Structure-activity relationship of group A streptococcus lipopeptide vaccine candidates in trimethyl chitosan-based self-adjuvanting delivery system.

Synthetic peptide vaccines based on epitopes derived from the conserved region of M-protein are proving to be a realistic option for protection against group A streptococcus (GAS). However, peptide epitopes alone are poorly immunogenic due to lack of pathogen-associated structural patterns. Therefore, we developed a GAS peptide vaccine based on combined lipidic TLR 2 agonist and self-adjuvanting polymers. We synthesized three α-poly- l -glutamic acid (PGA) conjugated lipopeptides composed of 2-amino- d,l -hexadecanoic acid, GAS B-cell peptide epitope J8 (QAEDKVKQSREAKKQVEKALKQLEDKVQ) and universal T-helper epitope PADRE (AKFVAAWTLKAAA) in different spatial arrangements. The anionic lipopeptide conjugates formed nanoparticles via ionic-complexation with a cationic polymer, trimethyl chitosan (TMC). We demonstrated that the spatial arrangement of vaccine components has a significant influence on peptide conformation and particle formation and, as such, contributes to the differential efficacy and opsonin-mediated killing potential of nanovaccines. Nanoparticles carrying branched helical lipopeptide with T-helper epitope on free N-termini (NP3) stimulated the most potent humoral immune responses. Lipopeptides without TMC (LP1-LP3) and TMC nanoparticles of peptide alone (without lipid) NP (P1) were poor inducers of antibody production, indicating that both TMC and lipid are required to induce a strong opsonic immune response. Image 1 • Spatial arrangement of vaccine components influenced its conformational properties. • The conformational change resulted in different nanoparticle morphology. • Nanovaccines carrying branched helical lipopeptides stimulated potent immune response. • Both cationic polymer and lipid were necessary to induce a strong opsonic response. [ABSTRACT FROM AUTHOR]