Abstract
Peptide vaccines are an attractive strategy to engineer the induction of highly targeted immune responses and avoid potentially allergenic and/or reactogenic protein regions. However, peptides by themselves are often unstable and poorly immunogenic, necessitating the need for an adjuvant and a specialised delivery system. We have developed a novel peptide delivery platform (PilVax) that allows the presentation of a stabilised and highly amplified peptide as part of the group A streptococcus serotype M1 pilus structure (PilM1) on the surface of the non-pathogenic bacterium Lactococcus lactis. To show proof of concept, we have successfully inserted the model peptide Ova324–339 into 3 different loop regions of the backbone protein Spy0128, which resulted in the assembly of the pilus containing large numbers of peptide on the surface of L. lactis. Intranasal immunisation of mice with L. lactis PilM1-Ova generated measurable Ova-specific systemic and mucosal responses (IgA and IgG). Furthermore, we show that multiple peptides can be inserted into the PilVax platform and that peptides can also be incorporated into structurally similar, but antigenically different pilus structures. PilVax may be useful as a cost-effective platform for the development of peptide vaccines against a variety of important human pathogens.
Highlights
Vaccines remain the most cost-effective and feasible means of infectious disease control in the community
We show that the model peptide Ova324–339 peptide alone (Ova)[324–339], a well characterised B cell epitope[29,30] inserted at suitable regions of the protease-resistant backbone pilus protein can be stably expressed in large numbers as part of the multimeric GAS pilus structure on the surface of L. lactis (Supplementary Figure 1) and triggers peptide-specific mucosal immune responses after intranasal immunisation of mice
The foremost challenge is that peptides are often poorly immunogenic on their own and undergo enzymatic degradation more quickly than folded proteins[34]
Summary
Vaccines remain the most cost-effective and feasible means of infectious disease control in the community. Vaccine development has progressed from live-attenuated or inactivated forms of microbial pathogens to subunit vaccines using one or a few selected proteins to elicit a protective immune response[2,3]. In Gram-positive bacteria, such as S. pyogenes, pili usually consist of 3 structural proteins that are covalently linked to each other by a specialised pilus-assembly sortase. Spy0128 (FctA, T-antigen) is the backbone pilin that generates the pilus fibre[15], and Spy0130 (FctB) is the anchor protein that links the FCT-2 pilus to the cell wall[16]. Non-pathogenic food grade bacteria, such as L. lactis were shown to work as safe and efficacious live antigen carriers that elicit specific and protective immune responses against the target protein[18,19,20,21,22]. L. lactis secreting human IL-10 has been used in a phase I clinical trial to treat patients with Crohn’s disease[23]
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