The germinal centre B cell response to SARS-CoV-2

Abstract

The germinal centre (GC) response is critical for the generation of affinity-matured plasma cells and memory B cells capable of mediating long-term protective immunity. Understanding whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or vaccination elicits a GC response has profound implications for the capacity of responding B cells to contribute to protection against infection. However, direct assessment of the GC response in humans remains a major challenge. Here we summarize emerging evidence for the importance of the GC response in the establishment of durable and broad immunity against SARS-CoV-2 and discuss new approaches to modulate the GC response to better protect against newly emerging SARS-CoV-2 variants. We also discuss new findings showing that the GC B cell response persists in the draining lymph nodes for at least 6 months in some individuals following vaccination with SARS-CoV-2 mRNA-based vaccines.

Fig. 1. B cell response to SARS-CoV-2 infection.

a | Severe infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a robust extrafollicular response but an impaired germinal centre (GC) B cell response in some individuals. Antigen-engaged B cells differentiate into memory B cells and short-lived plasmablasts that give rise to antibodies with a low level of somatic hypermutation. b | Mild SARS-CoV-2 infection induces both an extrafollicular response and GC B cell response. The GC B cell response gives rise to affinity-matured memory B cells and long-lived plasma cells. c | There is an increase in the number of SARS-CoV-2-specific memory B cells over time following mild infection. Memory B cells derived from the GC undergo continued clonal evolution for at least 1 year, with memory B cells found at later time points displaying increased levels of somatic hypermutation and encoding antibodies with enhanced neutralizing activity and breadth. The SARS-CoV-2-specific antibody titre decreases over the first 6 months following infection owing to the loss of antibodies derived from short-lived plasmablasts. The loss in protection attributable to this decrease in antibody titre is partially offset by a per antibody increase in neutralizing titre and breadth, likely owing the emergence of clonally evolved plasma cells from the GC. T_FH cell, T follicular helper cell.

Fig. 2. Germinal centre B cell response to SARS-CoV-2 vaccination.

a | The first dose of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA-based vaccine induces a robust germinal centre response that gives rise to plasma cells and memory B cells in previously uninfected individuals. Primary immunization induces a significant increase in the number of SARS-CoV-2-specific antibodies, with about half of individuals developing neutralizing antibodies. However, these antibodies are largely unable to neutralize SARS-CoV-2 variants. b | The second dose of the SARS-CoV-2 mRNA-based vaccine induces a significant increase in the antibody response in previously uninfected individuals. Antibodies derived from the secondary immunization have robust neutralizing activity, although there is a decrease in the ability to neutralize SARS-CoV-2 variants compared with the wild-type (D614G) virus. c | The first dose of the SARS-CoV-2 mRNA-based vaccine induces a significant increase in the antibody response in individuals who have recovered from previous SARS-CoV-2 infection. Antibodies induced by primary immunization have robust neutralizing activity, with equivalent ability to neutralize wild-type and variant viruses. The number of pre-existing SARS-CoV-2-specific memory B cells strongly correlates with the magnitude of the antibody response following vaccination. d | The second dose of the SARS-CoV-2 mRNA-based vaccine does not induce any further increase in antibody titre or neutralizing activity in individuals who have recovered from previous SARS-CoV-2 infection. T_FH cell, T follicular helper cell.

Fig. 3. The germinal centre B cell response at 30 weeks following vaccination.

Following vaccination with the Pfizer–BioNTech severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA-based vaccine, the fraction of B cells in the axillary lymph node that are spike protein-reactive germinal centre (GC) B cells increases rapidly. This population further increases upon administration of a second vaccine dose (indicated by the dotted line) and is stably maintained for at least 15 weeks. We have now found that 10 of 15 individuals tested maintain a persistent spike protein-reactive GC B cell response at 30 weeks after vaccination, with the remaining five individuals having no detectable response at this time point. This finding indicates that there is heterogeneity in the longevity of the GC response elicited by vaccination.

Fig. 4. Memory B cell subset development and function.

a | During an immune response, memory B cells emerging from the early germinal centre (GC) response are predominantly CD80⁻PDL2⁻. As the GC response matures, memory B cells begin to express PDL2 and CD80, with the memory B cells emerging from the late GC response predominantly being CD80⁺PDL2⁺. b | Upon antigen re-encounter, CD80⁻PDL2⁻ memory B cells predominantly differentiate into GC B cells, CD80⁻PDL2⁺ memory B cells differentiate into either GC B cells or plasma cells and CD80⁺PDL2⁺ memory B cells differentiate into plasma cells. c | A memory B cell population that is skewed towards CD80⁻PDL2⁻ memory B cells would be predisposed to differentiate into GC B cells upon antigen re-encounter. This response would promote the development of neutralizing antibodies to variant viruses but would generate a delayed response to wild-type viruses. d | A memory B cell population that is skewed towards CD80⁺PDL2⁺ memory B cells would be predisposed to differentiate into plasma cells upon antigen re-encounter. This response would promote the rapid clearance of wild-type viruses but would result in a delay in the induction of antibodies capable of neutralizing variant viruses. The dotted line in the plots on the right in parts c and d indicates the viral load necessary to enable spread of the virus to uninfected individuals. T_FH cell, follicular helper T cell.

Fig. 5. The B cell response following mucosal infection.

a | Viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza virus infect respiratory epithelial cells, leading to uptake of antigens by antigen-presenting cells (APCs). Activated APCs migrate to the draining lymph node, where they and lymph node-resident APCs present antigens to cognate T cells and B cells, leading the induction of a germinal centre (GC) response. Tertiary lymphoid structures may also form in response to mucosal inflammation and serve as sites for local GCs. The GC response in the draining lymph node typically precedes the response occurring in the mucosal tissue, with memory B cells that develop in the lymph node capable of migrating to mucosal tissues. Plasma cells derived from the GC response migrate to the bone marrow, where they reside long term. b | Upon antigen re-encounter, memory B cells residing in the mucosal tissues differentiate into plasma cells or re-enter the local GC. Antibodies derived from mucosal plasma cells cooperate with circulating antibodies to mediate early viral control. APCs that take up antigens will migrate to the draining lymph node, where they and lymph node-resident APCs will present antigens to cognate T cells and B cells. c | At later time points, antibodies derived from memory B cells that become reactivated in the draining lymph node contribute to viral clearance. Memory B cells and plasma cells that have undergone further affinity maturation in the mucosal and lymph node GCs will also help mediate viral clearance at later time points.