title: Immunological evaluation of lipopeptide group A streptococcus (GAS) vaccine: structure-activity relationship.
abstract: Streptococcus pyogenes (group A streptococcus, GAS) is a Gram-positive bacterial pathogen responsible for a wide variety of diseases. To date, GAS vaccine development has focused primarily on the M-protein. The M-protein is highly variable at the amino (N)-terminus (determining serotype) but is conserved at the carboxyl (C)-terminus. Previously a 29 amino acid peptide (named J14) from the conserved region of the M-protein was identified as a potential vaccine candidate. J14 was capable of eliciting protective antibodies that recognized many GAS serotypes when co-administered with immuno-stimulants. This minimal epitope however showed no immunogenicity when administered alone. In an attempt overcome this immunological non-responsiveness, we developed a self-adjuvanting vaccine candidate composed of three components: the B-cell epitope (J14), a universal helper T-cell epitope (P25) and a lipid moiety consisting of lipoamino acids (Laas) which target Toll-like receptor 2 (TLR2). Immunological evaluation in B10.BR (H-2k) mice demonstrated that the epitope attachment to the point of lipid moiety, and the length of the Laa alkyl chain have a profound effect on vaccine immunogenicity after intranasal administration. It was demonstrated that a vaccine featuring C-terminal lipid moiety containing alkyl chains of 16 carbons, with P25 located at the N-terminus, and J14 attached to the side chain of a central lysine residue was capable of inducing optimal antibody response. These findings have considerable relevance to the development of a broad spectrum J14-based GAS vaccine and in particular provided a rational basis for peptide vaccine design based on this self-adjuvanting lipopeptide technology.
authors.affiliation: The University of Queensland, School of Chemistry and Molecular Biosciences (SCMB), St. Lucia, Queensland, Australia.
authors.forename: Mehfuz
authors.initials: M
authors.lastname: Zaman
authors.forename: Abu-Baker M
authors.initials: AB
authors.lastname: Abdel-Aal
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Fujita
authors.forename: Karen S M
authors.initials: KS
authors.lastname: Phillipps
authors.forename: Michael R
authors.initials: MR
authors.lastname: Batzloff
authors.forename: Michael F
authors.initials: MF
authors.lastname: Good
authors.forename: Istvan
authors.initials: I
authors.lastname: Toth
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D000090266:Chromobox Protein Homolog 5; D000939:Epitopes / Q000276:immunology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007114:Immunization; D007074:Immunoglobulin G / Q000276:immunology; D055666:Lipopeptides / Q000737:chemistry / Q000276:immunology*; D051379:Mice; D022541:Streptococcal Vaccines / Q000737:chemistry* / Q000276:immunology*; D013297:Streptococcus pyogenes / Q000276:immunology*; D013329:Structure-Activity Relationship; D051195:Toll-Like Receptor 2 / Q000276:immunology
chemical_list: C000715594:CBX5 protein, human; D000939:Epitopes; D007074:Immunoglobulin G; D055666:Lipopeptides; D022541:Streptococcal Vaccines; D051195:Toll-Like Receptor 2; D000090266:Chromobox Protein Homolog 5