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

• DOI: 10.1016/j.ejmech.2019.06.047
• Publication Date: 2019-06-18T11:13:01Z
• Authors: Reshma J. Nevagi; Wei Dai; Zeinab G. Khalil; Waleed M. Hussein; Robert J. Capon; Mariusz Skwarczynski; Istvan Toth
• Keywords: Pharmacology; Chitosan; 0303 health sciences; Dose-Response Relationship, Drug; Molecular Structure; Streptococcus pyogenes; 3002 Drug Discovery; Organic Chemistry; General Medicine; Microbial Sensitivity Tests; 540; Anti-Bacterial Agents; 3. Good health; Lipopeptides; Structure-Activity Relationship; 03 medical and health sciences; 3004 Pharmacology; Drug Delivery Systems; Adjuvants, Immunologic; Drug Discovery; Bacterial Vaccines; Nanoparticles; 1605 Organic Chemistry

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.