What Can Antibody Tests Reveal about the State of SARS-CoV-2?
Discovery
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Regina Kelder

What Can Antibody Tests Reveal about the State of SARS-CoV-2?

Until we have a reliable way of widespread testing, the full extent of the pandemic cannot be fully determined   

For weeks now, researchers have been using antibody tests to try and glean the true spread of the pandemic, and as a screening tool to determine who should return to work.  Yet, the fact that we still do not know how many people contracted the virus shows how daunting a task it is to get a hard number on the infected vs. uninfected. While we know a lot about how people make antibodies against other viruses, SARS-CoV-2 is a brand new pathogen and we have much to learn how it behaves and how people’s immune systems respond to it. The good news is that there are many different studies underway specifically designed to try and answer the antibody question.  To answer some common questions people might have about how antibodies work and why we screen for them, we interviewed Katherine Vousden, PhD, Science Director at Charles River and an expert in antibodies. This is the second part of our Q&A series with Dr. Vousden. You can catch the previous interview, on how antibodies are being used to treat COVID-19, here.

Q: When we are exposed to viruses, such as SARS-CoV-2, we eventually develop antibodies. How do these antibodies work, i.e. help or clear the virus?

A: Antibodies are specialist proteins produced by cells of the immune system in response to infection. They have different domains, variable and constant, which combine together to give the antibody its unique properties. The variable domains bind specifically to the target (in this case the virus) and is highly diverse between antibodies. Some antibodies are able to bind to virus and then prevent it infecting a host cell – this is called ‘neutralization’. In addition, if an antibody binds to a virus then the constant domain can recruit other parts of the immune system to help the fight – this includes binding to cells called phagocytes, which are then able to engulf the virus and destroy it in a process called ‘phagocytosis’. In this way, antibodies can both prevent the virus from infecting healthy cells, as well as marking it for destruction.

Q: Do some people develop more robust antibodies than others, and is this a factor in their survival?

A: There are many factors at play in how well any one individual can fight a viral infection, but their ability to produce a robust antibody response is certainly one of them. The elderly and those individuals with a compromised immune system (through medication or underlying health conditions) are less able to mount an effective immune response, which is why those groups in particular need to reduce their possibility of exposure to COVID-19 during the current pandemic.

Q: How long do the antibodies stick around and will they prevent re-infection?

A: The research in this area for COVID-19 is at too an early stage to be certain that the antibody response to this virus reflects what is seen in other viral infections, but early work this area would indicate that it is Typically, an antibody response to a new virus isn’t detectable until the second week after onset of symptoms and peaks at around 28 days. This ‘primary immune response’ occurs too late for the antibodies to have had any real effect on the early onset of symptoms, so the patient will have become sick and may have required medical attention. The serum concentration of these first antibodies against virus will reduce over time.

However, there is also the potential for a ‘secondary immune response’ in an individual who has already been exposed to COVID-19 due to the process of ‘immunological memory’. This secondary immune response results in a rapid generation of higher amounts and higher affinity antibodies than the primary response, and so the re-infected individual may be able to clear the virus before they have suffered any symptoms, and not even be aware that they have been re-infected. Currently it is too early to tell whether or not this secondary immune response occurs robustly in individuals who have been previously infected with COVID-19, but it is hoped that this will be the case for otherwise healthy individuals.

Q: The US Food and Drug Administration recently approved an emergency use authorization for a blood test for antibodies against SARS-CoV-2.  Other countries are rolling out similar tests. How do these surveillance tools work?

A: These surveillance, or serology tests are typically ELISA-based assays (enzyme-linked immunosorbent assay) which detect antibodies in patient serum that are able to bind to proteins present in the viral capsid. These tests can identify individuals who didn’t realize that they had been infected, as well as confirming suspected cases.

Q: How accurate are the tests? Can they be done from home?

A: There are a wide number of variables that have to be considered when developing robust diagnostic tests. The choice of viral protein for inclusion, and how that is produced and presented in the assay - or the way that a patient sample is collected and stored, and the timing of obtaining that sample in relation to days post infection can all affect the assay outcome. False negatives can be reported if the antibody concentration in the serum is below the lower-limit of detection, and false positives can be reported if antibodies in the serum are present due to a related coronavirus infection that happen to cross-react with the COVID-19 protein chosen for the assay; the common cold can also be caused by the coronavirus family for example and cause false positives in certain tests. This type of false-positive is now thought to be a reason why there were reports of re-infection among patients in China.

The ultimate goal is to have a well-validated antibody test that can be performed with a finger-prick test at home but, to date, none have passed the required sensitivity and specificity testing to enable a high enough degree of confidence in the results obtained. A report published on April 16 ahead of peer-review, may offer hope that a reliable test isn’t far away.

Q: What can we glean from these tests that will help us understand the scope of the pandemic better?

A: The importance of reliable serological testing in the current pandemic cannot be understated. It is now believed that up to 25% of people infected with COVID-19 may have mild or no symptoms, and so, until we have a reliable way of widespread testing, the full extent of the pandemic cannot be fully determined. This is important for epidemiologists to generate accurate models of, for example, how many people any one infected person can typically infect (the transmission rate). This could feed into any future policies around social distancing and prevention measures, and allow us to be more prepared if the virus were to re-emerge.

Q: Will these antibody tests tell us anything about the variability or virulence of the virus?

A: These tests won’t tell us anything about the virulence of the virus. The number and variety of antibodies in an immune response against it is more a measure of how ‘immunogenic’ the virus is – i.e, how easily the immune system has been able to identify it as an invader and mount an immune response to it. This may naturally vary from one individual to another anyway. Variability is an interesting point. It’s not yet known how readily COVID-19 might mutate and what the implications both for individual immunity and diagnostic testing might be.

Q: Some locales want to use these antibody tests as a way of gauging who can return to work. Is this a sensible tactic and can they tell us if someone has built up enough antibodies to develop immunity?

A: Accurate testing will allow those that have tested positive for the presence of antibodies to return to work – which obviously has big implications for keeping essential healthcare and key supply chain services running, as well as enabling the general economic impact of the virus to be minimized. If anyone has generated antibodies – even if the levels appear low at the time of testing – they will have built up immunological memory of the virus and should be protected from future infection through the secondary immune response described earlier. However, the currently available tests don’t appear to be reliable enough to be making these kind of decisions right now.

Q: So in other words, more research is needed before we can use antibody tests for real-world decisions like this?

A: Absolutely! But with so many institutions and diagnostic companies working on this problem, and the massive positive implications to communities, health care systems and businesses when we get this right, it’s only a matter of time.

Antibody expert Katherine Vousden joined Charles River in early 2020 as a Science Director for Discovery, where she is leading the integration of large molecule projects. She was most recently an Associate Director at AstraZeneca within the Department of Antibody Discovery and Protein Engineering.