The fundamental challenge of dealing with this pandemic is uncertainty. There are just too many important things that we don’t know – and what’s more, they aren’t easy to find out, either. We’ve seen that with the waves of optimism and pessimism about various therapies, just to pick one. As everyone has been learning (if they didn’t know it before!), getting solid clinical data is not easy. The good numbers don’t come quickly and they don’t come cheaply, and data that are fast and cheap tend not to be any good.
That uncertainty extends deep into the biology of the disease. Let’s illustrate that with a look at a paper that’s come out recently that has shaken a lot of people up. It’s a valuable look at a controversial topic: people who have definitely been infected with the coronavirus, but who are asymptomatic. There are very important questions about this situation, among them how infectious such patients are and for how long, what might be different in their immune response as compared to people who become more overtly ill, and how the longer term effects on immunity might differ as well. And not least: how many such asymptomatic patients are there in general, and are they more common among some parts of the population than others? All of these questions are very important to our understanding of the pandemic and our responses to it, and none of them are as well-worked-out as we need them to be.
This group (from China) looked at 37 patients who tested positive (by RT-PCR) for coronavirus infection, but who had not displayed symptoms before testing (and continued to show none during subsequent monitoring), and compared them to the more well-studied symptomatic patients. One thing that stands out from a public health perspective is that the asymptomatic group had a much longer period of viral RNA shedding. That is not what one would have wanted to hear, since these are the people who are walking around without realizing that they’re sick at all.
But it’s also important to realize that this report, as with so many reports of viral shedding, it looking at it by detection of viral RNA. That does not mean that there is infectious virus present. (This distinction has confused a great number of reports about the persistence of the virus on surfaces as well). We still don’t know how long infected patients (symptomatic and asymptomatic) are shedding infectious virus – those are far harder data points to obtain than just detecting viral RNA. I should note that this goes for the recent reports, which were all over the media, about the possibility of spreading coronavirus through flushing toilets. Now, I think that closing the toilet lid is a pretty good precaution, because it’s an easy enough thing to do. But the spread of infectious virus through toilet aerosols has not been proven, to the best of my knowledge. You can find viral RNA in sewage, and monitoring it could be a useful public health measure in water-treatment plants. But infectious virus is something else again.
Now, when you hear of patients who are infected but are showing no symptoms, you could have a mental picture of a stronger immune response that’s keeping the virus knocked down more. But it’s clearly not that simple: this paper shows that the asymptomatic patients had a weaker antibody response that tended to disappear during the convalescent phase. That’s the result that’s gotten a lot of attention – as it should – although it’s important to not run with it too quickly. Remember, there is more than one type of immune response – you have T cells pitching in as well. That response is one of the great unanswered questions of the epidemic, from what I can see. We already have data about some of the T cell responses in symptomatic infected patients as compared to uninfected ones, and one of the most intriguing things about that earlier work was the finding that 40 to 60% of those uninfected people had CD4+ T cells that appear to already recognize the new coronavirus. The speculation is that this could be immune memory of past infections with other coronaviruses (such as the ones that can cause common-cold illnesses), and that they are cross-reacting with the current pathogen. (Update: from the comments, this work that raises the possibility that the T-cell response is from zoonotic coronavirus infections that we hadn’t appreciated). That’s very much in contrast to the antibody situation in uninfected patients – it seems clear that the human population had raised no circulating antibodies to the new coronavirus before the advent of this pathogen. Prior infection with other coronaviruses does nothing for you on the antibody side.
And that’s the missing piece from this new work. It is possible that these asymptomatic patients are showing a weak antibody response because they already had a more robust T-cell response ready to go. Now, this hypothesis could be wrong, but it has to be tested. In the same way, it’s possible that there is a percentage of the population that, because of their T-cell profile, are more likely to have only such an asymptomatic infection or perhaps to not become infected at all. That’s a very important thing to clear up, but it’s unfortunately a lot more labor-intensive to profile CD4+ and CD8+ T cells in people than it is to profile their antibody responses. This applies to the vaccines under development as well: T cell effects are an important component of vaccine efficacy, but there’s a lot that we don’t understand about how various vaccines raise such responses. There have been many reports of recovered patients who never seem to have raised much of an antibody response at all, and it’s not yet clear how they cleared the virus: was it the innate immune response that did the job before the adaptive system kicked in, particularly in younger patients? Was it the T-cell response instead? We just don’t know yet.
So my advice is not to panic, but not to be complacent, either. The complexities of the immune system mean that we have a whole range of possible situations in how this pandemic is unfolding. At the most optimistic end, it is possible that a larger percentage of the population than we realize might already be protected (to some degree) from the coronavirus. Unfortunately, it’s also possible that almost everyone is, in fact, still vulnerable and that we just haven’t seen the virus run through most of the population yet. Everyone will have seen the various population surveys with antibody testing that have suggested, in most cases, that a rather small percentage of people have been exposed. Think of the various ways you could get such a result: (1) it’s just what it looks like, and most people are unprotected because they have so far been unexposed. (2) the antibody results are what they look like – low exposure – but people’s T-cell responses mean that there are actually more people protected than we realize. (3) the antibody results are deceiving, because (as this latest paper seems to show) the antibody response fades over time, meaning that more people have been exposed than it looks like. And that means you can split that into (3a) the antibody response fades, but the T-cell response is still protective and (3b) the antibody response fades and so does the T-cell response. That last one is not a happy possibility.
You can extend this thinking to the effects of the coming vaccines. The protective effects of the antibody response versus the T-cell response are going to be important to figure out, of course. And keep in mind, the timelines that we’re seeing do not allow for time to see how quickly either of these responses might fade. So we could be in a situation where people would have to get re-vaccinated with a different agent after a few months when some of this comes into better focus. There’s no particular reason why the first workable vaccine to make it through trials should be the best long-term answer, but we also don’t know how much these things are going to vary, either.
So we need to take this new paper and its results about antibody persistence seriously, but we also need to keep our eye on the T-cell situation as well. We’re not going to know the whole picture until we know more about both of those. And in the end, we’re not going to know about the protective effects of recovery from a coronavirus infection, or the protective effects of being vaccinated against it, until enough time has passed in a large population of both cohorts. You’d want a faster, less difficult readout for those things, but I’m just not sure that there is one.