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.

Genomic evolution of epitopes and Low Complexity Regions in Plasmodium

“…Even from a structural point of view, epitopes do not necessarily follow expectations. While the vast majority of them in all species and genes are composed of extracellular sites, the exposure to an outside solvent would predict a high percentage of disorder (MacRaild et al 2018). Instead, we find that, on average, ~ 30% of the epitope sites are disordered and in Haemamoeba and Vinckeia this percentage is even lower (11% in Haemamoeba and 4% in Vinckeia; Figure 1C ).…”

“…The efficacy of antimalarial vaccines is dependent, in part, on the quality and accessibility of the target sequence. Desirable properties in a target include (i) conservation, which supports long-term stability, (ii) accessibility, for ease of targeting, (iii) specificity, which allows sequences to be targeted uniquely, and (iv) the presence of adjuvant targets that could strengthen and refine the targeting process (MacRaild et al 2018). For the epitopes of Plasmodium species, (ii) and (iii) are relatively well known but (i) and (iv) are not.…”

Short Disordered Epitope of CRTAM Ig-Like V Domain as a Potential Target for Blocking Antibodies

“…Evidence has shown that intrinsically disordered regions (IDRs), such as epitopes (disordered epitopes), are more enriched in linear B-cell epitopes, putative disordered binding sites, and disorder–order transitioning T cell epitopes [ 17 , 31 , 32 ]. Moreover, disordered epitopes can induce an adaptive immune response and efficient protective antibody production against pathogen surface proteins [ 18 , 33 , 34 , 35 ] due to the solvent exposure and entropic cost efficiency of the paratope–disordered epitope complex [ 36 ].…”

“…In a previous work, a linear antigenic peptide ( 257 DKEEKE 262 ) from the stalk region of CRTAM (here referred to as IDR4) was able to induce antibodies that recognized CRTAM expressed in MDCK epithelial cells and rat kidney cells [ 37 ]. These data suggest that disordered peptides are efficient in inducing a specific immune response, as reflected by their use in vaccine development [ 17 , 38 , 39 ].…”

“…Despite the high molecular disorder of pathogen or endogenous mammalian proteins, the hydrophilicity of exposed residues and the lengths of IDRs play roles in stimulating the immune system. There are several antigens under development as vaccines that have been predicted to be disordered proteins, such as the circumsporozoite protein and merozoite surface 2 of Plasmodium falciparum , the KMP-11 protein of Leishmania amazonensi , the preS antigen of hepatitis B, glycoprotein G of the herpes simplex virus, and the Neisserial heparin binding antigen of Neisseria meningitidis serogroup B [ 17 ]. In addition, IDRs can be highly immunogenic linear or conformational B-cell epitopes.…”