B cell memory: understanding COVID-19

Abstract

Immunological memory is a mechanism to protect us against reinfection. Antibodies produced by B cells are integral to this defense strategy and underlie virtually all vaccine success. Here, we explain how B cells memory is generated by infection and vaccination, what influences its efficacy and its persistence, and how characterizing these parameters in the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will help achieve protective immunity through vaccination.

Figure 1

Generating protective antibody-mediated memory: the germinal center reaction The initiation of a GC response takes place within a secondary lymphoid organ. Following T-B cell interaction, B cells rapidly proliferate, change their Ab class (isotype, e.g., IgM to IgG or IgA) and give rise to early PBs producing low-affinity Ab. At the same time, some cells will exit the immune response to become pre-GC MBCs. Remaining B cells go on to initiate and participate in the GC reaction where iterative cycles of proliferation, mutation, and selection increase the average antigen binding strength of the B cell receptors (affinity maturation). Throughout the response, some B cells will differentiate into short-lived PBs (secreting the now affinity-matured Abs), long-lived PCs, and MBCs. Upon recall, and if PC-derived Abs are insufficient for protection, both pre-GC and GC-derived MBCs can rapidly differentiate into PBs or initiate secondary GC responses together with mTfh. Ab, antibody; PB, plasmablast; PC, plasma cell; MBC, memory B cell; GC, germinal center; Tfh, follicular helper T cell; mTfh, follicular helper memory T cell.

Figure 2

Protective mechanisms of antibody-mediated memory during reinfection In an infection primarily controlled by Abs, protective immunity depends on the quantity and quality of available Abs, MBCs, and mTfh cells. The presence of sufficiently high amounts of neutralizing Abs will result in sterilizing immunity, negating the requirement for a recall response. If the production of neutralizing Abs is insufficient or has waned and is thus exceeded by the pathogen load, an infection will occur. The remaining neutralizing Abs will still limit the extent of infection, and both neutralizing and non-neutralizing Abs will facilitate the initiation of secondary immune responses by increasing the visibility of the pathogen to the IS (opsonization). If circulating Abs have dropped below effective levels, the initial pathogen entry can occur largely unchecked, resulting in an infection of increased speed and magnitude before MBCs and mTfh cells can provide protection via a recall response. In some cases, Ab memory may completely dissipate, resulting in susceptibility to full-blown infection and the requirement for a primary immune response. Ab, antibody; PB, plasmablast; MBC, memory B cell; GC, germinal center; mTfh, follicular helper memory T cell.

Figure 3

Immune response kinetics influence Ab diversity, affinity, and memory formation (A) The initial diversity of B cell reactivities participating in an immune response is high, while their antigen binding affinity is generally low. During this pre-GC phase, pre-GC MBCs and short-lived PBs differentiate (producing low-affinity Abs). Once the GC reaction commences, affinity-based selection results in an increase in Ab affinity, while the diversity of targeted epitopes decreases. This is due to limited availability of resources (e.g., antigen, T cell help) that favors dominant epitopes to which high-affinity Abs can be rapidly generated. Once the GC reaches maximal Ab affinity, the response starts to re-diversify, now allowing more sub-dominant epitopes to be targeted. The probability of generating high-affinity neutralizing Abs increases rapidly during the first phase of the GC reaction, but BN-Abs often require prolonged immune responses due to their epitopes being sub-dominant. The response output is as staged: early on, rapid PB generation and MBC differentiation, while later, once affinity increases, long-lived PC generation. (B) The immune response following vaccination is usually short lived, with the magnitude depending on the individual’s immune system. To achieve vaccine efficacy in a large fraction of the population, booster vaccination is often applied, recalling the memory cells already generated. The increased magnitude and duration of a secondary response improves memory generation to the point of sufficient quantity and quality for protection. GC, germinal center; Ab, antibody; BN-Ab, broadly neutralizing Ab; MBC, memory B cell; mTfh, follicular memory T cell; PB, plasmablast; PC, plasma cell. (^∗ when most mTfh differentiate is still largely unknown)