Group A Streptococcus (GAS) infection causes a wide range of diseases, from minor throat infections to serious life-threatening invasive infections (e.g., necrotising fasciitis). GAS is also the principal etiologic agent of rheumatic heart disease and rheumatic fever, which are responsible for more than 320,000 GAS-related deaths worldwide each year.1 The global burden of GAS and GAS-related diseases, highlight the need for a safe and effective vaccine.
This underpins our goal to investigate a cyclic decapeptide carrier incorporating a conserved B cell peptide epitope derived from the conserved region of the GAS M protein, a universal T-helper epitope and a synthetic toll-like receptor 2 targeting lipid moiety (lipoamino acid) as a possible self-adjuvant GAS vaccine. Vaccine candidates were synthesised using a variety of chemical techniques, including solid phase peptide synthesis, head-to-tail cyclisation and the Huisgen 1,3-dipolar cycloaddition. Compounds were purified by preparative RP-HPLC and characterised by analytical RP-HPLC and ESI-MS.
Structure-immune activity analysis of the cyclic lipopeptide vaccines showed successful induction of J8-specific IgG when administered subcutaneously without an additional adjuvant, with all lipidated vaccine candidates inducing antibody titres significantly higher than the negative control. Interestingly, the physically mixed vaccine showed the highest titres of all groups assessed. Further, these antibodies were shown to effectively opsonise multiple strains of clinically relevant GAS bacteria.2 An extension of this study showed the capability for a self-adjuvant cyclic delivery system to act as a vehicle for the delivery of GAS peptide antigens to treat GAS infection, with the orientation of the B cell and T helper epitopes important for the immune response. Results from these studies provide a vaccine delivery system capable of inducing high titres of opsonic antibodies capable of opsonising several clinically significant strains of GAS bacteria.