Disordered epitopes as peptide vaccines

Abstract

The development of clinically useful peptide-based vaccines remains a long-standing goal. This review highlights that intrinsically disordered protein antigens, which lack an ordered three-dimensional structure, represent excellent starting points for the development of such vaccines. Disordered proteins represent an important class of antigen in a wide range of human pathogens, and, contrary to widespread belief, they are frequently targets of protective antibody responses. Importantly, disordered epitopes appear invariably to be linear epitopes, rendering them ideally suited to incorporation into a peptide vaccine. Nonetheless, the conformational properties of disordered antigens, and hence their recognition by antibodies, frequently depend on the interactions they make and the context in which they are presented to the immune system. These effects must be considered in the design of an effective vaccine. Here we discuss these issues and propose design principles that may facilitate the development of peptide vaccines targeting disordered antigens.

Keywords: design; intrinsically disordered antigen; malaria; membrane interactions; peptide epitope; structure.

Figure 1

Disordered antigens are bona fide targets of antibody recognition. A, Epitopes within disordered protein regions are more likely to be targets of positive antibody binding assays. B, Antibodies to disordered epitopes (purple) and ordered epitopes (green) are subject to similar levels of somatic hypermutation. C, Disorder accounts for only a small fraction of the variability in antibody affinity. D, Disordered epitopes (purple) are exclusively short linear epitopes, while ordered epitopes (green) are predominantly conformational epitopes spanning many residues in the primary sequence. Modified with permission from Ref. 43

Figure 2

Schematic of the primary structure of the two allelic families of MSP2. Regions of conserved (blue), repetitive (green), dimorphic (yellow), and polymorphic (pink) sequence are shown. The epitopes of a panel of monoclonal antibodies are also shown, with antibodies that strongly recognize the parasite antigen in blue text, and those that do so only weakly or not at all in red

Figure 3

Interaction of different MSP2‐based conserved regions specific peptides with antibody and lipid. Comparison between A, lipid‐bound N‐terminal MSP2_1–25 70 and B, 6D8 mAb‐bound MSP2_14–22 (PDB ID 4QYO);71 key 6D8 paratope residues involved in binding are shown in white. The α‐helical configuration of the lipid‐bound peptide removes the backbone flexibility required for Arg22 to access Tyr16, which provides a structural rationale for 6D8 epitope masking at the parasite membrane. C, Schematic of lipid tethering of C‐terminal region of MSP2 (MSP2_172–221) where MSP2_172–221 was synthesized with a C‐terminal His₆‐tag to immobilize on nickel bound to nickel‐chelating lipid. D, ELISA showing the effects of lipid tethering on the binding of four C‐terminal region‐specific mouse mAbs for MSP2_172–221.72

Figure 4

Murine mAb 4D11 Fv in complex with its cognate 8‐residue epitope (PDB ID 5TBD).81 Intramolecular hydrogen bonds are indicated by green dashed lines. Interactions with 4D11 Fv paratope are shown in black dashed lines