Two new scientific preprints from the first two weeks of May look into how people who have never been exposed to the SARS-CoV-2, the scientific name for the novel coronavirus, might still have some form of immune response to it. It may seem counterintuitive that a blood sample taken before the novel coronavirus even appeared could have hints of potential immunity, but both papers point to the same suspect: other coronaviruses caught by humans. Specifically, the papers suggest that viruses behind some chest colds might leave behind at least a temporary immune response to COVID-19.
These works are far from definitive, but they are very interesting because they provide a possible answer to a number of issues, including why the response to COVID-19 varies from life-threatening to asymptomatic, why children rarely seem to get severe cases of the disease, and why some antibody tests seem to indicate that many more people have been exposed than other tests show.
Before we begin, here are two big caveats: First, both of these articles are in preprint. They may still be subject to change, or even withdrawal. Second, each of these papers contains information that is beyond my ability to properly evaluate and verify. To a large extent, I’m accepting the assertions of the authors, especially when it comes to the Cell paper, which requires a knowledge of immune system behavior that definitely does not linger from classes I last took in 1978. (Probably because it wasn’t even understood in 1978.) Okay, let’s continue:
T cells
The initial paper from Cell appeared on May 7 and comes from a team from UNC, UCSD, the La Jolla Institute for Immunology, and Mt. Sinai. They looked into an aspect of the immune system that is as important as antibodies, but gets far less coverage in the press: T cells. T cells are a type of white blood cell, or lymphocyte, that come from the thymus. Unlike some white blood cells, T cells are “adaptive.” That is, past exposures to proteins leave behind T cells that are prepped to respond if that protein is encountered a second time.
The team behind the Cell paper looked at two different kinds of T cells: CD8 cells, which go after cells that have been infected by a virus, and CD4 “helper” cells, whose main task is kicking off other parts of the immune response including signaling for production of more CD8 cells. These cells aren’t just behind a big part of the body’s effort to suppress viral infections, they’re also at the heart of a “cytokine storm” response that can cause a lot of damage—or even death—when the immune system overreacts to an intruder.
With that in mind, the team looked first at patients who had tested positive for active cases of COVID-19. In those patients, they found CD4 T cells with markers for the protein found on the “spike” of the SARS-CoV-2 virus, which is a critical component of how it enters cells. They also found markers for a number of other proteins including ones labelled M and N (I’m not going to bother to try to explain what those do). All three were found in 100% of the exposed samples. When it came to the CD8 T cells, the spike and M protein were again strongly indicated in all samples. N was a little less so.
This research alone has strong implications for anyone developing a COVID-19 vaccine because it suggests that these three proteins alone are likely enough for developing a strong, distinctive immune response. To be sure of a strong response, it would be good to use all three, and possibly a few others. The universality of these T cells is another good sign that long-term immunity to COVID-19 is a likely result of infection, and that effective vaccines are possible. So all good news.
But that was only the first step. The team then looked at samples of individuals who had definitely not been exposed to COVID-19, mostly because the blood samples were taking in 2018 or sooner when there was no COVID-19 virus (at least not in the human population). And here comes the moment that will (or already has) generate a thousand confusing tweets: 40% to 60% of unexposed samples had CD4 T cells that responded to the novel coronavirus. All of these samples showed indicators for a pair of “common cold” viruses that cause upper respiratory infections: HCoV-OC43 and HCoV-NL63. (The HCoV in both of these just stands for “human coronavirus.”) Both of these viruses are globally endemic, meaning they are widespread and common.
In particular, “non-spike specific” responses were above the limit of detection in 50% of the unexposed samples. That’s because while these other coronaviruses don’t share the same protein that SARS-CoV-2 uses to penetrate cells with its spike, they do have other proteins, like M and N, in common. Most discussion in the media—and much of the talk about vaccines—has focused on the spike protein, but the reaction to the M protein was just as strong in the samples examined by this team, with reactions to N not far behind. So it may be that these proteins are just as effective and important as the spike protein when it comes to an effective immune response.
(If you’re still with me at this point, grab a coffee or at least a deep breath, because we’re halfway. But trust me, it’s interesting.)
