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.
Highlights
Group A streptococcus (Streptococcus pyogenes, or Group A Streptococcus (GAS)) is a Grampositive bacteria that causes various diseases ranging from the relatively benign pharyngitis (‘strep throat’) to more invasive necrotizing fasciitis [1]
The higher J14specific IgG titers induced by lipopeptide 1 in comparison to the lipid core peptide (LCP) system and analogues of 1 with shorter lipoamino acids (Laas) alkyl chain length (Lipopeptides 2, 3) was not statistically significant (Figure 3; lipopeptide 1 vs LCP and lipopeptides 2-3, p.0.05)
DT/CFA (Figure 3; J14-DT/CFA vs lipopeptide 1, p.0.05). These data suggested that C16 Laa as in lipopeptide 1 was optimal for immunogenicity
Summary
Group A streptococcus (Streptococcus pyogenes, or GAS) is a Grampositive bacteria that causes various diseases ranging from the relatively benign pharyngitis (‘strep throat’) to more invasive necrotizing fasciitis [1]. The post-infectious complications arising from GAS such as rheumatic fever (RF) and rheumatic heart disease (RHD) are responsible for the greatest health burden by causing the majority of morbidity and mortality (estimated at 12 million cases annually with 380,000 fatalities) [2,3]. Inadequate or delayed treatment of GAS infections can result in the development of these diseases and highlights the need for a protective GAS vaccine [4]. Development of a vaccine against GAS infections focused on the M-protein, an abundant cell surface protein. The M-protein is expressed by all GAS and is a major virulence factor [4]. Protective immunity against GAS infections has been associated with antibodies directed against the N-terminal or C-terminal regions of the M-protein [4,5].
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