Antibody-Based Biologics and Their Promise to Combat Staphylococcus aureus Infections

Sause, William E.; Buckley, Peter T.; Strohl, William R.; Lynch, A. Simon; Torres, Victor J.

doi:10.1016/j.tips.2015.11.008

Cited by 82 publications

(89 citation statements)

References 74 publications

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“…44,45 Despite these limitations, PVL could play a role as a target for active and passive immunization, due to the structural homology of subunits among members of the bi-component cytotoxin family. 46 This structural homology allows for cross-neutralization of several virulence factors with antibodies generated against a single virulence factor. For example, LukS shares approximately 80% amino acid identity with leukocidin component LukE and gamma hemolysin component HlgA, while LukF is highly related to LukD and HlgB.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…This is especially critical in light of repeated experiences showing that vaccines and antibody-based approaches targeting S. aureus failed to show clinical efficacy despite supportive preclinical in vivo data generated in rodent models (mainly in mice) (21). Recent immune approaches increasingly employ cytolysins as vaccine antigens and as targets for human monoclonal antibody therapeutics (22,23). A previously described human MAb, Hla-F#5, binds to a region sufficiently conserved in alpha-hemolysin (Hla), LukF-PV, HlgB, and …”

Section: Discussionmentioning

confidence: 99%

Improved Protection in a Rabbit Model of Community-Associated Methicillin-Resistant Staphylococcus aureus Necrotizing Pneumonia upon Neutralization of Leukocidins in Addition to Alpha-Hemolysin

Diep

Visram

et al. 2016

Antimicrob Agents Chemother

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b Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA), especially the USA300 pulsotype, is a frequent cause of skin and soft tissue infections and severe pneumonia. Despite appropriate antibiotic treatment, complications are common and pneumonia is associated with high mortality. S. aureus strains express multiple cytotoxins, including alpha-hemolysin (Hla) and up to five bicomponent leukocidins that specifically target phagocytic cells for lysis. CA-MRSA USA300 strains carry the genes for all six cytotoxins. Species specificity of the leukocidins greatly contributes to the ambiguity regarding their role in S. aureus pathogenesis. We performed a comparative analysis of the leukocidin susceptibility of human, rabbit, and mouse polymorphonuclear leukocytes (PMNs) to assess the translational value of mouse and rabbit S. aureus models. We found that mouse PMNs were largely resistant to LukSF-PV, HlgAB, and HlgCB and susceptible only to LukED, whereas rabbit and human PMNs were highly sensitive to all these cytotoxins. In the rabbit pneumonia model with a USA300 CA-MRSA strain, passive immunization with a previously identified human monoclonal antibody (MAb), Hla-F#5, which cross-neutralizes Hla, LukSF-PV, HlgAB, HlgCB, and LukED, provided full protection, whereas an Hla-specific MAb was only partially protective. In the mouse USA300 CA-MRSA pneumonia model, both types of antibodies demonstrated full protection, suggesting that Hla, but not leukocidin(s), is the principal virulence determinant in mice. As the rabbit recapitulates the high susceptibility to leukocidins characteristic of humans, this species represents a valuable model for assessing novel, cytotoxin-targeting anti-S. aureus therapeutic approaches.

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“…preoperatively in cardiac surgery patients). [5][6][7] Therefore, studies investigating the profile of patients at high risk of S. aureus SSI are needed.…”

Section: Introductionmentioning

confidence: 99%

Temporal trends and epidemiology of Staphylococcus aureus surgical site infection in the Swiss surveillance network: a cohort study

Abbas

Aghayev

Kuster³

et al. 2018

Journal of Hospital Infection

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Antibody-Based Biologics and Their Promise to Combat Staphylococcus aureus Infections

Cited by 82 publications

References 74 publications

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

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

Improved Protection in a Rabbit Model of Community-Associated Methicillin-Resistant Staphylococcus aureus Necrotizing Pneumonia upon Neutralization of Leukocidins in Addition to Alpha-Hemolysin

Temporal trends and epidemiology of Staphylococcus aureus surgical site infection in the Swiss surveillance network: a cohort study

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