A few days ago, the World Health Organization caused a stir by saying that antibody tests may not indicate whether someone is immune from SARS-CoV-2. This led to some understandable confusion, and WHO spokespeople have subsequently walked the comments back a bit. While the messaging might’ve been handled better, the public health experts at the WHO were trying to make a very important point.
Several prominent politicians have advanced the idea of issuing “immunity passports” to people who’ve recovered from SARS-CoV-2 infection. The concept is that these people could safely return to work because they will have acquired immunity to the virus, so they won’t be at risk of developing COVID-19 again or reinfecting others. What the WHO was trying to say – correctly – is that while antibody testing has an important function in the response to the pandemic, immunity passports are a horrible idea. Yes, they were a major plot point in Contagion, but that was a movie. Reality doesn’t work that way.
My hot take on Twitter hinted at the problems, but I want to lay them all out here so folks understand this isn’t just a knee-jerk opinion.
If you’re in a hurry, the key problems are that current tests are far from perfect, immunity is neither binary nor fixed, and a scheme that rewards people for having been infected will have layers of unintended consequences, likely leading to a huge spike in new infections.
First, let’s talk about immunity. The standard SARS-CoV-2 clinical test right now is a PCR-based assay that detects viral RNA. It identifies – with exquisite sensitivity – an ongoing or very recent infection. After someone clears the virus, though, the viral RNA will gradually go away. At the same time, the immune system will ramp up the production of antibodies, proteins that bind specifically to SARS-CoV-2 and flag it as an intruder. Antibodies are one of the ways we become immune from infections we’ve had in the past.
While the PCR test requires a sophisticated laboratory and specific reagents, antibody tests are stupidly easy to manufacture and can be made extremely user-friendly. Home pregnancy tests available at your local pharmacy are antibody tests. So are the rapid HIV tests used in clinics around the world. These tests yield simple yes or no answers, and after years of careful validation they’re pretty good. The questions they’re addressing are also amenable to binary answers. If you’re knocked up today, you’ll probably still be knocked up tomorrow.
There are at least five crucial differences between the definitive answers of a home pregnancy test and the ambiguous results we’ll get from SARS-CoV-2 antibody tests. First, because these tests are easy to make and in high demand, a metric boatload of companies have started making them. Some are probably good, some are certainly crap, and nobody can be sure which is which yet. The FDA is issuing “emergency use” approvals for these tests, which sets a much lower bar than their usual approval process. It will be at least a few months before we have good enough data to identify the best tests, and even then they won’t be perfect.
The second problem is that a “yes or no” test for SARS-CoV-2 antibodies hides a critical nuance: different people will mount different levels of antibody responses. Test makers will set some threshold for saying “yes, this is a positive result,” so someone whose antibody level just barely hits that mark, and someone with a much more robust response, will both get a “yes” answer even though they don’t have equivalent levels of immunity. More sophisticated laboratory testing can yield a numerical score rather than a binary answer, but even then we’d have to set some threshold for issuing the hypothetical passport.
Third, we don’t really know what constitutes immunity from SARS-CoV-2. Antibody tests measure one part of one arm of the immune system, called humoral immunity. I think that’s probably important against this virus, but nobody really knows. There’s a whole other arm of immunity, called cellular immunity, that could be at least as important. Antibody tests will tell us nothing about that. So even if the test answer is correct, it may not be relevant.
Fourth, we don’t know what kind of immunity someone gets from clearing a SARS-CoV-2 infection. There are two possibilities. Sterilizing immunity is the one people think of first. Someone with sterilizing immunity can’t get reinfected at all. Not only will they not get sick, they can’t even act as carriers of the virus. That’s important. The second type of immunity is protective. People with protective immunity can still get infected and act as carriers, but won’t get sick, or at least not very sick. These aren’t hypothetical categories. We see them routinely with infections and vaccines; sometimes we get sterilizing immunity, sometimes we get protective immunity, and sometimes different people get different kinds of immunity.
Finally, immunity isn’t static. Someone can develop sterilizing immunity right after an infection that fades to protective immunity later, or they might have protective immunity that fades to non-immunity. This can happen over a period of weeks or decades, depending on the pathogen. It’s the reason we need booster shots for some vaccines but not others, and it’s one reason elderly people can catch diseases they previously resisted.
Looking just at the immunology, then, we’re seeing tests that will give misleading answers that may be irrelevant or become incorrect over time.
Beyond the immunology, though, things get even scarier. Let’s hypothesize a future – at least many months from now – in which scientists have proven (with real data and peer-reviewed publications) that SARS-CoV-2 antibodies are protective, provide sterilizing, long-lived immunity, and can be detected with near-perfect sensitivity and selectivity by a cheap, rapid test. Governments start issuing wristbands (just like in the movie!) to people who test positive, and those folks can move about freely, get jobs, and generally resume normal life. The unfortunates who test negative, however, remain effectively unemployable and under house arrest. What do you think will happen?
Even as a virologist with a detailed understanding of the risks, I’d be sorely tempted to get myself infected as soon as possible. In fact, even discussing an immunity passport policy is going to encourage people to get ahead of the rush, because the consequences of being on the wrong side of such a social divide would be so dire.
Some commentators have suggested a more limited version of the passport, perhaps just for healthcare workers. But how would that work? Would a positive result change one’s job assignment, employability, pay, or work hours? How would the nurses’ union feel about that? And if immunity isn’t both long-lived and sterilizing, wouldn’t the positive result just increase a worker’s risk of being an asymptomatic carrier in the future?
The problems of immunology, scientific uncertainty, and sociology also interact. It’s quite possible, for example, that scientists could report robust immunity from antibodies, but then later discover that it fades over a period of months. If we’ve sent all the antibody-positive folks out to socialize, they’ll now be able to support a whole new round of infections and transmit the virus further.
None of this means that antibody tests are inherently bad. They are, in fact, a crucial tool for reopening the global economy. If, for example, we discover that over half of a city has already been infected, that – along with several other pieces of information – could support a gradual reopening. We could also start learning what we’ll need to know to keep the virus contained in the future. What type of immunity does infection confer, how reliably does it confer it, and how long does it last? We’ll need lots of data to answer those questions, and widespread antibody testing is the way to get those data. Finally, knowledge is empowering. This is a serious disease that could have long-term health consequences. People should be able to find out whether they’ve been infected.