SARS-CoV-2 Antibody Testing
By Russ Leftwich, MD, Senior Clinical Advisor, Interoperability, InterSystems
Since January there has been much in the news about testing for COVID-19, the disease caused by the Severe Acute Respiratory Syndrome associated Coronavirus 2 (SARS-CoV-2). More recently there has been the appearance of antibody tests, also referred to as serology, for this coronavirus. But what is the difference in these tests and what are antibody tests? The test done “to see if you have COVID-19” is a test that detects genetic material from the virus itself, usually testing a swab from the nasal passages or fluid from the lungs. The antibody test involves a sample of blood to see if your immune system has responded to the virus by producing antibodies.
What are antibodies? Antibodies are proteins produced by a particular type of cell in the immune system called B-cells. Antibodies are produced in response to a foreign substance in called an antigen; in this case the SARS-CoV-2 virus. Antibodies, also called immunoglobulins, are Y-shaped protein molecules. The tip of each arm of the Y is an area which binds to a specific area of an antigen and fits like a piece of a jigsaw puzzle only to that area. The SARS-CoV-2 virus may have dozens, even hundreds of such distinct areas each recognized by a different antibody molecule. When there is an antibody response the immune system produces a family of antibodies recognizing different specific areas on the virus. This is called a polyclonal response, because each member of the family of antibodies is produced by a different clone of B-cells. And, two different individuals will produce two different families of antibodies based on their own genetics. When the immune system encounters an infectious agent for the first time, whether it is a bacterium or a virus, it first produces Immunoglobulin M (IgM). IgM starts to appear several days after the infection starts. A few days later, a second type of antibody, Immunoglobulin G (IgG), starts to appear. Both IgM and IgG are families of antibodies to the SARS-CoV-2 virus. The IgM produced usually starts to disappear within a few weeks. The IgG antibodies in the blood continue to increase for several weeks and may remain for months before they disappear.
Are all the SARS-CoV-2 antibody tests the same? By early May 2020 well over 100 antibody tests were available. Each test was developed separately. Some of the tests tested for IgM, some for IgG, some for both. Tests determined that antibody was present or absent. Although it is possible to measure the level of an antibody present, the titer, none of these tests actually do so. There is very limited information about the accuracy of the available tests, but it has been observed that some of the tests have a high false positive rate and that two or three different tests done on the same individual may not agree on the presence of antibody. In the U.S. over 20 different SARS-CoV-2 antibody tests were removed from the market because of inaccuracy.
What do we know about antibody responses to SARS-CoV-2? As with most infections, IgM to SARS-CoV-2 starts to appear in some individuals about 3-5 days after the start of infection. But, depending on the sensitivity of the antibody test, it may be 3 weeks before some individuals show IgM to SARS-CoV-2. IgG to SARS-CoV-2 begins to appear a few days after IgM. A small percentage of individuals, around 5% who have COVID-19 with symptoms and a positive test for the virus appear not to develop antibodies even when they have recovered from COVID-19. How is this possible? The answer is that antibodies are not the primary function of the immune system which eliminates a current viral infection. Antibodies are however the primary protection from a future viral infection.
Does the presence of antibodies mean immunity from future COVID-19? The answer is that we do not know the answer. We do not yet know whether the antibodies present will prevent future infection with SARS-CoV-2. And if they do, we do not know how long levels of those antibodies will remain high enough to provide protection. Antibodies that protect from future infection are referred to as neutralizing antibodies. There can be some assessment of the neutralizing capability of antibodies by taking antibodies from a recovered COVID-19 patient and using them to block SARS-CoV-2 infection in other animals, but the only absolute evidence is the prevention of re-infection of a human during an outbreak of the SARS-CoV-2 virus. The goal for a vaccination against COVID-19 is of course to induce high levels of neutralizing antibodies in a high percentage of individuals who receive the vaccine. Once again, the only absolute evidence that such antibodies are present, and the vaccine is effective is exposure of vaccinated individuals to SARS-CoV-2 in a future outbreak.
Testing for antibodies to SARS-CoV-2 will be of increasing importance as this pandemic evolves. It will be of critical importance to increase the understanding of the antibody response to this coronavirus and to understand what is being measured by the various antibody tests. Of perhaps greatest importance will be the ability to assess the accuracy of different antibody tests and how they compare to one another. The first step in this will be appropriate coding of the various tests to reflect the origin of the specimen tested, the identity of what is being tested, the method used to include the specific device, the encoding of results, and assessment of the predictive value of each test. Only then can we assess the level of protection of individuals by their antibody levels, the effectiveness of vaccines, and develop our knowledge of how to control COVID-19 at a population level. The practices around coding for tests related to COVID-19 including the antibody tests for the virus will be addressed in a future article.
This story originally appeared the July 10, 2020 – HealthShare Connections News Flash No.3: COVID-19 Pandemic newsletter and in the July 20, 2020- OnTrak News Flash No.5: The Fight Against COVID-19 newsletter