Siemens Healthineers AG snagged a key role in the mystery playing out across the world's pandemic stage – what do antibody test results mean in terms of immunity to SARS-CoV-2 and how do different tests assessing different proteins compare? The U.S. CDC and the Joint Research Centre (JRC) of the European Commission tapped the Erlanger, Germany-based company to take the lead in developing a process to standardize antibody assays across manufacturers and create a universal measurement system for the level of antibodies.

The process should show results quickly. “It’s on the order of weeks, not months before we expect to get data coming out of this collaboration,” Deepak Nath, president of laboratory diagnostics for Siemens Healthineers, told BioWorld. “We have a plan, know where we’re conducting tests, what tests we’re doing and how long it takes to perform those tests.”

Speed is important, with fall and flu season coming soon to the Northern Hemisphere. “There are a number of imperatives – flu season and the need to roll out tests that discriminate between infection with influenza A or B, SARS-CoV-2, and other respiratory infections, and preparing for deployment of vaccines,” Nath said. With nine vaccines in phase III trials and more than 20 in phase II testing, the need to have reliable, comparable assays that can be used to verify immunity and surveil populations is of increasing urgency.

Broadly, immune responses are captured by measuring the level of the three classes of antibodies, IgA, IgM, and IgG. IgA and IgM develop early in an infection and rapidly decline. IgG response typically develops 10 days or so after an infection and the antibodies continue to circulate in the blood for weeks, months, years or decades, depending on the pathogen.

“That’s the level that you want to measure and quantify over time,” Nath explained. “We want to be able to say, ‘Here’s the level that needs to be circulating for us to know that we’re immune.’” That would tell physicians and patients who have had COVID-19 whether they gained immunity and to tell how effective a vaccine might be.

Most antibody tests provide just a positive or negative result for the detection of SARS-CoV-2 antibodies. Siemens Healthineers’ COV2G assay is the only one to date to make a semi-quantitative claim that it can go further and assess the level of antibodies present.

The company’s COV2G test reports results as an index value, which permits comparison across patients and across time for the same patient. But, so far, no yardstick exists that permits comparison across tests made by different manufacturers.

The collaboration aims to change that. “Right now, we lack a yardstick,” said Nath. “This study will report that yardstick in international units of SARS-CoV-2 antibodies per liter of blood.” Ultimately, it will identify the threshold level of antibodies to specific proteins that confer immunity and then go through the process needed to establish it as an industry standard. Agreement on an international standard would permit tracking of patients’ antibody concentrations over time, regardless of the test used, as well as comparison of levels in various populations.

A uniform measure

First, the tests need to measure the same antibodies, however. Currently antibody tests vary substantially across manufacturers with different tests targeting different SARS-CoV-2 proteins.

Some tests today look for antibodies that target the nucleocapsid protein (N1), logically enough, because antibodies to N1 had a neutralizing effect in SARS, making it a leading option early in the outbreak caused by the novel coronavirus. Others test for the presence of antibodies to subunits of the spike protein, primarily S1, S2, and S1RBD. Evidence is building that S1RBD antibodies are the critical factor in neutralization for SARS-CoV-2 and the company will focus on measuring those levels.

Still, “neutralizing is different than immunizing,” Nath pointed out. The body has multiple types of responses that may confer immunity. It appears that at least some individuals who have contracted COVID-19 have mounted a cellular response in which T-cells kill infected cells before the virus can spread instead of attacking the virus itself. Research at this point, however, indicates that antibody-mediated responses are the dominant response and neutralization is the best starting point for assessing ultimate immunity.

"Different SARS-CoV-2 antibody targets produce different levels of neutralization. Our R&D team recognized that if you could define a level at which neutralization is conferred for different targets, you could create a common ground to standardize assays – not just on antibody production, but their ability to provide immunity,” Nath said. “Our collaboration with the CDC and JRC will develop the framework that all antibody test manufacturers would be expected to adopt moving forward for greater benefit to patient care as the pandemic evolves."