A Serologic Correlate of Protective Immunity Against Community-Onset Staphylococcus aureus Infection

Fritz, Stephanie A.; Tiemann, Kristin M.; Hogan, Patrick G.; Epplin, Emma K.; Rodriguez, Marcela; Al-Zubeidi, Duha; Wardenburg, Juliane Bubeck; Hunstad, David A.

doi:10.1093/cid/cit123

Cited by 126 publications

(136 citation statements)

References 40 publications

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“…Evidence is available suggesting the importance of antibodies in controlling S. aureus infections: in vitro and in vivo antibodydependent protection have been reported for S. aureus antigens (20)(21)(22)(23), antibody titers against S. aureus have been shown to rise during infections (24), and immunoglobulin deficiencies were related to an increase in susceptibility to the pathogen (25). Nevertheless, limited correlations have been established between antibody levels and disease severity or protection (22,26).…”

Section: Discussionmentioning

confidence: 99%

Four-Component Staphylococcus aureus Vaccine 4C-Staph Enhances Fcγ Receptor Expression in Neutrophils and Monocytes and Mitigates S. aureus Infection in Neutropenic Mice

et al. 2015

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Section: Discussionmentioning

confidence: 99%

Four-Component Staphylococcus aureus Vaccine 4C-Staph Enhances Fcγ Receptor Expression in Neutrophils and Monocytes and Mitigates S. aureus Infection in Neutropenic Mice

et al. 2015

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“…Intravenous drug users without endocarditis were more frequently antibody positive (Ͼ3.2 IU/ml; 44%) than were those with endocarditis (6%; P ϭ 0.01) (48). The most compelling data that anti-alphatoxin antibodies correlate with protection from S. aureus disease came from a recent report by Fritz et al (51). The data from that study showed that symptomatic subjects colonized with S. aureus exhibited the highest mean baseline Ab titers against alpha-toxin (P ϭ 0.002) and that patients with invasive S. aureus infections had the lowest preexisting Ab titers against alpha-toxin or LukF.…”

Section: Figmentioning

confidence: 99%

“…Twelve distinct alpha-toxin sequence types were identified from the 197 hla-positive isolates, and MEDI4893 neutralized alpha-toxin produced by all 12 different variants. Based on these observations, the correlation of higher anti-alpha-toxin antibody levels to better clinical outcomes in epidemiological studies (36,48,51) and the efficacy of alpha-toxin MAbs or vaccines in animal models (27,(32)(33)(34), we have initiated a phase 2 clinical trial with MEDI4893 to prevent ventilator-associated S. aureus pneumonia. Further studies are under way to verify these observations among S. aureus pneumonia patients.…”

Section: Figmentioning

confidence: 99%

Characterization of Alpha-Toxin hla Gene Variants, Alpha-Toxin Expression Levels, and Levels of Antibody to Alpha-Toxin in Hemodialysis and Postsurgical Patients with Staphylococcus aureus Bacteremia

Sharma-Kuinkel

Wu²,

Tabor³

et al. 2015

J Clin Microbiol

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c Alpha-toxin is a major Staphylococcus aureus virulence factor. This study evaluated potential relationships between in vitro alpha-toxin expression of S. aureus bloodstream isolates, anti-alpha-toxin antibody in serum of patients with S. aureus bacteremia (SAB), and clinical outcomes in 100 hemodialysis and 100 postsurgical SAB patients. Isolates underwent spa typing and hla sequencing. Serum anti-alpha-toxin IgG and neutralizing antibody levels were measured by using an enzyme-linked immunosorbent assay and a red blood cell (RBC)-based hemolysis neutralization assay. Neutralization of alpha-toxin by an anti-alpha-toxin monoclonal antibody (MAb MEDI4893) was tested in an RBC-based lysis assay. Most isolates encoded hla (197/200; 98.5%) and expressed alpha-toxin (173/200; 86.5%). In vitro alpha-toxin levels were inversely associated with survival (cure, 2.19 g/ml, versus failure, 1.09 g/ml; P < 0.01). Both neutralizing (hemodialysis, 1.26 IU/ml, versus postsurgical, 0.95; P < 0.05) and IgG (hemodialysis, 1.94 IU/ml, versus postsurgical, 1.27; P < 0.05) antibody levels were higher in the hemodialysis population. Antibody levels were also significantly higher in patients infected with alpha-toxin-expressing S. aureus isolates (P < 0.05). Levels of both neutralizing antibodies and IgG were similar among patients who were cured and those not cured (failures). Sequence analysis of hla revealed 12 distinct hla genotypes, and all genotypic variants were susceptible to a neutralizing monoclonal antibody in clinical development (MEDI4893). These data demonstrate that alpha-toxin is highly conserved in clinical S. aureus isolates. Higher in vitro alpha-toxin levels were associated with a positive clinical outcome. Although patients infected with alpha-toxin-producing S. aureus exhibited higher anti-alpha-toxin antibody levels, these levels were not associated with a better clinical outcome in this study. Staphylococcus aureus is a leading cause of bacterial infections (1-4), including skin and soft tissue infections (5), pneumonia (6), bacteremia (7), endocarditis (8-10), and bone and joint infections (11). The risk of invasive S. aureus infections is significantly higher among certain subgroups, including hemodialysisdependent patients and postoperative patients (12-14).These high-risk subpopulations are potential candidates for novel forms of prevention or treatment against invasive S. aureus infections.Alpha-toxin, a ␤-barrel pore-forming exotoxin encoded by hla (15, 16), is a key virulence factor produced by most S. aureus isolates (17, 18). It binds to ADAM10 (the A disintegrin and metalloproteinase domain-containing protein 10) on target cell membranes and then heptamerizes to generate a transmembrane pore, resulting in cell lysis (19). Hyperproduction of alpha-toxin is associated with enhanced virulence in strains of both epidemic (USA300 and USA500) and endemic (ST93) community-associated methicillin-resistant S. aureus (CA-MRSA) isolates (20,21). Studies with a number of animal models have also suggested that al...

