Today I saw a valuable article in the New York Times print edition entitled “If Antibody Check Shows Negative, Blame the Test” by Apoorva Mandavilli, (July 27, 2020, Page A4). I looked for the article online and only found a longer version, curiously entitled “Your Coronavirus Antibodies Are Disappearing. Should You Care?” Since the online title is less provocative, I thought many readers might miss this important article and its significance. Therefore, I decided to highlight it in today’s blog.
The change in title is important because the most newsworthy information in the article explains why antibody testing for coronavirus may produce erroneous results and may incorrectly suggest that antibodies to the virus go away after the infection. This has led to the stories about “COVID-19 reinfection syndrome” where internet news sites publish stories inspired by unpublished studies suggesting that immunity to COVID-19 does not last and people will be at risk for endless cycles of reinfection. More on that later.
First, it is important to review the immune response to COVID 19 that allows a person to clear the infection.
The immune system initially recognizes the presence of a foreign invader by recognizing components of the virus that are different from components of the human body. In the case of COVID-19, one of the first things that is recognized is single stranded RNA, the genetic material of this virus. Humans do not have a similar type of RNA and receptors in their cells that take up virus will activate what’s called the innate immune system to start a response against the virus. There is a specific cellular receptor for single stranded RNA called “toll like receptor seven (TLR7)”, and viral RNA binding to this receptor produces potent, antiviral hormones (cytokines) called interferons.
Interferons then activate immune cells (lymphocytes) that specifically recognize different parts of the virus, predominantly the proteins. They make a specific immune response to these proteins including lymphocytes that can recognize and kill virally infected cells, and antibodies that bind to viral proteins and either kill the virus or disrupt viral function.
There are four different viral proteins; Spike (S), Membrane (M), Envelope (E) and Nucleocapsid (N). In terms of infection, the S protein is most important because it binds to the target on the cell (ACE2 protein) and initiates viral infection of the cell. Antibodies that neutralize the virus mainly bind to the S protein and block the virus from infecting cells. Most people make antibodies to all the proteins, but some make antibodies to only one or a few. The reasons for this are not entirely clear but relate to difference in each person’s immune system.
You would think that if you are looking for antibodies against COVID-19 virus (SARS-CoV-2) you would look with all the proteins, or at least the S protein that mediates infection. However, the most common commercial tests — including those made by Abbott and Roche and offered by Quest Labs and LabCorp — are designed to detect only antibodies against the N protein. This is also a problem because these particular antibodies may go away even faster than the S protein antibodies that can destroy the virus. This is because N proteins are only present when there is a large amount of replicating virus in the patient (at the very beginning of the infection).
That these tests would focus on this one protein seems bizarre. The article quotes some scientists who were stunned to hear of this decision. “God, I did not realize that. That’s crazy,” said Angela Rasmussen, a virologist at Columbia University in New York. “It’s kind of puzzling to design a test that’s not looking for (antibodies against) what’s thought to be the major antigen.” Other experts suggested that what this means is that declining antibodies, as shown by these commercial tests, don’t necessarily mean declining immunity.
The problem described here is not with the handheld tests whose accuracy has raised concerns by the FDA. The Roche and Abbott are the supposedly more reliable commercial assays run at reference laboratories and hospitals. Most of the handheld assays actually screen for S protein antibodies. We are currently comparing the approved handheld devices that screen for antibody to S protein and compared these to the Roche assay which measures only antibody to N protein. Hopefully the S protein assays will be more accurate.
In any case, this is another reason you should believe immunity to COVID-19 will last.