Group A Streptococcus Cell Wall Oligosaccharide-Streptococcal C5a Peptidase Conjugates as Effective Antibacterial Vaccines.

Abstract

Group A streptococcus (GAS) is one of the common Gram-positive pathogenic bacteria accounting for a variety of infectious diseases. Currently, there is no commercial vaccine for GAS. To develop efficient GAS vaccines, synthetic tri-, hexa-, and nonasaccharides of a conserved group A carbohydrate (GAC) were conjugated with an inactive mutant of group A streptococcal C5a peptidase (ScpA), ScpA193, to create bivalent conjugate vaccines, which were compared with the corresponding CRM197 and TT conjugates. Systematic evaluations of these semisynthetic conjugates demonstrated that they could induce robust and comparable T-cell-dependent immune responses in mice. It was further disclosed that antibodies provoked by the ScpA193 conjugates, especially that of hexa- and nonasaccharides, could recognize and bind to GAS cells and mediate GAS opsonophagocytosis in vitro. In vivo evaluations of the hexa- and nonasaccharide-ScpA193 conjugates using a mouse model revealed that immunizing mice with especially the latter conjugate could effectively protect the animals from GAS challenges and GAS-induced pulmonary damage and significantly increase animal survival. Further in vitro studies suggested that the two ScpA193 conjugates could function through activating CD4+ T cells and promoting helper T cells (Th) to differentiate into antigen-specific Th1 and Th2 cells. In conclusion, the nonasaccharide-ScpA193 conjugate was identified as a particularly promising GAS vaccine candidate that is worthy of further investigation and development.