Those that follow my blog, follow me on Twitter, listen to me answering listener questions about the coronavirus on radio or watch me on local television news programming will know that I have been an outspoken critic of offering SARS-CoV-2 antibody testing to the general public dating back to March. I still am, and as it turns out, many of the reasons I provided for objecting to the testing are turning out to be supported by recently released research studies. So, with this blog post, I am going to try to help you understand what little we know about the immune response and potential immunity to the SARS-CoV-2 virus, and some of the implications. There is both good news and bad news. If you are not interested in all the background and discussion of the research, you can skip to the bottom for my summary take-away points.
But first, a few disclaimers.
- These early studies are fascinating and informative, but not definitive. In other words, they do provide us with insights, but every research study is limited in what information it can provide and how broadly applicable the implications can be. For example, the findings of a study that looks at the response in a laboratory or in an animal may or may not be the exact way the immune system works in a human being. The findings of a study testing adults may or may not be applicable to children. The findings of a study testing persons who were hospitalized may not be the same findings that would have been found in individuals who were less severely ill and did not require hospitalization. You get the idea. So, before we conclude that the research we are going to review is broadly applicable, we need to see this replicated in other studies and in various populations of persons tested to see whether these findings are validated for everyone, or whether there may be important differences in different groups of people.
- The field of immunology is extremely complicated, and because this is a summary for lay persons without any particular knowledge of immunology, I will of necessity be oversimplifying my explanations below (my apologies in advance to laboratory scientists and immunologists) and will make no attempt to provide a comprehensive discussion of the immune response.
- We must readily admit that there is much that we don’t know and still don’t understand about the immune response to this virus. While it is amazing how much we have learned in just six months about this novel virus, nevertheless, we have only scratched the surface. As more research is conducted, we may learn that things we thought were true today are no longer true in the future.
- Finally, the SARS-CoV-2 virus, like all RNA viruses, is rapidly mutating. The overwhelming number of mutations will be inconsequential and will not impact the discussion below. However, there has already been one significant mutation, and there very well be more in the future. When there is a significant enough mutation or mutations to actually constitute a new strain, that new form of the virus can be more or less virulent (the significant mutation I mentioned above resulted in the virus being more infectious [more transmissible], but surprisingly, does not appear to be causing more severe illness), and if the mutations are of extreme significance, it could affect how well our current antibody tests work, how effective our immune response is and how well a vaccine (when we have one) will work.
Okay, here we go.
The first thing we need to do to understand possible immunity to the SARS-CoV-2 virus is understand the parts of the immune system. One of my criticisms of those who have been publicly promoting antibody testing is that they have not been clear with the public and likely contributing to further misleading the public because they tend to place all of the emphasis only on antibodies and seem to imply that having antibodies is to some degree synonymous with immunity. While people are probably most familiar with antibodies when they think of the immune system and immunity, I would make a wager that most people are under the misconception that antibodies = immunity. They do in some cases, but we have many examples where they do not.
First of all, antibodies come in various kinds. The kind most people are aware of is IgG and this has been the target of the current antibody tests. But, IgG has limitations. It cannot attach to a virus that has already gotten into a cell. It also is not present in mucosal tissues, like the gut, which happens to be a huge source of the receptor that the SARS-CoV-2 virus attaches to. To combat SARS-CoV-2 in the lining of the gut, you need IgA, not IgG. None of the current antibody tests check for the presence of SARS-CoV-2-specific IgA antibody.
Even within IgG, there will be many different specific IgG antibodies that target different proteins on the coronavirus – some are specific for the spike protein, some are specific for protein in the envelope of the virus, and so on. In other words, different IgG molecules will attack different parts of the virus. Some of these will be more effective than others, and not all, or even most, will accomplish the end-goal of preventing the virus from entering into a cell where it can replicate and perpetuate itself. Antibodies that do this are called neutralizing antibodies. The currently, widely available antibody tests just test for IgG and are unable, in most cases, to tell us how much antibody someone has and how protective those antibodies are.
The antibody response is just one part of a complicated and interrelated immune response. Antibodies take time to be produced. If you have not been exposed to SARS-CoV-2, then you will have no SARS-CoV-2-specific IgG antibodies in your blood. Once infected, it will take you a week or even more to develop and produce IgG antibodies. In the meantime, your immune system does not just let the virus have its way with your body. We have what is called an innate immune system, which is actually quite robust and complicated, but it recognizes that this virus is not part of you and will begin to attack it. The attack is a general response, not a targeted, specific one, so it can result in the mobilization of many types of white blood cells and chemicals whose role is to produce inflammation and an environment hostile to the virus, including cells that try to swallow the virus and destroy it inside these white cells before the virus can get into other cells that don’t have this capability and instead the virus can hijack its cellular machinery to mass produce new virus. Basically, there is a race between the virus and the immune system with the virus trying to invade the body and enter into cells, where it will be relatively safe (at least from the innate immune system and antibodies (which are called the humoral immune system) long enough to produce large amounts of new virus. Meanwhile, the innate immune response is racing to capture and destroy the virus before it can get into cells to replicate, and if the innate immune response cannot thwart the virus infection, at least buy time for the next part of the immune response called the adaptive immune response, which is a targeted and specific attack against this particular virus both with humoral immunity (antibodies) and cellular immunity (specialized immune cells that can enhance the antibody response and, unlike antibodies, can identify the cells that the virus has entered and kill those cells to stop production of new virus). This innate immune system response can be so intense that it produces wide ranging nonspecific symptoms, such as fever, fatigue, and a sense of feeling ill or unwell.