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“…25 In addition, long-term follow-up of children with invasive S. aureus disease reveals a protective association between anti-a-toxin antibody titers and recurrent infection. 26 PVL is a pore-forming cytotoxin consisting of 2 subunits, LukS-PV and LukF-PV, which cause leukocyte destruction and tissue necrosis. 27 Although produced by <5% of S. aureus strains, a large proportion of methicillin-resistant (MRSA) strains that cause invasive community-acquired infections such as necrotic skin and soft-tissue infections and necrotizing pneumonia are positive for the PVL gene.…”

Section: Introductionmentioning

confidence: 99%

Safety and immunogenicity of a recombinant Staphylococcus aureus α-toxoid and a recombinant Panton-Valentine leukocidin subunit, in healthy adults

Landrum

Lalani

Niknian³

et al. 2017

Human Vaccines & Immunotherapeutics

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We conducted a randomized, double-blind, placebo-controlled dose-escalation study in healthy adults to evaluate the safety and immunogenicity of recombinant Staphylococcus aureus candidate vaccine antigens, recombinant a-toxoid (rAT) and a sub-unit of Panton-Valentine leukocidin (rLukS-PV). 176 subjects were enrolled and randomized within 1 of 11 treatment cohorts: monovalent rAT or rLukS-PV dosages of 10, 25, 50, and 100 mg; bivalent rAT:rLukS dosages of 10:10, 25:25, and 50:50 mg; and alum or saline placebo. All subjects were assessed at Days 0, 7, 14, 28, and 84. Subjects in the 50:50 mg bivalent cohort received a second injection on Day 84 and were assessed on Days 98 and 112. Incidence and severity of reactogenicity and adverse events (AEs) were compared. Geometric mean serum concentrations (GMC) and neutralizing activity of anti-rAT and anti-rLukS-PV IgG were assessed. Reactogenicity incidence was significantly higher in vaccine than placebo recipients (77% versus 55%, respectively; p D 0.006). However, 77% of reactogenicity events were mild and 19% were moderate in severity. The AE incidence and severity were similar between the cohorts. All monovalent and bivalent rAT dosages resulted in a significant increase in the anti-rAT IgG and anti-rLukS-PV GMCs between day 0 and 28 compared with placebo, and persisted through Day 84. Exploratory subgroup analyses suggested a higher GMC and neutralizing antibody titers for the 50 mg monovalent or bivalent rAT and rLukS-PV dose as compared to the other doses. No booster effect was observed after administration of the second dose. We conclude that the rAT and rLukS-PV vaccine formulations were well-tolerated and had a favorable immunogenicity profile, producing antibody with neutralizing activity through day 84. There was no benefit observed with a booster dose of the vaccine.

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A Serologic Correlate of Protective Immunity Against Community-Onset Staphylococcus aureus Infection

Cited by 126 publications

References 40 publications

Four-Component Staphylococcus aureus Vaccine 4C-Staph Enhances Fcγ Receptor Expression in Neutrophils and Monocytes and Mitigates S. aureus Infection in Neutropenic Mice

Four-Component Staphylococcus aureus Vaccine 4C-Staph Enhances Fcγ Receptor Expression in Neutrophils and Monocytes and Mitigates S. aureus Infection in Neutropenic Mice

Characterization of Alpha-Toxin hla Gene Variants, Alpha-Toxin Expression Levels, and Levels of Antibody to Alpha-Toxin in Hemodialysis and Postsurgical Patients with Staphylococcus aureus Bacteremia

Safety and immunogenicity of a recombinant Staphylococcus aureus α-toxoid and a recombinant Panton-Valentine leukocidin subunit, in healthy adults

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