The persistence of memory in B cells: indices of stability in COVID immunity



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Cartoon diagram of some of the immune system cells.
Enlarge / The immune response involves many moving parts.

There is still a lot of uncertainty about how exactly the immune system responds to the SARS-CoV-2 virus. But what has become clear is that re-infections are still very rare, despite an ever-growing population of people who were exposed at the start of the pandemic. This suggests that, at least for most people, there is some degree of long-term memory in the immune response to the virus.

But immune memory is complicated and involves a number of distinct immune characteristics. It would be good to know which ones are caused by SARS-CoV-2, because it would allow us to better judge the protection offered by vaccines and previous infections, and to better understand whether the memory is likely to fade. The first such studies were all in very small populations, but there are now a few that have found reasons for optimism, suggesting that immunity will last at least a year, and possibly longer. But the picture is still not as simple as we might like.

Only a memory

The immune response requires the coordinated activity of a number of cell types. There is an innate immune response that is triggered when cells sense they are infected. Various cells present pieces of protein to immune cells to alert them to the identity of the invader. B cells produce antibodies, while different types of T cells perform functions such as coordinating the response and clearing infected cells. In all of this, a variety of signaling molecules modulate the strength of the immune attack and induce inflammatory responses.

Some of these same parts are recruited into the system that preserves the memory of the infection. These include different types of T cells which are converted into memory T cells. A similar thing happens with antibody-producing B cells, many of which express specialized subtypes of antibodies. Fortunately, we have the means to identify the presence of each of them.

And that’s the subject of a major study that was published a few weeks ago. Nearly 190 people who have had COVID-19 have been recruited and details of all of these cells have been obtained for periods of up to eight months after infection. Unfortunately, not everyone donated blood samples at all times, so most populations were quite small; only 43 people provided the data for six months after infection, for example. There was also a wide range of ages (age influences immune function) and disease severity. The results should therefore be interpreted with caution.

Months after infection, T cells in this population still recognized at least four different viral proteins, which is good news in light of many variants of the spike protein that have evolved. T cells specialized in removing infected cells (CD8 expressing T cells) were present but had largely been converted into a form of memory maintenance. The number of cells decreased over time, with a half-life of approximately 125 days.

Similar things have been observed with T cells involved in the coordination of immune activities (T cells expressing CD-4). Here, for the general population of these cells, the half-life was around 94 days, and 92 percent of people tested six months after infection had memory cells of this type. A specialized subset that interacts with the antibody-producing B cells appears to be relatively stable, with almost everyone still having memory cells over six months old.

So overall, when it comes to T cells, there are some clear signs that memory is being established. It decreases over time, but not so quickly that immunity would go away within a year. However, for most of the cell types examined, there are individuals for whom some aspect of memory appears to have disappeared by six months.

Side B

Like T cells, antibody-producing B cells can take on a specialized memory fate; cells can also specialize in producing various subtypes of antibodies. The first article followed both antibodies and memory cells. Overall, levels of antibodies specific to the viral spike protein fell after infection with a half-life of 100 days, the number of memory B cells increased during this period and remained at a plateau. which started about 120 days after infection.

A second article, published this week, examined the trajectory of the antibody response in much more detail. Again, it involved a fairly small population of participants (87 in this case), but monitored for over six months. Just under half of them exhibited long-term symptoms after their initial infections cleared. As with the previous study, the levels of antibodies found by researchers declined in the months following infection, from a third to a quarter, depending on the type of antibody. Oddly enough, people with persistent symptoms tended to have higher levels of antibodies during this time.

But when the team looked at the antibody-producing memory cells, they noticed that the antibodies changed over time. In memory cells, there is a mechanism by which parts of the genes that code for the antibody pick up many mutations over time. By continuing to select cells that produce antibodies with a higher affinity level, it may improve the immune response in the future.

This appears to be exactly what is happening with these post-COVID patients. During the first sampling, the researchers identified the sequences of many genes encoding antibodies against the proteins of the coronavirus. By the time of the second check months later, they couldn’t find 43 of these original antibody genes. But 22 new ones were identified, resulting from the mutation process – at six months, the typical gene for the antibody had picked up between two and three times the number of mutations. In some cases, the authors were able to identify the ancestral antibody gene that picked up mutations to create the one present at six months.

The system seems to be working. One of the first antibodies was unable to bind to some of the spike protein variants that have evolved in some strains of coronavirus. But replacements with more mutations could, suggesting it had a greater affinity for the spike protein than the previous version. While the average antibody had similar affinities at the early and late time points, specific antibody lines increased their ability to neutralize the virus.

The immune system has ways of preserving the spike protein to select for improved antibody variants after infections are cleared, and that may be part of what’s going on here. But in a number of participants (less than half of those tested), there were still indications of active SARS-CoV-2 infections in the gut, even though nasal tests came back negative. It is therefore possible that at least part of the enhanced binding results from continued exposure to the actual virus.

The big picture

Again, these are two small studies, and we really need to see them replicated with larger populations and more consistent sampling. But at least when it comes to antibodies, consistency between these two studies is a step towards confidence in the results. And these results are pretty good: clear signs of long-term memory and that the immune system’s ability to sharpen its defenses appears to be working against SARS-CoV-2.

Beyond that, the T cell findings, while more tentative, also seem to suggest long-term immunity. But here the results are not as consistent, different aspects of T cell immunity persisting in different patients. The researchers divided the different aspects into five categories and found that less than half of their study population still had all five categories of memory present after five months. But 95 percent of them had at least three categories present, suggesting the persistence of at least some memory. At this point, however, we don’t really understand what would provide protective immunity, so it’s hard to judge what these findings mean.

Science, 2021. DOI: 10.1126 / science.abf4063
Nature, 2021. DOI: 10.1038 / s41586-021-03207-w (About DOIs).

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