The U.S. FDA gave an emergency use authorization (EUA) to the first semi-quantitative antibody test from Siemens Healthineers AG for the SARS-CoV-2 virus. Existing serology antibody tests detect the presence or absence of antibodies, but not an assessment of relative levels that are present in the blood. This test, known as the SARS-CoV-2 IgG (COV2G) antibody test, could potentially be used repeatedly over time to assess relative levels to gauge potential immunity.
The test has 100% sensitivity and 99.9% specificity. It is the fifth antibody test from Erlangen, Germany-based Siemens Healthineers that has secured an EUA, all of which have sensitivities and specificities that exceed 99%. These include various test iterations for specific equipment.
In addition to the new semi-quantitative SARS-CoV-2 antibody test, Siemens Healthineers also markets a total antibody test that is designed to detect all the antibodies from a COVID-19 infection, which makes it useful shortly after symptoms appear.
Total or semi-quantitative?
“Typically, in terms of antibody response in the body, it's usually initially the IgM or IgA antibodies that are released,” Deepak Nath, president of Laboratory Diagnostics for Siemens Healthineers, told BioWorld. “For this virus, it’s really the IgM. The IgA antibodies tend to present mostly in the mucosal membranes, there’s a little bit present in blood. But for this respiratory borne pathogen, it's really more of the IgM. That's the initial antibody response from the body.”
“Following that, after some period of time is when the IgG response gets provoked. Depending on the patient, the amount of time does vary,” he continued. “So, typically post-symptoms anywhere from two to four days is when the IgM response peaks, and then anywhere between four days and about 10 days is when the IgG response starts to get going – and then that persists over time. What we don't know is what kind of changes happened to the body to the IgG levels over time.”
Typically, with other viruses, it is the IgG antibody class that confers immunity, which is why it has emerged as key in the context of the SARS-CoV-2 virus. The expectation is that physicians will be able to compare numerical results over time, and that this might offer some insight into individual immunity.
The next step toward an accurate assessment of relative immunity to the virus could potentially come with a fully quantitative version of a serological test. But this would require the setting of international standards on the meaningful thresholds that are precisely defined, and correlated with immunity.
To establish that, studies will have to be done that correlate IgG antibody levels over time in people who are in environments where they are re-exposed to the novel coronavirus and then track their re-infection rates over time.
“Our high-quality antibody test helps clinicians assess the level of a person‘s immune response, which is an important tool to have at this stage of the pandemic,” said Nath. “Siemens Healthineers offers a robust portfolio of reliable tests to help support patient care and fight COVID-19.”
The new semi-quantitative test includes detection of the spike protein, particularly an area known as S1RBD. This is a key protein on the surface on the SARS-CoV-2 virus – and is included in many of the vaccine candidates that are in development. Presumably, this could make the test relevant for detecting and monitoring both any natural immunity after an infection, as well as immunity that could be induced by a vaccine.
“Both of our tests, the total antibody test and the IgG test, detect antibodies that target the spike protein,” said Nath. “Our tests are specifically aimed at the S1 receptor-binding domain (S1RBD) on the spike protein. There's now ample evidence that antibodies that attack or bind to the S1RBD have a neutralizing effect on the antigen.”
“Therefore, we chose antibodies that target that site to do our tests,” he added. “That's important because not all tests do that, in particular for IgG. That's also important because most vaccine companies are creating vaccines that produce antibodies that target that site. So, if you want to gauge effectiveness of vaccines, you want to do antibody tests that look for antibodies that have a neutralizing effect.”
Siemens Healthineers has the largest installed base of equipment to conduct serology antibody tests, noted Nath. The COV2G antibody test is available on an installed base of analyzers installed in the U.S. and in countries that accept the CE mark worldwide. This includes the Atellica Solution and ADVIA Centaur XP and XPT families of analyzers. Comparable tests for Siemens Healthineers Dimension Vista and Dimension EXL systems also are being pursued.
SARS-CoV-2 antibody tests have gotten something of a bad reputation for a lack of accuracy, generating several headlines in major mainstream publications. But Nath argued that this isn’t based on high-throughput, automated testing results, but rather on results from lateral flow, or rapid antibody, tests. These are strip-based tests, akin to pregnancy tests, that tend to have a much larger margin of error when it comes to results but offer a very fast turnaround time of 10 to 15 minutes.
Lateral flow tests tend to have significantly lower accuracy rates, particularly with specificity, which then is amplified since the population prevalence is so low. For example, if a lateral flow test has 90% sensitivity and 95% specificity – and it’s applied to a population with only 5% prevalence – then the positive predictive value is wrong more than half of the time.
“So, the reason there's a lot of confusion in this field right now is people use the words antibody test without specifically referring to whether the test is a serology-based antibody test or a lateral flow test,” summed up Nath. “That's one point of confusion. The second point of confusion is the market in the United States and other parts of the world is that we're flooded with a large number of lateral flow tests from manufacturers that were not necessarily present in the U.S. market prior to this pandemic. And there is quite a big variation in quality among these lateral flow tests.