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Different memory cells against SARS-CoV-2

In the early stages of infection by SARS-CoV-2 we mainly develop antibodies targeting the N protein (nucleocapsid, responsible for organisation of the viral genome) and the S protein (spike, responsible for the binding of the virus to the cell). Some of these are neutralizing, meaning that they target the spike and block its interaction with the cellular receptor. These antibodies are produced by B cells specific to the virus. During the primary infection, naïve B blood cells, which have never encountered pathogens, are activated by the presence of the virus. They gravitate towards the germinal centres (spleen, lymph nodes) to mature and to undergo mutations that will improve their effectiveness against the virus. Finally, they become either antibody-producing cells that go back into the circulation but last only a short time, or B-memory cells that can sometimes last a lifetime.

Long-term immunity depends mainly on the memory B-cells (MBC) which can, after contact with the virus, produce B cells with a brief life-span, as well as MBCs, which keep the pool intact. This process takes place primarily outside the germinal centres (extrafollicular activation), but these MBCs can also adapt to new variants if necessary. With regard to responses to COVID-19, the question of long-term protection is still subject to debate since there are several contradictory studies. For example, some studies suggest that long-term antibody response to seasonal coronaviruses does not exist. Others suggest that in severe cases, the functioning of germinal centres is altered, blocking the production of MBCs.

It is crucial to understand the longevity and functioning of MBCs to know if natural infection or vaccination offers long-term protection. To investigate this question, French teams at the Necker Hospital in Paris and the Henri Mondor Hospital in Créteil carried out a 6 month study on anti-spike MBCs in two distinct cohorts of COVID-19 patients, moderate cases (18 subjects, hospital staff) and severe cases (21 subjects, receiving oxygen). The researchers undertook a huge amount of work by using a combination of classical approaches (RT-PCR, ELISA, flow cytometry and cell sorting, sequencing, neutralization tests). In addition they carried out analysis at a cellular level in order to be able to precisely characterise the B-cell populations and the antibody sequences they were expressing.

They showed that the population of anti-spike MBCs is remarkably stable over longer than 6 months and that it originates from naïve cells activated by SARS-CoV-2. In these patients, the germinal centres are fully active, which suggests long-term MBC production. This population was even found to be expanding in severely affected patients. What is interesting is that the researchers characterized two distinct MBC populations: one specific to  current SARS-CoV-2, from maturation in germinal centres; and the other pre-existent, having undergone numerous mutations and deriving from previous infection by common coronaviruses. This latter population allows cross-reaction between the common coronaviruses and SARS-CoV-2, probably targeting conserved spike domains.

However this population declines between 3 and 6 months after infection by SARS-CoV-2, probably due to it being little called upon. It was observed that the more severe the pathology, the stronger and more stable the memory-response. The researchers believe, in common with the conclusions of other studies, that these cells remain active through the persistence of viral proteins in certain zones.

This can be represented schematically as follows:

This study shows that in the majority of non-critical cases, SARS-CoV-2 can prompt an immediate antibody response, providing possible protection thanks to previous infections from seasonal coronaviruses. Then continued maturation of memory B-cells takes place in germinal centres, producing neutralizing antibodies that are more and more effective over the long term.

These observations are very positive with regard to current vaccination campaigns. But the results need to be confirmed in larger cohorts where age factors and pre-existing conditions can be taken into account. The duration of longer-term protection remains to be defined.

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