Laboratory test procedures not comparable

The demand for Sars-CoV-2 antibody tests is high. To date, over 218,700 recovery certificates based on antibody tests have been issued in Switzerland. Around 500 of these can be traced back to tests offered by Safetest AG from mid-November to mid-December 2021 in the Corona test center at the Stadelhofer Passage.

Safetest operates the test center at the Stadelhofen train station in Zurich and intends to use more antibody tests there again from the end of January. If the pilot test is successful, the concept will eventually be extended to the 39 other test centers in Switzerland.

Safetest Managing Director Ehad Beqiri assumes that the demand for antibody tests will continue to rise. Some people want to get their antibody status checked before boosting, he says. The others who come for the test want to use it to apply for their recovery certificate.

With the help of a new diagnostic device that it wants to use in an antibody test study, the company wants to be able to determine the results of the blood tests in 15 minutes in the future. Currently, people would have to wait up to four days.

These tests have been in demand since the Federal Council decided in November that people who can detect sufficient antibodies against Sars-CoV-2 in their blood using a positive antibody test (serological test) and who have recovered can receive a certificate. The Federal Office of Public Health (BAG) justifies the decision by saying “that the data situation has recently increased with regard to the very good protection provided by a previous infection”. That is why a 90-day recovery certificate can be obtained through an antibody test.

But how do you interpret these antibody tests? What are the requirements for doing this?

Definitely positive

The recommendations for the laboratories in connection with the Sars-CoV-2 antibody tests come from the Swiss Society for Microbiology (SGM). The antibody tests must be CE-certified and carried out by a Swissmedic-certified laboratory.

According to the BAG, it must be clearly proven that there was contact with the virus. The authority writes: “The regulation stipulates that a quantitative result must be determined and the result must be clearly positive.»

The expert group of the SGM saw the greatest risk in the fact that there could be false positive results. Therefore, the measured values ​​would have to be above the test manufacturer’s limit value with a certain safety margin in order to receive the certificate. Their specification is pragmatic and can be applied to all test procedures, explains Adrian Egli, Head of the Clinical Microbiology Section at SGM. Together with other experts, he wrote the recommendations for the Swiss laboratories. This requirement is intended to ensure that only people with a clearly positive result receive a certificate.

Different lab, different test, different limit

A laboratory in Zurich, which does not want to be named, writes that the specifications of the SGM result in a limit of 15 BAU/ml (binding antibody units) for the test they use. If you have that many BAU or more in your blood, you will receive a certificate.

In other laboratories, however, other limit values ​​apply, for example 42 BAU/ml. The laboratory, which works together with Safertest, issues certificates from 250 BAU/ml.

This leads to people choosing or changing labs to get a certificate. This is how a 42-year-old from Zurich did it, who would like to remain anonymous: The 20.8 BAU/ml he measured at one laboratory was not enough for a convalescent certificate, and he was able to obtain the certificate from the second laboratory at the end of November. “I have the freedom to do my job until the end of February,” says the man. Before that, he had himself tested three times a week for a month and a half. This was necessary for the practice of his profession in accordance with federal regulations.

But then the validity of the test was reduced to 24 hours. The effort would have been even greater. He first considered vaccination. Since he had been somewhat ill in the summer, he first tried an antibody test. He is not opposed to vaccination, but sees no reason to be vaccinated at his age. At the end of February he will do another antibody test. If it is not enough for a certificate, he is faced with the same question again: should he be vaccinated freely?

Why was the man’s antibody value not enough for a convalescent certificate in one laboratory, but in the other it was?

With all serological tests one tries to prove an immune response, but the different providers, the test procedures and methods of the laboratories are difficult to compare with each other, explains Adrian Egli from the SGM. The different methods measure the signal strength of the antibodies differently. From what limit (BAU/ml) the test is positive depends on how and what the test measures exactly, says Egli. Also, not all laboratories used the same unit. In addition to BAU/ml, there are others, says Egli.

The tests have different target antigen structures, which the antibody recognizes, explains Philipp Walter, President of the Swiss Union for Laboratory Medicine (Sulm). These could deviate from each other and cannot be directly converted. The different test methods could deviate from each other by a factor of up to 100. The limit value is an arbitrarily determined quantity, there is no “standard meter” by which to measure.

