Protection Against Staphylococcus aureus by Antibody to the Polyglycerolphosphate Backbone of Heterologous Lipoteichoic Acid

Theilacker, Christian; Kropec, Andrea; Hammer, F.; Sava, Irina G.; Wobser, Dominique; Sakinc, Tuerkan; Codée, Jeroen D. C.; Hogendorf, Wouter F. J.; Marel, Gijsbert A. van der; Hüebner, Johannes

doi:10.1093/infdis/jis022

Cited by 42 publications

(52 citation statements)

References 47 publications

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“…Although OPK mediated by sera from pgp-TT-immunized mice was demonstrated against both encapsulated and unencapsulated S. aureus strains, better killing was observed for the latter. This may reflect the previously described ability of the staphylococcal capsular polysaccharide to at least partially mask components of the underlying cell wall, although this phenomenon is highly variable (18,(50)(51)(52). Finally, we demonstrated that the ability of pgp-TT to elicit specific IgG capable of opsonic killing is correlated with its ability to promote clearance of live S. aureus from the blood following i.p.…”

Section: Discussionsupporting

confidence: 75%

“…Subsequent to our initial development of synthetic pgp, several reports were published describing a similar method, although pgp was not evaluated for use as a prophylactic vaccine (18,46,47). Utilizing synthetic pgp in an ELISA, we demonstrated that intact heat-killed S. aureus elicits a boosted T celldependent secondary pgp-specific IgG response in vivo.…”

Section: Discussionmentioning

confidence: 94%

“…Antibody specific for the (poly)glycerolphosphate (pgp) backbone of LTA, expressed by a number of Grampositive bacteria, including S. aureus, has been shown to confer passive host protection in a mouse infection model (18). To explore a potential role for pgp in eliciting active antibody-mediated antistaphylococcal host protection when used as a conjugate vaccine, we first developed a method for efficiently producing large amounts of pure, synthetic pgp.…”

Section: Resultsmentioning

confidence: 99%

“…Anti-pgp antibody is generally present in low titers in sera from noninfected humans, and antibody titers often increase during staphylococcal infections (17). A recent study demonstrated that polyclonal rabbit anti-LTA antibodies with specificity for synthetic pgp mediate opsonophagocytic killing (OPK) of S. epidermidis and S. aureus in vitro and upon passive transfer reduced mortality in a murine S. aureus peritonitis model (18). Major bacterial pathogens expressing pgp-containing LTA include S. aureus, S. epidermidis, group A Streptococcus, and Enterococcus (19).…”

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confidence: 99%

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Novel Synthetic (Poly)Glycerolphosphate-Based Antistaphylococcal Conjugate Vaccine

et al. 2013

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g Staphylococcal infections are a major source of global morbidity and mortality. Currently there exists no antistaphylococcal vaccine in clinical use. Previous animal studies suggested a possible role for purified lipoteichoic acid as a vaccine target for eliciting protective IgG to several Gram-positive pathogens. Since the highly conserved (poly)glycerolphosphate backbone of lipoteichoic acid is a major antigenic target of the humoral immune system during staphylococcal infections, we developed a synthetic method for producing glycerol phosphoramidites to create a covalent 10-mer of (poly)glycerolphosphate for potential use in a conjugate vaccine. We initially demonstrated that intact Staphylococcus aureus elicits murine CD4؉ T cell-dependent (poly)glycerolphosphate-specific IgM and IgG responses in vivo. Naive mice immunized with a covalent conjugate of (poly)glycerolphosphate and tetanus toxoid in alum plus CpG-oligodeoxynucleotides produced high secondary titers of serum (poly)glycerolphosphate-specific IgG. Sera from immunized mice enhanced opsonophagocytic killing of live Staphylococcus aureus in vitro. Mice actively immunized with the (poly)glycerolphosphate conjugate vaccine showed rapid clearance of staphylococcal bacteremia in vivo relative to mice similarly immunized with an irrelevant conjugate vaccine. In contrast to purified, natural lipoteichoic acid, the (poly)glycerolphosphate conjugate vaccine itself exhibited no detectable inflammatory activity. These data suggest that a synthetic (poly)glycerolphosphate-based conjugate vaccine will contribute to active protection against extracellular Gram-positive pathogens expressing this highly conserved backbone structure in their membrane-associated lipoteichoic acid.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Novel Synthetic (Poly)Glycerolphosphate-Based Antistaphylococcal Conjugate Vaccine

et al. 2013

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“…The recent progress in the identification of antibodies that react with highly conserved epitopes on diverse variants of a single virus or common epitopes on related viruses, such as for HIV-1, hepatitis C and influenza (Burton et al, 2012; or paramyxoviruses , bears promise for the development of antibody therapy of infectious diseases. Similar strategies are being pursued for treatment of bacterial infections (Garcia-Rodriguez et al, 2007;Theilacker et al, 2012). Potentially, such antibodies could be combined with strategies to improve their complement activating capabilities, such as described in the next section.…”

Section: Infectious Diseasesmentioning

confidence: 99%

Complement in therapy and disease

Melis

Strumane

Ruuls

et al. 2015

Molecular Immunology

119

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Complement is recognized as a key player in a wide range of normal as well as disease-related immune, developmental and homeostatic processes. Knowledge of complement components, structures, interactions, and cross-talk with other biological systems continues to grow and this leads to novel treatments for cancer, infectious, autoimmune- or age-related diseases as well as for preventing transplantation rejection. Antibodies are superbly suited to be developed into therapeutics with appropriate complement stimulatory or inhibitory activity. Here we review the design, development and future of antibody-based drugs that enhance or dampen the complement system.

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An Overview of Structural Features of Antibacterial Glycoconjugate Vaccines That Influence Their Immunogenicity

Khatun

Stephenson

Tóth

2017

Chemistry A European J

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Bacterial cell-surface-derived or mimicked carbohydrate moieties that act as protective antigens are used in the development of antibacterial glycoconjugate vaccines. The carbohydrate antigen must have a minimum length or size to maintain the conformational structure of the antigenic epitope(s). The presence or absence of O-acetate, phosphate, glycerol phosphate and pyruvate ketal plays a vital role in defining the immunogenicity of the carbohydrate antigen. The nature of the carrier protein, spacer and conjugation pattern used to develop the glycoconjugate vaccine also defines its overall spatial orientation which in turn affects its avidity and selectivity of interaction with the desired target(s). In addition, the ratio of carbohydrate to protein in glycoconjugate vaccines also makes an important contribution in determining the optimum immunological response. This Review article presents the importance of these variables in the development of antibacterial glycoconjugate vaccines and their effects on immune efficacy.

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Protection Against Staphylococcus aureus by Antibody to the Polyglycerolphosphate Backbone of Heterologous Lipoteichoic Acid

Cited by 42 publications

References 47 publications

Novel Synthetic (Poly)Glycerolphosphate-Based Antistaphylococcal Conjugate Vaccine

Novel Synthetic (Poly)Glycerolphosphate-Based Antistaphylococcal Conjugate Vaccine

Complement in therapy and disease

An Overview of Structural Features of Antibacterial Glycoconjugate Vaccines That Influence Their Immunogenicity

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