So, what is wrong with someone who thinks that they had an illness getting a SARS-CoV-2 antibody test to see if they had COVID? Well, it turns out there are plenty of reasons this may not be a good idea.
- If you just have an overwhelming sense of curiosity, a hundred bucks to spare, you understand all the limitations of this test and you are committed to continue to practice all of the recommended infection control measures (frequent hand washing, physically distance, wear a mask when you cannot physically distance, etc.), then I actually don’t have an objection to you getting the test.
- There is wide variation in the quality of antibody tests. Some are more reliable than others. It is challenging for a non-expert to be able to differentiate the better tests from the ones that are far less accurate. Further, none of these tests have been validated by the FDA. We often have to rely on the manufacturer’s own representations without much information about how they did their own testing and with the realization that they have a tremendous financial conflict of interest with an incentive to make a determination that the test is accurate, and it may not be. As a case in point, one test produced by a very reputable manufacturer and commonly used self-reported the sensitivity of the test as being 97.2 percent, which is considered very good. However, when independently tested, the sensitivity was determined to be only 82.1 percent, which would not be considered to be a good test.
- Even with an accurate test, if you test a population that has a low prevalence of infection, a positive test can be more likely to be a false positive test than a true positive test. In other words, the test may indicate the presence of antibodies, but you actually don’t have the antibodies to the SARS-CoV-2 virus. Obviously, it would be dangerous for someone to think that the positive test means they were infected and now are immune and then not take precautions that might now put the person at greater risk for infection. As an example, the pregnancy test is a pretty good test. But, if you test people who are unlikely to be pregnant, for example, a woman who is in her fifties or a woman who has had a hysterectomy, a positive test is more likely to be a false positive than a true positive. To take it even further, imagine that you take one thousand biological men and administer a pregnancy test. You might end up with a handful of positive tests. Obviously, they are not pregnant. It could be a problem in processing the test or a cross-rection with something else that is causing the test to appear positive, but there actually could be a few men who are producing the same pregnancy hormone that pregnant women produce, but it is because the men have a tumor that produces that same hormone, even though they obviously are not pregnant. So, we have to be very cautious in interpreting antibody tests when used on people in Idaho, where it is estimated that perhaps only two percent of the population has been infected.
A significant part of my argument against this testing has been we really don’t know how accurate it is, we don’t know if everyone produces antibodies to infection (e.g., it has been the case with other infections that mild or asymptomatic infections may not result in a significant antibody response, and in fact, many people with COVID have had mild illness or no symptoms), we have the risk to have false positive and false negative tests, and even if someone does make antibodies, we don’t know how much or how good the antibodies are and whether they will confer immunity, and even if so, for how long. Further, one large provider here in Idaho was pushing performing antibody testing on employees and reporting the results to their employer. For the life of me, I cannot imagine why I would want my employer to know my antibody test results. What would they do with that? If I was positive, would they put me in situations where I was more likely to be exposed to SARS-CoV-2 than other employees thinking that I could not catch COVID again? Would the employer decide I didn’t need to have all the expensive and limited PPE that is made available to other employees? I can think of a situation where an employer might want to know if certain areas of its business created high risk and infections, but in my opinion, employers should only receive aggregate rates of positivity and not individual employee’s test results.
It turns out that these recent studies confirm my concerns. While most people who have recovered from COVID do produce some antibodies, the amount and type of antibodies vary widely from person to person. It does appear that those with more severe infections produce higher levels of antibodies, and this is not unique to SARS-CoV-2 infections. However, the studies suggest that 2 – 8.5 percent of those who were infected do not seroconvert (in other words, have a positive antibody test) even weeks following infection. One study of individuals who were infected (confirmed with a PCR test) showed that 10 – 11 percent did not have a positive antibody test after 14 days, and another study of persons who were infected, but remained asymptomatic, showed that at 3 – 4 weeks following infection, about 19 percent of these individuals did not have a positive antibody test for IgG. Similarly and surprisingly, almost 16 percent of those who were symptomatic that they compared this study group to, also did not develop a positive antibody test. Further disappointing was the fact that over 2 – 3 months, 40 percent of the asymptomatic individuals who did initially produce antibodies, no longer produced them in amounts that could be detected by the antibody tests. Similarly, almost 13 percent of those who were symptomatic and initially produced antibody became negative on antibody testing after 2 – 3 months.
