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Designing immunogenic peptides

Nature Chemical Biology volume 9, pages 749–753 (2013)Cite this article

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Peptides fulfill many roles in immunology, yet none are more important than their role as immunogenic epitopes driving the adaptive immune response, our ultimate bulwark against infectious disease. Peptide epitopes are mediated primarily by their interaction with major histocompatibility complexes (T-cell epitopes) and antibodies (B-cell epitopes). As pathogen genomes continue to be revealed, both experimental and computational epitope mapping are becoming crucial tools in vaccine discovery1,2. Immunoinformatics offers many tools, techniques and approaches for in silico epitope characterization, which is capable of greatly accelerating epitope design.

The poor performance of BCE prediction is troubling. Defying our naive assumptions, BCEs remain poorly understood, despite an extraordinary wealth of experimental studies. Both structure-driven3 and data-driven4 prediction of linear or discontinuous antibody-mediated epitopes have proved unreliable. Most methods use properties relating to surface exposure, such as flexibility or hydrophobicity, as it is thought that epitopes must lie at the protein surface for antibody binding to occur. It seems unlikely that prediction methodology is at fault for failures of BCE prediction as data mining has proved successful for other applications. It is more likely that our understanding of existing experimental data is to blame. Most data derive from PEPSCAN, a procedure for mapping epitopes using overlapping peptides that are assayed, using enzyme-linked immunosorbent assays or ELISAs, for binding against pre-existing antibodies that also have affinity for the whole-protein antigen being targeted. However, when these epitopes are mapped onto their native antigens, they do not form the discrete patches one might have expected had they been simple mimics of discontinuous epitopes, as shown by crystallography; such in situ epitopes can be completely inaccessible to antibody binding. Recognition of epitopes defined by PEPSCAN cannot be explained by the simplest mechanism, and instead we must seek more complicated physical, chemical and biological mechanisms leading to their recognition by the immune system. One such explanation might be that denatured antigen is recognized in vivo by the preformed antibody. Another is that the isolated peptide adopts a conformation that is radically different yet is able to imitate the recognition surface of a discontinuous epitope.

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Figure 1: Peptide epitopes come in many guises but the most important are mediated by the MHC-TCR recognition system and by antibodies.
Figure 2: MHCs come in two varieties, with different structures and different functions.
Figure 3: The complexity of antigen presentation.

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  1. Darren R. Flower is in the School of Life and Health Sciences, Aston University, Birmingham, UK.,

    Darren R Flower

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Flower, D. Designing immunogenic peptides. Nat Chem Biol 9, 749–753 (2013). https://doi.org/10.1038/nchembio.1383

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