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B-cell memory persistence: hints of stability in COVID immunity

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

There is still much uncertainty about exactly how the immune system responds to the SARS-CoV-2 virus. But what has become clear is that re-infections are still very rare, despite the ever-growing population of people who were exposed in the early days 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 complex and involves a number of different immune characteristics. It would be good to know who is involved in SARS-CoV-2, as this will allow us to better assess the protection offered by vaccines and previous infections and to better understand whether memory is at risk of fading. The earliest studies of this type included all very small populations, but now there is a couple who have found reasons for optimism, suggesting that immunity will last at least a year, and perhaps longer. But the picture is still not as simple as we would like.

Just a memory

The immune response requires coordinated activity of a number of cell types. There is an innate immune response that is triggered when cells feel infected. Different cells present pieces of protein to the immune cells to warn them of the invader̵

7;s identity. The cells produce antibodies, while different types of T cells perform functions such as coordinating the response and eliminating infected cells. During all this, various signaling molecules modulate the strength of the immune attack and cause inflammatory reactions.

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

And this is the focus of a large study published a few weeks ago. Nearly 190 people who had COVID-19 were recruited, and details of all these cells were obtained for periods as long as eight months after infection. Unfortunately, not everyone donated blood samples at any given time, so many populations were quite small; only 43 individuals provided data for six months after infection, for example. There was also a huge range of ages (age affects immune function) and the severity of the disease. So the results should be interpreted with caution.

Months after infection, T cells in this population still recognize at least four different viral proteins, which is good news in light of many variants of the protein that is being developed. T cells that specialize in eliminating infected cells (CD8-expressing T cells) are present, but have largely been converted into a memory-supporting form. The number of cells decreases over time, with a half-life of about 125 days.

Similar things have been observed in T cells, which are involved in coordinating immune activities (CD-4-expressing T cells). Here, for the total population of these cells, the half-life was about 94 days, and 92% of people who were tested six months after infection had memory cells of this type. A specialized subgroup that interacts with antibody-producing B cells appeared to be relatively stable, with almost all still having memory cells more than six months old.

So in general, as far as T cells are concerned, there are clear signs of memory establishment. Over time, it decreases, but not so fast that the immunity disappears within a year. However, for most of the cell types studied, there are some individuals in whom some aspects of memory appear to have disappeared at six months.

In the country

Like T cells, antibody-producing B cells can assume a specialized fate in memory; cells may also specialize in the production of various antibody subtypes. The first paper tracks both antibodies and memory cells. In general, antibody levels specific for the viral protein decreased after infection with a half-life of 100 days, the number of memory B cells increased during this time and remained on a plateau that began about 120 days after infection.

A second article published this week examines the trajectory of the antibody response in much more detail. Again, it included a fairly small population of participants (87 in this case), but observed for more than six months. Just under half of them had some long-term symptoms after the initial infections disappeared. As in the previous study, the levels of antibodies found by the researchers decreased in the months after infection, dropping by about a third to a quarter, depending on the type of antibody. Interestingly, people with persistent symptoms usually had higher levels of antibodies during this period.

But when the team examined the memory cells that produce antibodies, they noticed that the antibodies changed over time. There is a mechanism in memory cells by which parts of the genes that encode the antibody capture many mutations over time. By continuing to select those cells that produce antibodies with a higher level of affinity, this may improve the immune response in the future.

This appears to be the case in these patients after COVID. In the first sampling time, researchers identified the sequences of many of the genes that encode antibodies to coronavirus proteins. During the second test months later, they failed to find 43 of these original antibody genes. But 22 new ones resulting from the mutation process have been identified – within six months, the typical antibody gene has taken between two and three times the number of mutations. In some cases, the authors were able to identify the gene of the previous antibody that took mutations to create the one present at six months.

The system seems to be working. One of the early antibodies was unable to bind some of the variants of the protein that had evolved in some coronavirus strains. But substitutes with more mutations could, assuming they have a higher affinity for the jump protein than the earlier version. While the average antibody has similar affinities in the early and late moments, specific antibody lines see their ability to neutralize the growth of the virus.

The immune system has ways to preserve the thorn protein to select for improved antibody variants after clearing the infections, and this may be part of what is happening here. However, a number of participants (less than half of those tested) still had indications for active intestinal SARS-CoV-2 infections, although nasal tests were negative. So it is possible that at least part of the improved binding comes from prolonged exposure to the actual virus.

The big picture

Let’s emphasize again: both are 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, the consistency between these two studies is a step toward building 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 seems to work against SARS-CoV-2.

In addition, T-cell results, although more indicative, also suggest long-term immunity. But there the results are not so consistent, as different aspects of T-cell immunity continue to exist in different patients. The researchers divided the various aspects into five categories and found that less than half of the study population still had all five memory categories after five months. But 95 percent of them had at least three categories, which suggests the permanence of at least some memory. At this stage, however, we really do not understand what would provide protective immunity, so it is difficult to assess the significance of these results.

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

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