Because the tests have different limit values, these would be validated by the manufacturer or the laboratory carrying out the test and the limit value would not be set across all test systems, writes the BAG on request.

According to Egli, comparability would have to be established and diagnostics would have to be standardized. However, standardization rarely succeeds. Sulm President Walter also says that international standards are being developed, but such efforts for standardization would usually fail because there is no single “correct” test procedure, but different ones, which, depending on the question, have their correctness but also their limitations .

A troubled business?

“The enormous influx of antibody tests surprised everyone. BAG also confirmed to me that they had never expected such a large number of certificates to be issued,” says Philipp Walter. Sulm therefore fears for the credibility of the laboratories.

Providers positioned themselves in the market who wanted to provide the lowest possible access using test procedures from capillary blood sampling. Some of these have entered into cooperation with laboratories approved by Swissmedic in order to comply with the formal requirements, said Walter on behalf of the Sulm Board of Management in an early December public comment warning. A development in demand was provoked, which is managed by providers outside the established competence centers. Sulm regards this as critical.

Sulm is pushing for compliance with the minimum quality standards defined by the SGM, so that the security risk when accessing certificates through antibody detection remains “calculable”. In fact, however, this will not succeed comprehensively, since the resources are lacking to monitor compliance with these standards. According to its own statements, it fears that the quality standards of in-vitro diagnostics will be undermined if these tests are used more and more widely without being able to provide differentiated expert advice on the statement of the result.

Despite criticism, the antibody tests have already become a business. According to Adrian Egli, however, there is no gold rush mood as with the antigen rapid tests. “There are also a few colleagues who tend to promote antibody testing with technically questionable statements. The head of a Basel private laboratory is quoted in the media as saying that senior citizens should have their antibody titer measured before the booster because the booster could be dangerous for people with a high titer. This unsettles and harms the credibility of the industry,” criticizes Sulm President Walter. Reputable laboratory medicine is needed that offers society and patients added value. The current development cannot keep up with this ethical claim.

Can we make statements about the protection?

Does the antibody test and thus the certificate say anything about how well someone is protected against corona? This question applies to both those who have recovered and those who have been vaccinated. There are more and more studies and experts who are making statements about the amounts of antibodies from which there is protection against another disease or infection. A laboratory surveyed by the NZZ assumes that at values ​​of over 500 BAU/ml an almost secure protection can be assumed. And refers to scientific publications from France and Finland.

Andreas Bobrowski, Chairman of the Board of the Professional Association of German Laboratory Doctors, has already commented specifically on this in the German media. He assumes that with a value below 21 BAU/ml you have no immune protection, but with over 44 you do. In between there is a gray area, he said in an interview with “Focus”. Bobrowski says a person with a BAU score above 1000 can be assumed to be fully protected. It is not yet possible to say whether this also applies to 30 or 40 BAU. According to the article, Bobrowski advises patients with a value above 1000 against a third vaccination.

The BAG, Sulm and SGM explain that a positive test result in an antibody test only shows that someone has come into contact with the virus. “The certificate says nothing about the protection,” explains Egli, “there is a misunderstanding that a positive antibody test is completely protected. This is a misconception. You are probably already protected from a severe course, but not from an infection – just like the vaccinated.” We still know little. The numbers per se would not say much. It is unclear from what level of antibodies a person is considered protected, as this also depends on many personal factors such as age and underlying disease.

According to Sulm President Walter, which limit value is still protective must also be defined separately for each test system. He says that the discussion about protection through certificates with “positive/negative” and thus “protected / not protected” is being oversimplified. There are many misunderstandings about test interpretations, which laypeople can hardly understand, and therefore the antibody test cannot be part of a mass-market concept.

In the future, will antibody values ​​be decisive for obtaining a certificate if the test methods are comparable? We still know little about what the antibody tests say. It is not yet possible to say how protected those who have recovered and those who have been vaccinated are. At the current state of knowledge, the certificate can actually only identify those who are protected from a severe course. However, many who have a certificate can be infected.