Staphylococci as a group, are the leading cause of bacteremia, surgical wound infections and infection of prosthetic materials in the United States, and the second leading cause of nosocomial infections. Currently, there exists no anti-Staphylococcal vaccine in clinical use. In preliminary studies we made use of a proprietary synthetic (poly)glycerolphosphate (pgp), a highly-conserved substitute for natural Gram-positive cell wall lipoteichoic acid (LTA), to produce a conjugate vaccine that elicited protective, pgp-specific IgG antibodies against Staphylococcus aureus in mice. Of interest, we further demonstrated that pagibaximab, which is the only available opsonic and protective anti-LTA mAb currently in clinical trials, specifically recognizes pgp, and that LTA competes with pgp for pagibaximab binding. In addition to S. aureus and S. epidermidis (Coagulase-negative Staphylococcus [CoNS]), multiple other Gram-positive bacteria express pgp-containing LTA in their cell walls. Thus, a pgp-based conjugate vaccine has the potential to be widely cross-protective against a wide range of Gram-positive bacteria. Synthetic pgp has distinct advantages over natural LTA, in its being completely defined and pure, relatively inexpensive to produce, without pro-inflammatory properties, and highly likely to yield reproducible lots of material for use in clinical vaccines.
In this proposal, we will determine the parameters required for an optimally effective pgp-based conjugate vaccine, delivered locally (s.c.) or systemically (i.p.), and determine its ability to cross-protect mice against systemic infections (introduced intraperitoneally) with a number of clinically relevant Gram-positive bacteria known to express pgp-containing LTA in their cell walls. Specifically, we will determine the:
- 1) immunogenicity and protective ability of pgp that contains different chain lengths (i.e. 5, 10, 15, or 20 glycerol phosphate monomers),
- 2) effect of several different pgp-protein conjugation chemistries (i.e. hexylamine, aminooxy, or carboxyl linkers)
- 3) ability of several distinct protein carriers (i.e. tetanus toxoid, CRM197, or outer membrane protein complex (OMPC) from N. meningitidis) and adjuvants (i.e. alum +/- CpG-oligodeoxynucleotide [Toll-like receptor 9 ligand]) to elicit high-titer pgp-specific IgG antibodies,
- 4) potency of a purely synthetic pgp-PADRE (Pan DR helper T cell epitopes) conjugate vaccine,
- 5) effectiveness of pgp conjugate vaccine to protect neonatal and adult mice,
- 6) the capacity of pgp conjugate vaccine to cross-protect against several clinically-relevant Gram-positive bacteria that express pgp in their LTAs (i.e. S. aureus, CoNS, and Enterococcus species.
Collectively, these data will lay a strong foundation for the eventual production and testing of an optimal pgp-based conjugate vaccine for use in human clinical trials, either separately, or part of a multi-component vaccine, with enormous potential impact on global morbidity and mortality secondary to a number of major Gram-positive bacterial human pathogens.
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