Can We Improve Vaccine Efficacy by Targeting T and B Cell Repertoire Convergence?

Abstract

Traditional vaccine development builds on the assumption that healthy individuals have virtually unlimited antigen recognition repertoires of receptors in B cells and T cells [the B cell receptor (BCR) and TCR respectively]. However, there are indications that there are "holes" in the breadth of repertoire diversity, where no or few B or T cell are able to bind to a given antigen. Repertoire diversity may in these cases be a limiting factor for vaccine efficacy. Assuming that it is possible to predict which B and T cell receptors will respond to a given immunogen, vaccine strategies could be optimized and personalized. In addition, vaccine testing could be simplified if we could predict responses through sequencing BCR and TCRs. Bulk sequencing has shown putatively specific converging sequences after infection or vaccination. However, only single cell technologies have made it possible to capture the sequence of both heavy and light chains of a BCR or the alpha and beta chains the TCR. This has enabled the cloning of receptors and the functional validation of a predicted specificity. This review summarizes recent evidence of converging sequences in infectious diseases. Current and potential future applications of single cell technology in immune repertoire analysis are then discussed. Finally, possible short- and long- term implications for vaccine research are highlighted.

Keywords: B cell receptor (BCR); T cell receptor (TCR); immune repertoire analysis; infectious diseases; personalized vaccination.

Figure 1

Schematic illustration of the human (A) BCR and (B) TCR mRNA organization and approximate transcript length. Nucleotide values are estimates based on the amino acid lengths reported in: https://www.uniprot.org/uniprot. Ab heavy chain (HC) variable region: 110–120amino acids (aa). HC constant region for IgG1 isotype: 330aa, Ab light chain (LC) variable region: 110–120aa, LC constant region kappa: 107aa, lambda 106aa. TCRbeta and TCRalpha variable region: 110–120aa. TCRbeta constant region: 176aa, TCRalpha constant region: 140aa. The mRNA is assembled from one allele of the variable (V), diversity (D), and joining (J) genes, which are illustrated in red, blue, and green, respectively. CDR3, Complementarity-determining region 3. Schematic structures of the expressed BCR and TCR are shown on the right with the CDR3 spanning V(D)J sequence. In the real structures, the CDR3 loops are exposed at the tips of the BCR or TCR.

Figure 2

Current and future immune repertoire research areas for personalized vaccines for infectious diseases. (A) level of personalization compared with the level of complexity for vaccine development. The size of the antigen and adjuvant fields illustrates the number of different options. (B) areas of current research in the field of immune repertoire analysis for infectious diseases and potential areas for future application.