While a recent study shows that almost everyone makes some neutralizing antibody, a third of patients make them in very low titers, and only one percent of patients made these types of antibodies in very high levels that would likely be associated with immunity if neutralizing antibodies can confer immunity (which we do not know at this time). Another study of convalescent plasma donors from New York City showed that about 10 percent of donors had very high levels of neutralizing antibodies, but around 16 percent of donors had undetectable levels. Interestingly, this study also showed that antibody levels declined after 3 weeks.
To the extent that antibodies following natural infection are critical to immunity (and, we do not know that they are), the news is discouraging and suggests that most people may have limited protection and for a much shorter duration than we had contemplated. On the other hand, several of the neutralizing antibodies that nearly all persons made following infection were extremely potent, even though most people made them in very small amounts. This is very good news for our vaccine efforts, because if the vaccine can be designed to trigger the production of these particular neutralizing antibodies, then the vaccine may be highly effective.
All the discussion about antibodies and antibody testing ignores the fact that for most viral infections, cellular immunity generally plays an even more important role in fighting and preventing the infection than antibodies do. And, the good news from recent studies is that a very strong cellular immunity response was noted in everyone who has recovered from COVID, even those who had mild illness or who were asymptomatic, including family members who were exposed by a confirmed case in their family, but never determined to have become infected themselves.
Two key parts of the cellular immunity response are the development of helper and memory cells and cytotoxic or killer cells, all of which are specific to this virus. It turned out that everyone tested in this recent study developed specific memory/helper T cells. These cells can cause antibodies to be produced quickly upon exposure to the virus instead of the week or more delay that occurs when the person is exposed the first time to the virus and they can amplify the antibody production against the virus. Seventy percent of all those tested developed killer cells, which are the cells that detect the body’s cells that have been infected by the virus and kill those cells to terminate the replication of the virus. The helper cell response to the spike protein of the SARS-CoV-2 virus was very strong and robust. The good news about these findings is the suggestion that, as opposed to the case if antibody response is critical to immunity, if cellular immunity plays a key or the key role in immunity, many more persons previously infected could be likely to be immune and the duration of immunity may be considerably longer since the antibody levels declined rapidly and significantly with time, but the cellular immunity would likely be much more durable.
So, there remains much more to be learned about the immune response to SARS-CoV-2 and what is required for immunity, and if there is immunity, how long-lasting it will be. However, we certainly have interesting research studies from which we can make some inferences:
- A significant number of people appear not to develop antibodies in sufficient amounts that can be detected by the commercially available antibody tests, especially if they had very mild or an asymptomatic infection. This will result in false negative tests.
- Even if persons who were infected initially developed antibodies, a significant percentage of people stopped making sufficient levels of antibodies that could be detected after several months. This will result in false negative tests.
- We still do not know whether the presence of antibodies means that the person is likely to have immunity, but if it does, it appears that a very small percentage of people are likely to have strong protection.
- Even if antibodies do confer immunity, there is reason from these studies to be concerned that this immunity is short-lived, perhaps only lasting for months.
- Based upon all of these findings, a positive antibody test has the real potential to create a false sense of security for the person who tests positive, and potentially for their employer, which could cause the individual to take less precautions than he or she otherwise would, but yet the person may not be protected or fully protected, and if it has been months, the person may have lost their immunity.
- On a different note, the cellular immunity response (compared to the humoral immunity or antibody response) is far more encouraging, and this leads me to speculate as to whether this could explain why we are seeing relatively low levels of disease activity in some of the earlier hotspots in our country, at a time when many other places in the country are seeing marked increases in cases.
- Finally, these recent studies provide encouraging news for our developing vaccine options.
Here are the key take-a-ways:
- 2 – 16 percent of people don’t develop a positive antibody test after infection. These people will have false negative tests.
- Even if people do develop a positive antibody test after infection, in 2-3 months, 13 – 40 percent of those will have declining antibody levels to the point that they may no longer be detectable on the commonly used antibody tests.
- If antibodies are critical to immunity, it appears that only 1 – 10 percent of those infected make the kind of antibodies that we would predict would confer immunity. And, these antibodies, too, appear to decline in just a matter of weeks to months.
- While these antibody studies are discouraging, the other branch of immunity (cellular immunity) is very encouraging and studies showed that everyone infected (and even those who had significant exposures to infected individuals) developed a robust cellular immunity response even if they did not develop antibodies, and we have reason to believe that this immunity might be far more lasting than what is likely if antibodies are key to immunity.
So, for now, stay at home and work from home when you can. When you have to go out, physically distance. When you are unable to physically distance, wear a mask or face covering. And, instead of shelling out a hundred bucks for an antibody test that tells you little and provides no actionable results, consider donating that hundred bucks to a COVID relief effort.