April 6, 2020 -- It's easy to see the appeal a rapid antibody test for the novel coronavirus would have in the imagination of the general public. Results come in a matter of minutes and promise to tell you if you have immunity to a potentially deadly disease -- the masses could maybe be screened and go back to work if they get the "all clear."
But not so fast. Lab medicine professionals are cautioning about important caveats:
It's not surprising that serology tests for COVID-19 have captured attention recently. These serum-based immunoassays are inexpensive and run on high-volume analyzers that are very common in hospital and reference labs. This is in contrast to molecular polymerase chain reaction (PCR) tests, which tend to be more complex and expensive.
Additionally, antibody tests could provide researchers with information on the spread and scope of infections. While much of the initial effort around testing has focused on scaling PCR-based testing for the virus, serology tests will likely play a larger role in managing the virus in the coming months.
Serology tests look for the presence of host antibodies that a patient may have developed in reaction to the disease, rather than detecting the disease itself, as a PCR system does. In doing so, serology tests at some point could ascertain whether the patient has immunity, though mechanisms of immunity have not been fully explored with COVID-19.
On March 16, the U.S. Food and Drug Administration (FDA) announced it was further relaxing regulations on diagnostics used to test for the novel coronavirus, including granting permission to vendors to sell tests before getting emergency use authorizations from the agency. At the time, the FDA said that it "does not intend to object to the development and distribution by commercial manufacturers or development and use by laboratories of serology tests to identify antibodies to SARS-CoV-2," and that developers can proceed with validation and provide notification about its status to the agency as well as customers. Immunoassay makers must notify users that false negatives and false positives are possible, and that results cannot be used to confirm a case.
That warning is necessary because immunoassays tend to be less accurate. Testing for antibodies relies on test makers to model those antibodies produced by patients exposed to the test. Whereas the DNA structure of SARS-CoV-2 is well documented, immune responses are still being modeled.
And while molecular testing can look for a specific genome region unique to the novel coronavirus, it's possible a COVID-19 test would pick up some of the many coronaviruses that cause colds. Despite the pronouncements of developers, it's not yet clear if a definitive COVID-19 test could be developed.
Antibody tests emerge
The first antibody test to get emergency use authorization (EUA) from the U.S. Food and Drug Administration came on April 1 -- Cellex's immunoglobulin G/immunoglobulin M (IgG/IgM) rapid test. Just prior to that, a company called BodySphere had issued a press release stating that its two-minute antibody test for the novel coronavirus had received an EUA from the FDA. The company received enormous media attention only to rescind the claim later under scrutiny. BodySphere said it is now awaiting an emergency use authorization. On April 3, Ortho Clinical Diagnostics announced the launch of an antibody test for SARS-CoV-2/COVID-19 designed for use with the company's Vitros immunodiagnostic systems.
Medical and dental supplies distributor Henry Schein has pledged to ship pinprick blood tests that it said can deliver results within 15 minutes to physicians, hospitals, and other healthcare providers. The company's Standard Q COVID-19 IgM/IgG rapid test, made by South Korea-based SD Biosensor, is intended to be administered at the point of care (POC).
BioMedomics, a small research and development firm in Research Triangle Park, NC, has developed a 15-minute POC antibody test. On April 1, Henry Schein announced that it was now the exclusive U.S. distributor for the assay, in partnership with BioMedomics and Becton Dickinson.
The FDA published a list of companies and laboratories that have notified the agency that they have validated and are offering serology tests on the frequently asked questions (FAQ) section about diagnostic testing for SARS-CoV-2.
"The FDA has not reviewed the validation of tests offered by these developers, who will not be pursuing EUAs, and is including this list here to provide transparency regarding the notifications submitted to FDA," the agency explained.
Writing in an article about testing in mBio, the open access journal of the American Society for Microbiology (ASM), on March 26, Dr. Robin Patel and colleagues noted that there is a broad category of tests that detect immunoglobulin G, M, or A (IgG/M/A) or total antibodies, typically in blood.
"Development of an antibody response to infection can be host dependent and take time; in the case of SARS-CoV-2, early studies suggest that the majority of patients seroconvert between 7 and 11 days postexposure to the virus, although some patients may develop antibodies sooner. As a result of this natural delay, antibody testing is not useful in the setting of an acute illness," wrote Patel, who is president of the ASM, and colleagues.
Patel commented in an interview that those who have had SARS-CoV-2 may develop immunity, measured in antibody response, and be protected from getting infected again, but researchers don't know that for certain. It's unclear whether that protective immunity exists, but some data from rhesus macaque studies suggest it could be the case, she said.
Patel said she would feel good about an antibody test that had sensitivity in the high 90s (greater than 95%) with similarly high specificity, aside from patients who are immunocompromised and don't develop antibodies. She sees the process of validating an antibody test for coronavirus as fairly straightforward -- those who have had the disease should test positive for antibodies, and those who haven't should test negative.
Amid a contagion crisis, governments have seemed ready to settle for what is available now. Governments in the Philippines, China, Italy, and Spain have cleared serology tests.
But experience in Spain provides a cautionary tale about the use of serology tests. Microbiology laboratories found that the tests acquired by the government have unusable levels of sensitivity -- 30% when they should exceed 80%, according to a report in the daily Madrid-based newspaper El País. The rapid tests were manufactured by the Chinese company Shenzhen Bioeasy Biotechnology, and the government is relying on PCR tests even though it takes longer to get results, while also seeking new suppliers of serological tests, according to the report.
In the U.S., there are also concerns about the quality of testing. The FDA has relaxed requirements to get the products to market more quickly, so the onus is really on the performing laboratory to validate the products and make sure they are accurate and precise, said David Grenache, PhD, chief scientific officer at TriCore Reference Laboratories and clinical professor of pathology at the University of New Mexico.
Labs do that routinely in normal circumstances, but this time they may have little data from manufacturers to guide them because the products are coming to the market so quickly, he said in an interview. Given the fast rate of introduction and/or clearance, labs are really getting a Pandora's box in a test and need to do greater due diligence than usual, he said.
"Laboratories will do what laboratories do best, which is to provide quality tests to patients," Grenache said.
He proposed an online forum for labs to exchange information about which tests work and which ones don't to the American Association for Clinical Chemistry (AACC). Very quickly, the online forum was up and running, he noted.
Grenache said he is concerned that some of the language of the antibody test developers suggests that the assays are good for diagnosis, when that is not the case. The main role of antibody tests is for identifying whether people who have been confirmed to have been exposed have developed antibodies. The focus initially should be on healthcare and other essential workers, he said.
The ASM's Patel noted that other important uses are for identifying patients who are candidates for harvesting of antibodies for therapeutic research development.
Using antibody testing more broadly is new, but she said we will see more of this unfolding.
"There's no guidance that is out there that is preexisting for how to use a brand new test for a brand new infection," said Patel, who is also the director of the Infectious Diseases Research Laboratory at the Mayo Clinic in Rochester, MN.
A lot of work is underway to define how best to use this in clinical practice and in general, she added.
Bruce Carlson is the publisher of Kalorama Information, part of Science and Medicine Group.
Disclosure: LabPulse.com is a sister company of Kalorama Information.
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