NEW YORK ─ Semi-quantitative serology assays that measure quantities of antibodies to specific SARS-CoV-2 proteins may enable insights into immunity, monitoring of patients who have taken future vaccines, and greater adoption of antibody tests, according to IVD industry executives.
In August, Siemens Healthineers became the first company to receive US Food and Drug Administration Emergency Use Authorization for semi-quantitative tests that it believes can point the way to future growth for serology testing.
On the back of the authorization, the Erlangen, Germany-based firm recently inked a collaboration with the US Centers for Disease Control and Prevention and the Joint Research Centre (JRC) of the European Commission that involves establishing standards by which many manufacturers can compare semi-quantitative tests in the future.
Serology tests that had been authorized prior to Siemens' August EUA provide 'yes' or 'no' answers to whether a patient has antibodies that show past exposure to SARS-CoV-2, but they don't measure quantities of antibodies to specific viral proteins.
Tests that provide 'yes' or 'no' answers still play an important role for patients who want to know whether they have been exposed to SARS-CoV-2 and for tracking disease prevalence, among other purposes, Deepak Nath, president of laboratory diagnostics at Siemens Healthineers, said in an interview. However, "we need to get more than just a 'yes' or 'no' answer from an antibody test to address many of the questions associated with immunity and prevention from SARS-CoV-2 reinfection, and that is why we need more semi-quantitative tests in the market."
Indeed, the lack of an established process to determine immunity is among the main hurdles for antibody test adoption, he said.
Siemens Healthineers received EUA for two semi-quantitative tests, the Advia Centaur SARS-CoV-2 IgG (COV2G) and Atellica IM SARS-CoV-2 IgG (COV2G), so named for the analyzers on which they run.
The new process, under development with CDC and JRC, seeks to standardize SARS-CoV-2 assays by connecting SARS-CoV-2 proteins to a threshold, or level of antibody, needed to block the virus from entering cells. Thresholds associated with a standardized unit of measure for IgG that arise either from natural infection or vaccination may contribute to a standardized interpretation of immunity through test results, Nath said.
The firm's semi-quantitative tests target different SARS-CoV-2 proteins ─ the spike protein, S1/S2, receptor-binding domain (RBD) of the spike protein, and the N protein. "These different SARS-CoV-2 antibody targets produce different potential for neutralization, and now there's considerable evidence that antibodies that target the RBD of the spike protein are neutralizing," Nath said.
There is not enough evidence to say the antibodies to the RBD of the spike protein or other parts of the virus provide immunity and protection, but semi-quantitative assays are essential to addressing these questions about immunity, he said. A semi-quantitative test that provides measurements of antibody concentrations associated with the RBD of the spike protein enables measurements in blood at different points in time.
"The first step along the path toward answering questions about immunity is to determine the level of a specific neutralizing antibody needed to confer immunity," Nath said. With that threshold, clinicians will be able to obtain more actionable results from the testing of patients who have been infected or who have taken a vaccine, he said, adding, "The second step is to develop a reference standard that applies to all manufacturers developing quantitative tests, to report a level of neutralizing antibodies in a standard set of international units."
The term semi-quantitative, he noted, is a regulatory requirement reflecting that an international yardstick that allows comparability among tests has not yet been established for the SARS-CoV-2 virus.
If successful, the new process would enable people to compare results from the tests of one IVD manufacturer with that of another manufacturer taken days or months later, inspiring more trust in testing results and accelerating acceptance of antibody testing, Nath said.
David Boyle, scientific director at Seattle-based PATH Diagnostics, which has developed a separate process to help accelerate the development and adoption of rapid coronavirus tests, said he believes serology testing has an important role in helping to mitigate the pandemic.
"The best way to understand the performance of future vaccines and whether people are immune to COVID-19 is to do serologic testing," Boyle said. "Though you may have antibodies to the coronavirus, it doesn't mean you have neutralizing antibodies. So, you need antibody tests to evaluate whether you have neutralizing antibodies such as the RBD of the spike protein that could actually prevent infection."
As such Siemens Healthineers' collaboration with CDC and JRC is an important initiative, he said. Similar to PATH's project, recently launched to help manufacturers thoroughly validate the tests they are developing, the Siemens project could lead to greater traction for serology tests, Boyle added.
Antibody test adoption
Though they have garnered suspicion by many, tests that provide a 'yes' or 'no' answer to whether antibodies are present are useful not only for prevalence studies and to answer questions about past exposure, Nath noted. They also have utility as screening tools for convalescent plasma, and they are sometimes used as an adjunct to PCR testing when clinicians want more information and more certainty about results for specific patients, he said.
However, their adoption has been hampered by uncertainty about whether SARS-CoV-2 can confer immunity and protect people from future infection.
Indeed, by mid-September, serology SARS-CoV-2 testing accounted for less than 3 percent of all US lab volume, while SARS-CoV-2 molecular tests accounted for around 40 percent.
