Enlarge /. SOUTH TANGERANG, INDONESIA – JANUARY 7, 2021: A patient recovered from COVID-19 donates plasma at the Indonesian Red Cross Transfusion Center in South Tangerang.
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It is clear that the immune system can show a robust response to SARS-CoV-2, as the vaccine trials have made clear. Beyond that, however, there are many question marks. People exposed to the virus do not always make high levels of antibodies to the virus, and there have been a number of reinfection cases. We're not sure how long immunity lasts, or whether it correlates with antibody levels or anything else – there isn't even good evidence that antibodies are helpful.
To get a sense of the challenge of clearing all of this up, we're going to look at three recently published articles examining the interplay between the immune system and COVID-19. Finally, one provides some evidence that antibodies might be protective, another suggests that curbing the inflammatory response might be helpful, while the third suggests that immunosuppressants may not affect disease outcomes at all.
Antibodies are a relatively easy way to track an immune response, and they have been used for this throughout the pandemic. However, early studies found that the number of antibodies produced in response to infection varied dramatically between patients. Clinical studies have also been conducted to test whether the use of antibodies obtained from previously infected people can help treat patients with COVID-19 symptoms. The FDA eventually gave it a controversial emergency approval. President Trump also received experimental treatment for mass-produced SARS-CoV-2 specific antibodies.
The strange thing is that we're not sure if antibodies are actually protecting. Further attempts with antibody treatments for infected people have led to ambiguous results, with no clear benefit from an antibody boost. And while immunity levels seem to correlate with antibody levels in some studies, we can't be sure that the two are not both linked to some other aspect of immune function – perhaps antibody levels simply reflect T cell activity, for example.
A new paper from researchers from Argentina is small, but it suggests that antibodies can help those with COVID-19 – but only if treatment is given early enough. The research design is solid: a randomized, blinded study in which some people received a saline transfusion while others had antibodies from those who had previously been mixed with their saline solution. From a critical point of view, all transfusions took place within a few days of the onset of COVID-19 symptoms. The only caveat to the study is that it took place while case numbers in Argentina were declining. Therefore, it was canceled as soon as they had problems recruiting patients.
Of the 160 patients over 65 years of age included, 25 of the 80 in the control group had severe respiratory symptoms. Only 13 of these symptoms occurred in those who received the antibody-containing plasma. By eliminating the six people who had to drop out of the study, the numbers continued to improve. Finally, those who received plasma with the highest antibody levels tended to have an even better prognosis, although the number of patients here is even smaller.
Those who received the plasma also tended to have less severe outcomes, such as ICU admission and the need for ventilation. However, the number of individual expenditures was small, so that none of these measures achieved statistical significance.
The researchers note that in some other studies, those who received early plasma treatments tended to do better, but the overall population treated at different stages of infection showed no effect. If this turns out to be correct – and this study is small enough that it really needs to be replicated – it would provide the first clear evidence that antibodies are helpful. This could be vital not only for treating those infected, but also for tracking immunity and monitoring risk in populations with different levels of vaccination.
The other lesson from the antibody study is that carefully defining your treatment population – in this case newly symptomatic elderly – can be critical to identifying a clear effect, although it can be more difficult to find enough patients for a thorough study . This lesson can also apply to a draft manuscript describing a study on whether we can limit the effects of COVID-19 by suppressing the inflammatory immune response. Studies of the genetics of COVID-19 patients had shown that variations in some immune signaling molecules were linked to disease severity. However, studies of drugs that blocked the action of an inflammatory signaling molecule called interleukin-6 had shown no effect. The researchers suggested that this was because they were accepting a wide range of patients.
To narrow the situation down, they started treatment with the interleukin-6 blockers when the patients were admitted to the intensive care unit. About 800 people took part in the study, about half of whom served as controls. The rest received one of two different anti-inflammatory drugs. Among those who did not receive the drug, the death rate was about 36 percent. For those treated, however, the mortality rate was 27 percent.
That might not be a huge difference, but if it holds up it could make a significant difference in population survival. And the UK's National Health Service already informed its doctors of the results when it began re-evaluating these drugs.
Is the Immune System Overrated?
All of this would apparently put the immune system at the center of COVID-19 results, which shouldn't be the least bit surprising. But another study published this week also raises questions about this. Here, researchers tracked the results of over 2,000 COVID-19 cases that came through the Johns Hopkins medical system in March. Of these, over 100 were taking drugs that made them immune to weakness. And when the patients' results were analyzed, there was no noticeable difference between those who were immunocompromised and the rest of the population. The researchers measured mortality, length of stay, and ventilation needs, but none of them were significantly different.
It is important to emphasize that "immunocompromised" does not mean "unable to develop an immune response". However, the response is generally quite limited.
What should you do with it? The good news is that antibodies, if they persist, indicate that antibodies can not only provide us with therapy for those at high risk of serious infections, but also an easy way to track who will be protected in the future could be. These results are not really confused by the results in immunocompromised individuals, as antibodies are usually not produced during an initial infection unless they drag on for a while (they take a few weeks to show up in measurable amounts).
But beyond that, things get very complicated. The immune system has several aspects (T-cell-based immunity, dendritic cells, innate immunity, etc.) and we don't really know how many of these have been completely suppressed in immunocompromised individuals. Additionally, if inflammation proves harmful in some cases, it is possible that some forms of immunosuppression are actually helpful.
But the big picture that these papers really bring home is that both the immune system and its interactions with this virus are extremely complex. If there are not enough people in a study to focus on certain patient populations or to perform treatments at certain points during the infection, there is a chance that important effects will be averaged out. One problem is that by this point in time, many smaller, less focused studies have been published, leading to an incomplete and confused picture. After all, there is undoubtedly a great deal of patient-to-patient variability which further confuses things.
All of this explains why there are so many confusing and seemingly contradicting publications. It reinforces the need to treat each and every result as conclusive. Over time, we will create a clearer picture of how SARS-CoV-2 infection is progressing and how the immune system is responding to it. Given the time it will take, the focus will undoubtedly be on getting as many people as possible vaccinated as soon as possible.