.
The company plans to develop a SARS-CoV-2 that, like its HIV test, will be suitable for home use, Tang said, noting that the goal is to develop a lateral flow immunoassay "that can be administered and read by somebody with no medical background in the privacy of their own home and get a result in under an hour."
He said the company aims to launch the product with FDA EUA in September.
The ability to self-administer the test combined with the capacity for large scale production could enable significantly expanded SARS-CoV-2 testing. Tang said that OraSure currently has a manufacturing capacity of around 13 million tests per year and that it shipped 2.9 million home HIV tests in Q4 2019.
He noted, however, that some published plans for using testing to support reopening the economy call for on the order of a billion tests per year.
"We're going to have to find a way to massively scale up," he said. "We're looking to design massive manufacturing of this from the start. Our job is to find facilities and manufacturers and partners who can jump in quickly to that manufacturing environment."
He said he anticipated being able to reach "full-scale manufacturing sometime in 2021," with a target of "tens of millions to a billion units per year."
Nanomix CEO David Ludvigson said his company anticipated submitting its antigen test to FDA for EUA in around six weeks. The test will use nasal swabs for sample collection and will run on the company's eLab point-of-care analyzer. Ludvigson said Nanomix aimed to get production up to around 500,000 tests per month by Q4 of this year.
The movement of large in vitro diagnostic players like Roche, BD, and Quidel into the space could also provide significant antigen test capacity.
On Quidel's Q1 earnings call on Wednesday, President and CEO Doug Bryant said that the company was in the final stages of development of a SARS-CoV-2 antigen test that will run on its point-of-care Sofia immunoassay system. He said Quidel plans in the near future to ship around 40,000 tests that it will use in studies to determine the performance of the test.
In terms of capacity, Bryant said Quidel could currently produce 84 million tests a year for all of its Sofia assays as well as another 30 million QuickVeu lateral flow immunoassays. He said that the company is adding a new manufacturing line that would boost Sofia test production capacity by 30 million tests and aims ultimately to ramp to a total of 50 to 60 million tests a year that would be split between SARS-Cov-2 antigen testing and serology testing.
The company is also ramping up production of the Sofia analyzer units, with the goal of ramping from 1,000 a month to around 7,000 a month by September, Bryant said.
On BD's Q2 earnings call on Thursday, President and CEO Tom Polen said the company was in the process of developing a SARS-Cov-2 antigen test on its Veritor immunoassay system. He said the company was currently evaluating its performance in patient samples and that pending the outcome of that evaluation it will submit the test for EUA, potentially in the next several weeks.
He said BD had invested in manufacturing capacity to scale the production of the test over the balance of the year and that it aimed to produce on the order of millions of tests per week.
Roche reiterated this week in a discussion with Cowen analysts its plans to develop a SARS-CoV-2 antigen test but did not provide a timeline for when it hoped to have it available.
The ultimate impact of these tests will, of course, hinge on their performance.
On an FDA town hall this week about SARS-CoV-2 for test developers and clinical labs, Timothy Stenzel, director of the US Food and Drug Administration's Office of In Vitro Diagnostics and Radiological Health, noted that molecular testing had not been able to keep up with demand and that the agency was "very encouraged that there are a number of developers that are developing rapid antigen tests."
"The advantage of the rapid antigen tests is that they can be produced in quantities of millions and that they can be point of care and obviously yield a rapid result," he said, adding that FDA is "working very hard with some rapid antigen test developers in order to try to make those available in the not too distant future."
Stenzel added that while, traditionally, rapid antigen tests have not been as sensitive as molecular tests, "there may still be value if users understand the performance of these tests and the proper use of these tests and the proper interpretation and use of results."
For instance, he said, rapid antigen tests with high specificity could allow for quick action on positive results while negative results could potentially be reflexed to molecular testing.
Ledeboer said that IVD firms have had success developing effective infectious disease antigen tests using both point-of-care analyzer technology and lateral flow-based home testing formats, though, like Stenzel, he noted that sensitivity can pose a challenge given the lack of the sort of antigen amplification afforded by PCR-based techniques.
"When you start thinking about [antigen testing for] infectious diseases, you really run into sensitivity challenges in many cases," he said. "Are there ways around it? Sure. But the technological hurdles become greater."
Emerging research on the progression of COVID-19 could bode well for antigen test developers, Ledeboer said, citing the success researchers have had using saliva samples and nasal swabs (as opposed to more invasive nasopharyngeal swabs) for PCR testing.
"We're beginning to understand more and more that some of these less invasive specimen types do have high levels of virus, particularly in the early stages of the disease," he said, noting that some research indicates that people are shedding virus at the highest rate in the earlier stages of the disease when the virus is concentrated in the upper respiratory system.
"It's likely that as people move a little bit later in the disease that the virus moves into the lower respiratory tract, especially as you start to see things like shortness of breath, and then you may lose a little bit of [test sensitivity] later in the disease," he said.
Ludvigson said he expected the Nanomix test would have a sensitivity "well above 90 percent." Tang said OraSure was aiming for sensitivity and specificity in the high 90 percent range for its test. He noted that the company's HIV, HCV, and Ebola tests all have sensitivity and specificity in that range.