Poster Presentation 8th Australasian Vaccines & Immunotherapeutics Development Meeting 2020

Structure-activity analysis of a self-adjuvanting cyclic lipopeptide delivery system for group a streptococcus peptide antigens (#307)

Harrison Y.R. Madge 1 , Waleed M. Hussein 1 , Istvan Toth 1 2 3 , Zeinab G. Khalil 2 , Robert J. Capon 2 , Rachel J. Stephenson 1
  1. The University of Queensland, School of Chemistry and Molecular Biosciences, Brisbane, Queensland, Australia
  2. The University of Queensland, Institute for Molecular Biosciences, Brisbane, Queensland, Australia
  3. The University of Queensland, School of Pharmacy, Brisbane, Queensland, Australia

Group A Streptococcus (GAS) infection causes a wide range of diseases, from minor throat infections to serious life-threatening invasive infections such as necrotising fasciitis. GAS is also the principle etiologic agent of rheumatic fever and rheumatic heart disease, which are responsible for the largest proportion of the over 320,000 GAS related deaths worldwide per year.1 The ever-present global burden of GAS and the large number of cases, which manifest to rheumatic heart disease, highlight the need for a safe and effective vaccine.

Here, we have investigated 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-adjuvanting GAS vaccine. Vaccine candidates were synthesised using a variety of standard techniques, including solid phase peptide synthesis, head-to-tail cyclisation and Huisgen 1,3-dipolar cycloaddition chemistry. Compounds were purified by preparative reverse phase high performance liquid chromatography (RP-HPLC) and characterised by analytical RP-HPLC and electrospray ionisation mass spectrometry.

A structure-activity relationship analysis of the cyclic lipopeptide vaccine candidate showed successful induction of GAS-specific IgG titres when administered subcutaneously without an additional adjuvant, with all lipidated vaccine candidates inducing antibody titres significantly higher than the negative control. Interestingly, a physical mixture of the vaccine components (instead of a conjugated vaccine) showed the highest antibody titres of all vaccine groups. Further, vaccine-generated antibodies were shown to effectively opsonise multiple strains of clinically relevant GAS bacteria.2 This proof-of concept study showed the capability for a self-adjuvanting cyclic delivery system to act as a vehicle for the delivery of GAS peptide antigens to treat GAS infection. Results from this study provide a vaccine delivery system capable of inducing high titres of opsonic antibodies capable of opsonising several clinically significant strains of GAS bacteria.

  1. Watkins, D. A., Global, Regional, and National Burden of Rheumatic Heart Disease, New England Journal of Medicine, 377 (8), 713-722 (2017).
  2. Madge, H. Y. R.; Sharma, H.; Hussein, W. M.; Khalil, Z. G.; Capon, R. J.; Toth, I.; Stephenson, R. J., Structure–Activity Analysis of Cyclic Multicomponent Lipopeptide Self-Adjuvanting Vaccine Candidates Presenting Group A Streptococcus Antigens, Journal of Medicinal Chemistry, 63 (10), 5387-5397 (2020).