Germinal center enhancement by extended antigen availability

Abstract

Vaccine elicitation of protective antibody responses has proved difficult for a number of important human pathogens, including HIV-1. The amount of somatic hypermutation associated with the development of broadly neutralizing antibodies against HIV has not been achieved using conventional immunization strategies. An underexplored aspect of vaccine design is modulation of antigen kinetics. Immunization strategies with extended antigen availability have recently been shown to enhance humoral responses. In this review, we explore the mechanisms through which sustained antigen availability can enhance germinal center responses and the potency of antibody responses. These potential mechanisms include shifting B cell recognition away from non-neutralizing immunodominant epitopes, altered kinetics of immune complex deposition, improved T follicular helper (Tfh) cell responses, enhanced affinity maturation, and enhanced development of B cell memory. Finally, we discuss immunization strategies that result in extended antigen availability.

Figure 1. Slow immunogen release improves the availability of intact antigen

(A) Soluble immunogen can lose native structure due to lability or proteolysis over time. This can lead to exposure of irrelevant and potentially distracting epitopes. (B) Sustained release of immunogen limits the amount of soluble antigen available to proteases, and ensures availability of intact immunogen at later times during the immune response.

Figure 2. Sustained immunogen release enhances immune complex deposition and GCs

Low-affinity antibodies bind antigen as immune complexes and are deposited on follicular dendritic cells (FDCs). Some B cells that have sufficient affinity to antigen will differentiate into plasma cells early in the immune response and secrete higher affinity antibodies, which then bind remaining free antigen. (A) During a conventional protein immunization, most antigen is presented to B cells early relative to the peak of the GC response. Thus, B cell affinity maturation rates may peak relatively early under those conventional immunization conditions. (B) Sustained antigen release immunization introduces new antigen during a time window when higher affinity IgG is produced, allowing for increased immune complex formation and deposition onto FDCs. This antigen is retained at higher concentrations and for longer durations on FDCs. Thus, the magnitude of the GC response is larger, and B cell affinity maturation rates may be sustained better than under conventional immunization conditions.

Figure 3. A model of Tfh help modulation by extended immunogen release

(A) During a conventional immunization, the presence of low numbers of GC Tfh cells usually restricts the number of GC B cells, limiting BCR diversity. (B) Extended immunogen release can support increased GC Tfh cell numbers, or greater GC Tfh help quality. More GC B cells are able to proliferate and undergo SHM in the presence of increased GC Tfh cell help. More GC Tfh help both generates a larger pool of clonotypic BCR diversity and lowers competition between B cells, allowing for the generation of GC B cells with more complex BCR antigen recognition features.