When designing vaccines, consider the starting material: the human B cell repertoire

Abstract

Most viral vaccines provide protection from infection through the generation of neutralizing antibodies (nAbs). The repertoire of B cells responding to immunization is the starting material from which nAbs eventually arise. Immunization strategies are increasingly targeting precise B cell specificities to mimic nAbs generated during natural infection, in an effort to maximize the potency of the vaccine-elicited Ab response. An understanding of the human B cell specificities capable of immunogen recognition can aid in immunogen design and inform decision-making for clinical advancement. Here, we review what is known about antigen-specific and epitope-specific naive B cell repertoires in humans and mice, and we consider the challenges for identifying and analyzing antigen-specific naive B cell repertoires. Finally, we provide a framework for further exploration, interpretation, utilization of the B cell repertoire to facilitate vaccine discovery.

Graphical abstract

Figure 1

Classification of eOD-GT8 specific naive human B cells by epitope specificity and BCR sequence characteristics. The colored area represents the eOD-GT8 specific naive human B cell repertoire. ‘On-target’ naive B cells (blue) with BCR sequence characteristics (VH1-2⁺ and 5aa L-CDR3 length) and CD4bs epitope specificity are classified as VRC01-class naive B cells.

Figure 2

Consideration of B cell frequencies and bnAb coverage. ‘Potential bnAb precursor frequency’ is plotted as the inverse of naive B cell frequency (i.e. 1 in ‘x’ number of B cells) for each class or subclass. The IOMA class naive B cell frequency may be underestimated, as eOD-GT8 was not specifically designed to target IOMA-like cells. However, based on human B cell repertoire bioinformatics, the frequency of the IOMA lambda LC is expected to be lower than or similar to that of the kappa VRC01-class LCs, as lambda LCs are longer and less common than kappa LCs. BnAb class and subclass percentage neutralization coverage are plotted using values of the named bnAb (i.e. ‘VRC01 class’ coverage value is the neutralization of VRC01 bnAb [47]). Detected subclasses are shown in blue [21]. Naive B cell subclasses that are below the limit of detection are plotted in the grayed area (plotted values vary due to differences in experimental approach).