There is still a lot of uncertainty about exactly how the immune system responds to the SARS-CoV-2 virus. But what has become clear is that reinfections are still very rare, despite an ever-growing population of people exposed in the early days of the pandemic. This suggests that, at least for most people, there is a 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 affected by SARS-CoV-2, as this would allow us to better assess the protection offered by previous vaccines and infections and to better understand whether memory is at risk of fading. All the first studies of this type involved very small populations, but now there is a couple who have found reasons for optimism, suggesting that immunity will last at least a year, perhaps longer. But the image is still not as simple as we would like.
Just a memory
The immune response requires the coordinated activity of several types of cells. There is an innate immune response that is triggered when cells feel they are infected. Several cells present pieces of protein to the cells of the immune system 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 eliminating infected cells. Throughout this, a variety of signaling molecules modulate the strength of the immune attack and induce inflammatory responses.
Some of these same pieces are recruited into the system that preserves the memory of the infection. This includes different types of T cells that are converted to memory T cells. Something similar happens with antibody-producing B cells, many of which express specialized antibody subtypes. Fortunately, we have the means to identify the presence of each one.
And that is the focus of a large study published a few weeks ago. About 190 people who had COVID-19 were recruited, and details about all of these cells were obtained for periods of up to eight months after infection. Unfortunately, not everyone donated blood samples at all points of time, so many of the populations were very small; only 43 individuals provided the data for six months after infection, for example. There was also a wide range of ages (age influences immune function) and the severity of the disease. Therefore, the results should 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 of the variants in the peak protein that have evolved. T cells specialized in eliminating infected cells (CD8-expressing T cells) were present, but had been largely 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 that are involved in the coordination of immunological activities (T cells that express CD-4). Here, for the general population of these cells, the half-life was about 94 days, and 92% of the people who were examined six months after the infection had such memory cells. A specialized subset that interacts with antibody-producing B cells appeared to be relatively stable, with almost all of them still having memory cells in more than six months.
So in general, as far as T cells are concerned, there are clear signs of memory establishment. It decreases over time, but not so quickly that immunity decreases in one year. However, for most cell types examined, there are some individuals where some aspects of memory appear to have disappeared by six months.
The B side
Like T cells, antibody-producing B cells can adopt a specialized memory destination; cells can also specialize in producing a variety of antibody subtypes. The first study tracked antibodies and memory cells. Overall, levels of specific antibodies to the viral protein spike fell after infection with a half-life of 100 days, the number of memory B cells increased over that time and remained at a plateau that started about 120 days after infection.
A second article, published this week, looked at the path of the antibody response in much more detail. Again, it involved a very small population of participants (87 in this case), but monitored for more than six months. A little less than half of them experienced 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 from a third to a quarter, depending on the type of antibody. Interestingly, people with continuous symptoms tend to have higher levels of antibodies during this period.
But when the team looked at antibody-producing memory cells, they noticed that the antibodies were changing over time. In memory cells, there is a mechanism by which parts of the genes that encode the antibody acquire many mutations over time. By continuing to select cells that produce antibodies with a higher level of affinity, this can improve the immune response in the future.
This seems to be exactly what is happening in these post-COVID patients. In the first moment of sampling, the researchers identified the sequences of many of the genes that encode antibodies against coronavirus proteins. At the time of the second scan months later, they were unable to find 43 of those early antibody genes. But 22 new ones were identified, emerging from the mutation process – in six months, the typical antibody gene had acquired between two and three times the number of mutations. In some cases, the authors were able to identify the ancestral antibody gene that took the mutations to create the gift at six months.
The system seems to be working. One of the first antibodies was unable to bind to some of the variants of the spike protein that evolved in some strains of coronavirus. But substitutions with more mutations did, suggesting that he had a greater affinity for the spike protein than the previous version. While the average antibody had similar affinities at the start and end time points, specific antibody strains saw its ability to neutralize the increase in the virus.
The immune system has ways of preserving the peak protein to select for improved antibody variants after infections are eliminated, and that may be part of what is happening here. But in several participants (less than half of those tested), there were still indications of active infections of SARS-CoV-2 in the intestine, although the nasal tests were negative. Therefore, it is possible that at least part of the enhanced link comes from continuous exposure to the real virus.
The big picture
Let’s emphasize again: these are two small studies and we really need to see them replicated with larger populations and a more consistent sample. But, at least when it comes to antibodies, the consistency between these two studies is a step towards building confidence in the results. And these results are very good: clear signs of long-term memory and that the immune system’s ability to improve its defenses appears to be working against SARS-CoV-2.
In addition, T cell results, while more provisional, also seem to suggest long-term immunity. But there, the results are not as consistent, with 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 the 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. However, at this point, we don’t really understand what would provide protective immunity, so it is difficult to judge the significance of these results.
Science, 2021. DOI: 10.1126 / science.abf4063
Nature, 2021. DOI: 10.1038 / s41586-021-03207-w (About DOIs).