Abstract
Lipoteichoic acids (LTA) are amphiphilic polymers that are important constituents of the cell wall of many Gram-positive bacteria. The chemical structures of LTA vary among organisms, albeit in the majority of Gram-positive bacteria the LTAs feature a common poly-1,3-(glycerolphosphate) backbone. Previously, the specificity of opsonic antibodies for this backbone present in some Gram-positive bacteria has been demonstrated, suggesting that this minimal structure may be sufficient for vaccine development. In the present work, we studied a well-defined synthetic LTA-fragment, which is able to inhibit opsonic killing of polyclonal rabbit sera raised against native LTA from Enterococcus faecalis 12030. This promising compound was conjugated with BSA and used to raise rabbit polyclonal antibodies. Subsequently, the opsonic activity of this serum was tested in an opsonophagocytic assay and specificity was confirmed by an opsonophagocytic inhibition assay. The conjugated LTA-fragment was able to induce specific opsonic antibodies that mediate killing of the clinical strains E. faecalis 12030, Enterococcus faecium E1162, and community-acquired Staphylococcus aureus strain MW2 (USA400). Prophylactic immunization with the teichoic acid conjugate and with the rabbit serum raised against this compound was evaluated in active and passive immunization studies in mice, and in an enterococcal endocarditis rat model. In all animal models, a statistically significant reduction of colony counts was observed indicating that the novel synthetic LTA-fragment conjugate is a promising vaccine candidate for active or passive immunotherapy against E. faecalis and other Gram-positive bacteria.
Highlights
The incidence of infections caused by multidrug resistant enterococci has become a worldwide problem over the last decades, in immunocompromised patients [1]
We have previously shown that opsonic antibodies directed against lipoteichoic acid (LTA) from E. faecalis are cross-reactive against LTA present in Staphylococcus epidermidis, Staphylococcus aureus and group B streptococci, and that they mainly bind to the poly-1,3(glycerolphosphate) backbone, suggesting that this minimal structure may be sufficient for vaccine development against some Gram-positive bacteria [8]
Synthetic antigen selection and synthesis of the teichoic acid carrier protein conjugates The library of teichoic acid fragments we have synthesized contains fragments varying in length, glycosylation pattern (a-glucosyl, a-kojibiosyl, a-glucosamine and a-N-acetyl glucosamine) and terminal functionality [8,16,17]
Summary
The incidence of infections caused by multidrug resistant enterococci has become a worldwide problem over the last decades, in immunocompromised patients [1]. Synthetic oligosaccharide-protein conjugate vaccines have emerged recently as an interesting strategy in vaccinology, since they offer two major advantages: a well-defined chemical structure (chain length, nature of the epitope, well-established carbohydrate/protein ratio, single type of linkage between the antigen and the carrier) and lack of impurities present in polysaccharides obtained from bacterial cultures [14,15]. This would apply for a teichoic acid-based vaccine. Chen et al did not evaluate the potential use of this PGP-based conjugate vaccine against other Gram-positive pathogens, they suggest cross-protection against organisms expressing this highly conserved backbone [11]
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