Antibodies may help, inflammation may hurt, but immunosuppressants are irrelevant?
Enlarge/ SOUTH TANGERANG, INDONESIA – JANUARY 7, 2021: A patient recovered from COVID-19 donates plasma at Indonesia Red Cross Transfusion Center.
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Vaccine trials have made clear that the immune system can mount a robust response to SARS-CoV-2. Beyond that, though, there are a lot of question marks. People exposed to the virus don’t always produce much in the way of antibodies to it, and there have been a number of cases of reinfection. We’re not sure how long immunity lasts or whether it correlates with antibody levels or something elsethere hasn’t even been great evidence that antibodies are helpful.
To give some sense of the challenge of sorting all of this out, we’re going to look at three recently published papers that get at the interplay between the immune system and COVID-19. One finally provides some evidence that antibodies might be protective, another indicates that tamping down the inflammatory response might help, while the third suggests that immunosuppressives don’t affect disease outcomes at all.
Antibodies are a relatively easy way to track an immune response, and they’ve been used for that throughout the pandemic. But early studies found the number of antibodies produced in response to an infection varied dramatically between patients. There have also been clinical trials testing whether using antibodies obtained from those formerly infected could help treat those suffering from COVID-19 symptoms, with the FDA eventually granting this a controversial Emergency Use Authorization. US President Donald Trump also received an experimental treatment of mass-produced SARS-CoV-2-specific antibodies.
The odd thing about this treatment is that we’re not certain that antibodies are actually protective. Further trials of antibody treatments for those infected have produced ambiguous results, with no clear benefit from receiving an antibody boost. And while immunity levels seem to correlate with antibody levels in some studies, we can’t be certain that the two aren’t both linked to some other aspect of immune functionperhaps antibody levels are simply a reflection of T-cell activity, to give one example.
A new paper from researchers in Argentina is small, but it hints that antibodies can help those with COVID-19but only if a treatment is administered early enough. The research design is solid: a randomized, blinded trial in which some people were given a transfusion of saline solution, while others had antibodies from those infected previously mixed in with their saline. Critically, all transfusions took place within a couple of days of the onset of COVID-19 symptoms. The only limitation of the trial is that it took place while case numbers were dropping in Argentina, so it was cut short once they had trouble recruiting patients.
Of the 160 patients that were enrolled, all over 65 years of age, and 25 of the 80 in the control group ended up with severe respiratory symptoms. In those who received the antibody-containing plasma, only 13 experienced these symptoms. Eliminating the six individuals who had to drop out of the study improved the numbers further. Finally, those who received plasma with the highest levels of antibodies in it tended to have an even better prognosis, although the number of patients here is even smaller still.
Those who received the plasma also tended to have fewer severe outcomes, such as admission to the ICU and need for ventilation. However, the numbers of each individual issue were all small, so none of these measures reached statistical significance.
The researchers note that, in a few other studies, those who received plasma treatments early tended to do better, but the overall population treated at different stages of the infection showed no effect. If this turns out to be rightand this study is small enough that it really needs to be replicatedthen it would present the first clear evidence that antibodies are helpful. That could be critical not only for the treatment of those who get infected, but in tracking immunity and monitoring risk in populations with various levels of vaccination.
The other lesson of the antibody study is that defining your treatment population carefullynewly symptomatic elderly, in this casemay be critical for identifying a clear effect, even though it can make it harder to find enough patients to do a thorough study. That lesson may also apply to a draft manuscript that describes a study of whether we can limit the effects of COVID-19 by tamping down on the inflammatory immune response. Studies of the genetics of COVID-19 patients had indicated that variations in some immune signaling molecules were associated with disease severity. But studies of drugs that blocked the effects of an inflammatory signaling molecule called interleukin-6 had shown no effect. The researchers suspected that this was because they accepted a wide range of patients.
So, to narrow things down, they started treatments with the interleukin-6 blockers as patients were admitted to the ICU. The trial enrolled about 800 people, about half of whom served as controls. The remainder received one of two different inflammatory blockers. Among those who didn’t receive a drug, the mortality rate was about 36 percent. For those who were treated, however, mortality was 27 percent.
That may not be an enormous difference, but if it holds up, it could make a significant difference in survival at the population level. And the UK’s National Health Service has already alerted its doctors of the results as it starts a re-evaluation of these drugs.
Is the immune system overrated?
All of this would seemingly place the immune system at the center of COVID-19 outcomes, which shouldn’t be in the least bit surprising. But another study published this week raises questions about even that. Here, researchers tracked the outcomes of over 2,000 COVID-19 cases that came through the Johns Hopkins medical system back in March. Of those, over 100 were taking drugs that left them immunocompromised. And when the outcomes of the patients were analyzed, there wasn’t a noticeable difference between those who were immunocompromised and the rest of the population. The researchers measured mortality, length of stay, and need for ventilation, but none of them were significantly different.
It’s important to emphasize that “immunosuppressed” does not mean “incapable of mounting any immune response.” But the response is generally quite limited.
What to make of all of this? The good news is that, if the antibody results hold up, they indicate that antibodies can provide us not only with a therapy for those at high risk of severe infection, but an easy way of tracking who might be protected in the future. Those results aren’t really confused by the results with immunocompromised individuals, since antibodies aren’t typically produced during an initial infection unless it drags on for a while (they take a few weeks to start appearing at measurable levels).
Beyond that, however, things get very complicated. The immune system has multiple aspects (T-cell based immunity, dendritic cells, innate immunity, etc.), and we don’t really know how many of these were fully suppressed in the immunocompromised individuals. In addition, if inflammation does turn out to be harmful in some cases, it’s possible that some forms of immunosuppression could actually be helpful.
But the big picture that these papers really drive home is that both the immune system and its interactions with this virus are extremely complex. If a study doesn’t have enough people to focus on specific patient populations or provide treatments at specific points during the infection, then there’s a chance that important effects will be averaged out. One problem is that, at this point, we’ve got many smaller, less focused studies already published, leading to an incomplete and confused picture. Finally, there’s undoubtedly a lot of patient-to-patient variability that confuses things further.
All of that explains why there’s so many confusing and seemingly contradictory publications out there. This confusion reinforces the need to avoid treating any single result as if it’s conclusive. Over time, we will build up a clearer picture of the course of a SARS-CoV-2 infection and the immune system’s response to it. Given the time that will take, however, the focus will undoubtedly be on rushing to get as many people vaccinated as quickly as possible.