Getting peptide vaccines to work: just a matter of quality control?

Optimizing peptide vaccine composition Synthetic peptide–based vaccines, which are designed to elicit T cell immunity, are an attractive approach to the prevention or treatment of infectious diseases and malignant disorders (1–4). CTLs recognize antigens as small protein fragments of eight to ten residues (known as peptide epitopes) that associate with MHC molecules, which are expressed on the surface of antigen-presenting cells (APCs) such as infected or malignant cells (5). As the result of the specific interaction between the T cell receptor for antigen (TCR) and the peptide/MHC complexes, the CTLs are able to kill target cells expressing infectious or tumorderived antigens. In consequence, manufacturing these T cell epitopes by conventional organic peptide synthesis methods is a relatively simple, expedient, and cost-effective way to produce vaccines for any type of disease in which CTLs could play a role in the elimination of the offending agent. Unfortunately, the advantages that peptide vaccines have to offer are to some extent diminished by their inherent lack of immunogenicity, which so far has been reflected by their not-sospectacular results in the clinic. Because the immune system in most species has evolved through time to fight life-threatening infectious agents (and perhaps tumors), it should not be surprising that vaccines consisting of aseptic, endotoxin-free peptides are likely to be ignored and will likely be ineffective at inducing T cell immunity. In addition, peptides that are injected in aqueous solutions will be unsuccessful at stimulating CTL responses, either because of their rapid biodegradation (e.g., by proteases) or, worse, because of the induction of T cell tolerance/anergy, which results from the antigenic stimulation of CTLs by nonprofessional APCs (6, 7). A means for enhancing the immunogenicity of synthetic peptide vaccines has been the use of adjuvants, which aim at mimicking the danger signals produced by pathogens, provoking inflammatory reactions that awaken the immune system (8). In addition, some adjuvants also create a depot effect, preventing access of the immunogen to proteases and allowing their slow release into the extracellular compartments. Thus, it is hoped that peptides that are appropriately formulated in adjuvants can elicit CTL responses that in some instances will have positive effects against infections or tumors. An additional complication resulting from the use of synthetic peptide–derived vaccines is the induction of CTLs that, while capable of killing target cells that are exogenously pulsed with peptide, are not able to recognize target cells that naturally process and present the peptide epitope, such as infected or malignant cells. Obviously, these “low-quality” CTLs would have little effect in fighting and controlling disease. One of the reasons for the generation of such lowquality CTLs by peptide vaccines is the induction of CTLs with low affinity for antigen, which will require a high density of specific peptide/MHC complexes on the target-cell surface to exert their effector function. In vitro, the induction of low-affinity CTLs usually results from the use of high concentrations of peptide, generating a high level of specific peptide/MHC complexes on APCs, which will effectively activate these CTLs (9). The prediction is that high densities of peptide/MHC complexes on APCs in vivo resulting from an excessive peptide dose will also produce low-quality CTLs with low affinity for antigen. Another cause for the induction of low-quality CTLs is the use of vaccines produced with synthetic peptides representing cryptic T cell epitopes, which are not expressed on the surface of the infected or tumor target cells (10). The peptides corresponding to cryptic epitopes are immunogenic, because they bind well to MHC molecules on APCs and are able to activate T cells. However, because the same peptide/MHC complexes are not generated through the natural antigen-processing machinery in the infected or tumor cells, CTLs recognizing cryptic epitopes will be unable to interact with infected or tumor target cells and will also be useless in disease control.