"Since this is such a dynamic situation, and these tests have been developed in such a short timescale, it has taken the clinical community a while to establish an appropriate clinical use for them," Nath said. "All of us became aware months ago that we don't have firm scientific evidence to say that the presence of antibodies equals immunity, but, related to that, we also don't know how much of an antibody you need to have immunity."
That has also been a major contributor to the lack of adoption for serology testing in the pandemic, he said.
"Significant and legitimate questions about quality of the first set of antibody tests that came to market" provided another barrier to adoption, Nath noted. "Simply put, there were inaccurate results from many of these tests, and many ended up having to be withheld or withdrawn from the market."
Both Chembio Diagnostics and Autobio Diagnostics, for example, had FDA EUAs revoked for serology tests, and the FDA removed from a notification list the names of 141 manufacturers that claimed to have validated and intended to distribute a SARS-CoV-2 serology assay.
Though the FDA by Monday had granted EUA to manufacturers for 52 serology assays since the beginning of the pandemic, adoption has been overshadowed by the uptake of molecular tests to detect active SARS-CoV-2 infection.
Thus far, the agency has given the green light to manufacturers for five antigen tests and 213 molecular tests.
While the demand for serology tests has slowed, testing entities are prioritizing tests for active infection, such as antigen screening tests, which are fast and cheap but "not the most sensitive," and RT-PCR assays that have established themselves as the go-to tests for hospitals, said Scott O’Brien, senior vice president of global marketing and international sales for molecular test manufacturer GenMark Diagnostics.
Though serology tests are largely not being used to diagnose current infection, they could prove particularly useful for monitoring the immune response to vaccines, O'Brien noted.
Roche said that it has received CE marking for such an antibody test to support the evaluation of vaccines, and it has launched the test for use in countries that accept the designation. The Basel, Switzerland-based firm has also applied for FDA EUA.
The Elecsys Anti-SARS-CoV-2 S test can measure the level of antibodies to SARS-CoV-2 in patients who have been exposed to the virus, targeting antibodies to the spike protein, which Roche noted is also a focus of vaccines in development and the application of convalescent plasma therapy.
The immunoassay "targets antibodies that are directed to a particular region of the viral spike protein, the receptor-binding domain, responsible for binding of the virus to the host cell receptor and enabling the virus to enter the host cell," a Roche spokesperson said in an email. "The most potent virus-neutralizing antibodies target this particular region on the top of the viral spike protein."
Though "no definitive proof" exists that the presence of antibodies to SARS-CoV-2 confers immunity to subsequent infection, "multiple studies have shown that SARS-CoV-2 elicits neutralizing antibodies that can effectively inactivate the virus," the spokesperson said.
Luminex recently announced that it is looking to do further development of a test that identifies prior infection and targets neutralizing antibody activity. The Austin, Texas-based company recently received a $683,500 award from the US Department of Health and Human Services' Biomedical Advanced Research and Development Authority (BARDA) for further development of its xMap SARS-CoV-2 Multi-Antigen IgG assay. The firm said it anticipates applying for an FDA EUA when the development project is completed.
"Semi-quantitative tests may be important tools to enable longitudinal monitoring of patients, blood donors, and vaccine recipients to better understand the levels and dynamics of antibody and T-cell responses across periods in time," Matthew Lesho, senior director of global strategic marketing at Luminex, said in an interview. "It is important to provide an accurate assessment of neutralizing activity to properly inform studies investigating the direct link between neutralizing activity and immunity from reinfection or immunity post-vaccination."
In other work on the development of assays that measure quantities of specific antibodies, Shenzhen, China-based Snibe Diagnostics said recently that it has received the CE mark for its fully automated quantitative serology test for detecting IgG antibodies to the receptor-binding domain of the SARS-CoV-2 spike protein and is ready to ship the test worldwide.
Additionally, New York-based Mount Sinai recently announced that it has received EUA from the New York State Department of Health (NYSDOH) for the quantitative use of its SARS-CoV-2 antibody test, which employs two virus antigens ─ the full-length spike protein and its receptor-binding domain. Mount Sinai said in a statement that researchers at the Icahn School of Medicine at Mount Sinai recently used the test in a study that found most people with COVID-19 mount a robust antibody response that is stable for at least three months.
Further, a team led by researchers at Harvard Medical School announced it has extensively profiled the viral epitopes recognized by antibodies present in the blood of COVID-19 patients. The Harvard researchers believe that the profiling data demonstrates the complexity of the antibody response to SARS-CoV-2 and could be useful in the development of serology tests and vaccines as well as possibly identifying patients at risk of severe disease.
In addition, on Monday, the National Cancer Institute said that it is getting ready to announce the launch of the Serological Sciences Network for COVID-19 (SeroNet), a collaboration with the US research community to understand the immune response to COVID-19. As part of the Paycheck Protection Program and Health Care Enhancement Act, the US Congress authorized $306 million for NCI to develop, validate, and implement serological testing and associated technologies. NCI said that SeroNet is the largest of its serological science initiatives funded by the COVID-19 emergency appropriation and accounts for more than half of the allocation.