Antibodies
The second paper arrived on the preprint site bioRxiv on May 15. And while the Cell team might have been circumspect in discussing the possible implications of their results, the bioRxiv group goes for the jugular right in the title of this one: “Pre-existing and de novo humoral immunity to SARS-CoV-2 in humans.” Or, in slightly more quotidian language: They looked at the antibodies found in people who had not been exposed to the novel coronavirus and compared them to antibodies from those who had been exposed.
The list of authors here includes no fewer than 32 names, and the number of institutions involved is almost as varied, with a core team from University College, London. This sprawling team examined the contention that endemic human coronaviruses, like the ones from the Cell paper, might provide “Immune cross-reactivity” for SARS-CoV-2. Instead of looking at T cells, they went directly after antibodies … and they found them.
The work of the antibody group was based around a theory that infection by a number of human coronaviruses can provide a level of ”cross-protection, albeit transient” against other human coronaviruses. That is, catching one kind of cold virus may provide temporary protection against another kind, even if they are not the same virus, because the first virus may generate some antibodies that are still reactive against the second.
On an antibody basis, the spike protein was broken down into two “subunits.” One of these involved how the virus attached to the cells, while the other was more involved with how the virus entered the cell after attachment. Those samples from patients exposed to SARS-CoV-2 had a strong reaction for both subunits. When it came to the samples from those who had not been exposed, there was no sign of antibodies to that first part—the attachment subunit. However, antibodies to the second subunit were detectable. So were antibodies to some of the other portions of SARS-CoV-2, including the antibody counterpart to the N protein in the first paper. This was particularly true when the samples came from “individuals with recent HCoV infection.”
The conclusion of the antibody team isn’t only that patients who have had other human coronaviruses possibly share some immunity in the technical sense of just having antibodies, but this could have a very real effect on the outcome of cases. For example, they take note of a 60-year-old patient who tested positive for COVID-19 but whose case remained mild and whose antibodies, even after infection, looked more like that of a patient who had never been exposed. In fact, the patient appeared to be “chronically infected”—he had sporadic positive results to COVID-19 testing for over a month while never showing more than mild symptoms. The antibody team took this as confirmation of what they had been hypothesizing: Existing antibodies to HCoVs that shared some components with SARS-CoV-2 left behind at least some level of transient immunity that protected against the development of more severe disease.
In particular, their results showed a strong response of SARS-CoV-2 antibodies in people who had recently been infected by the “cold virus” HCoV-OC43—one of the two viruses that the T cell team pointed out as generating a response that overlapped with that of the novel coronavirus.
Conclusions
Both papers suggest that patients who have had other human coronaviruses—and in particular those who have recently had a chest cold caused by human coronavirus HCoV-OC43—have immune systems that are to some degree primed to fight off an infection by SARS-CoV-2. A study of that cold virus found it was generally connected to a mild upper respiratory infection … which is a lot better than having severe COVID-19.
- This virus, and others that share similar proteins and structures, are endemic and common. Infection by these viruses may be a major factor in why about 85% of those infected with COVID-19 have relatively mild cases while around 50% of that 85% appear to have cases that are very mild or asymptomatic.
- Testing of COVID-19 patients has indicated that a percentage of them—something on the order of 15% in at least two studies—have low levels of SARS-CoV-2-specific antibodies. These results have been correlated with those who have had mild cases, and may also be connected to those who have had recent infections by other human coronaviruses and acquired a higher level of transient immunity.
- Children may be more immune to COVID-19 at least in part because they are more likely to have a recent infection by HCoV-OC43, or a related coronavirus.
- The shared antibodies with other human coronaviruses may be part of the reason that antibody tests, including those conducted directly on patients and those looking at sources like antibodies found in waste, seem to so often suggest a higher level of infection than might be indicated by testing or medical outcomes.
- This might also explain why some group exposures form a hot spot while others don’t—in some cases, there may have been some “herd immunity” in effect, just from chance clusters of people carrying existing transient immunity.
None of this is certain—in this conclusion I’ve taken things at least half a logical leap beyond the position of either paper. But if substantiated, these results could go a long way toward explaining why the immune response to COVID-19 is so extremely varied.
These papers also strongly suggest that some people have at least a partial safety shield when it comes to developing a severe case of COVID-19. That cough you had back in December or January may not have been COVID-19, but it may save you from catching COVID-19.
But please—don’t test that.