Abstract
Peptide-based vaccines can be safer and more cost effective than whole organism vaccines. Previous studies have shown that inorganic polystyrene nanoparticles (PSNPs) covalently conjugated to the minimal immunodominant peptide epitope from murine liver stage malaria (SYIPSAEKI) induced potent CD8+ T cell responses. Many pathogens, including malaria, have polymorphic T cell epitope regions. Amino acid changes in positions that are contact residues for the T cell receptor (TCR) often alter the specific cross-reactivity induced by the peptide antigen, and it is largely assumed that changes outside of these residues have little impact. Herein, each amino acid residue (except major histocompatibility complex (MHC) anchors) was systematically changed to an alanine. Peptide epitopes with altered amino acids outside T cell contact residues were still recognized by T cells induced by PSNPs-SYIPSAEKI (KI) vaccines, albeit at lower levels, except for the variant SYIPSAAKI (A7). PSNPs-SYIPSAAKI vaccines further elicited high responses to the index KI peptide. None of the epitopes displayed altered peptide ligand (APL) antagonism in vitro, and re-stimulating SYIPSAEKI and SYIPSAAKI together synergistically enhanced IFN-γ production by the T cells. These results show epitope variation in non-TCR recognition residues can have effects on T cell reactivity, suggesting that such natural variation may also be driven by immune pressure. Additionally, when re-modelling peptides to enhance the cross-reactivity of vaccines, both TCR recognition and non-recognition residues should be considered.
Highlights
Attenuated live pathogen vaccines often activate potent immune responses, these vaccines carry the risk of pathogen reactivation and cannot be given to immunocompromised or vulnerable populations
One natural delivery system is through the use of ex vivo peptide pulsed dendritic cells (DCs), which is mostly used in immune-therapies to boost recognition and activation of tumor antigens in cancer patients [4]
The opposite was shown where there was evidence of a synergistic restimulated response between the index KI peptide and A7, elicited from A7 peptide primed cells. These results suggest altered peptides outside the known key T cell receptor (TCR) contact site should be considered as important parts of the motif for influencing the immunogenic response
Summary
Attenuated live pathogen vaccines often activate potent immune responses, these vaccines carry the risk of pathogen reactivation and cannot be given to immunocompromised or vulnerable populations. Current licensed adjuvants or vaccine delivery vehicles capable of inducing such T cell responses include MF59 [1] and other oil or squalene-based emulsion adjuvants (i.e., adjuvant system AS02) [2], as well as viral vectored vaccines (i.e., Chimpanzee adenoviral (ChAd) and modified vaccinia Ankara (MVA)) [3]. Delivery systems such as virus like particles (VLPs) and immune stimulating complexes (ISCOMs) are potent inducers of T cell responses. Autologous DCs naturally induce T cell responses, without the need for an additional adjuvant, though as it is a highly individualized therapy, it is expensive and would not be suitable for widespread use in developing countries
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