Structurally Designed Attenuated Subunit Vaccines for S. aureus LukS-PV and LukF-PV Confer Protection in a Mouse Bacteremia Model

Karaüzüm, Hatice; Adhikari, Rajan P.; Sarwar, Jawad; Devi, V. Sathya; Abaandou, Laura; Haudenschild, Christian; Mahmoudieh, Mahta; Boroun, Atefeh R.; Vu, Hong; Nguyen, Tam Luong; Warfield, Kelly L.; Shulenin, Sergey; Aman, M. Javad

doi:10.1371/journal.pone.0065384

Cited by 44 publications

(70 citation statements)

References 43 publications

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“…Similarly, the administration of anti-PVL antibodies to the eyes of S. aureusinfected mice using a keratitis model demonstrated increased efficacy for the resolution of CA-MRSA (327). An additional study showed that immunization of mice with rationally designed mutants of PVL leads to significantly improved outcomes in a lethal systemic infection model, although the protection observed in this model is likely due to the broadly neutralizing capacity of the sera (lytic factors other than PVL were blocked by sera obtained from PVL-immunized animals) (328). Currently, it is difficult to reconcile the conflicting evidence both in favor of and against leucocidin immunization strategies as viable therapeutic options.…”

Section: Targeting Of Leucocidins As a Therapeutic Modalitymentioning

confidence: 99%

“…Thus, not only are anti-PVL antibodies capable of reducing PVL-induced inflammation in in vivo rabbit models, it is also possible to generate antibody molecules that neutralize more than one leucocidin pair. Work by Karauzum and colleagues also demonstrated that the generation of broadly neutralizing antibodies after immunization with PVL can have dramatic effects on pathogenic outcomes using a lethal murine systemic infection model (328). It is likely that antibodies with cross-neutralizing capabilities such as these will prove far more efficacious, highlighting promise toward the development of antitoxin molecules that may be able to target multiple toxins at the same time.…”

Section: Targeting Of Leucocidins As a Therapeutic Modalitymentioning

confidence: 99%

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The Bicomponent Pore-Forming Leucocidins of Staphylococcus aureus

Alonzo

Torres

2014

Microbiol Mol Biol Rev

235

306

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SUMMARY The ability to produce water-soluble proteins with the capacity to oligomerize and form pores within cellular lipid bilayers is a trait conserved among nearly all forms of life, including humans, single-celled eukaryotes, and numerous bacterial species. In bacteria, some of the most notable pore-forming molecules are protein toxins that interact with mammalian cell membranes to promote lysis, deliver effectors, and modulate cellular homeostasis. Of the bacterial species capable of producing pore-forming toxic molecules, the Gram-positive pathogen Staphylococcus aureus is one of the most notorious. S. aureus can produce seven different pore-forming protein toxins, all of which are believed to play a unique role in promoting the ability of the organism to cause disease in humans and other mammals. The most diverse of these pore-forming toxins, in terms of both functional activity and global representation within S. aureus clinical isolates, are the bicomponent leucocidins. From the first description of their activity on host immune cells over 100 years ago to the detailed investigations of their biochemical function today, the leucocidins remain at the forefront of S. aureus pathogenesis research initiatives. Study of their mode of action is of immediate interest in the realm of therapeutic agent design as well as for studies of bacterial pathogenesis. This review provides an updated perspective on our understanding of the S. aureus leucocidins and their function, specificity, and potential as therapeutic targets.

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Section: Targeting Of Leucocidins As a Therapeutic Modalitymentioning

confidence: 99%

Section: Targeting Of Leucocidins As a Therapeutic Modalitymentioning

confidence: 99%

The Bicomponent Pore-Forming Leucocidins of Staphylococcus aureus

Alonzo

Torres

2014

Microbiol Mol Biol Rev

235

306

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“…19 a-toxin and Panton-Valentine leukocidin (PVL) are 2 toxins of interest for a toxoid based approach that have shown efficacy in animal models. [20][21][22] a-toxin is a highly conserved toxin that causes tissue barrier disruption at host interfaces lined by epithelial or endothelial cells, and undermines the host immune response. 23 Reduced skin lesion size and dermonecrosis were observed in mice immunized with a nontoxigenic form of a-toxin, following infection with USA300.…”

Section: Introductionmentioning

confidence: 99%

“…34 Protection against USA300 sepsis was demonstrated in a murine model using a vaccine composed of highly attenuated forms of PVL sub-units (rLukS-PV or rLukF-PV). 21 …”

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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“…We have previously demonstrated that the presence of higher titers of antiexotoxin antibodies at the time of sepsis is associated with improved outcomes in patients with invasive S. aureus infection (7). We have previously shown that a toxoid vaccine for S. aureus poreforming toxins, such as alpha-hemolysin (Hla) and leukocidins, can provide protection against S. aureus infection in mice (29,30). A multivalent toxoid vaccine can also be combined with surface antigens to induce both toxin neutralization and opsonophagocytic activity.…”

Section: Discussionmentioning

confidence: 99%

Safety and Immunogenicity of a Parenterally Administered, Structure-Based Rationally Modified Recombinant Staphylococcal Enterotoxin B Protein Vaccine, STEBVax

Chen

Pasetti

Adhikari

et al. 2016

Clin Vaccine Immunol

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S everal staphylococcal enterotoxins (SEs) are bacterial superantigens (SAgs) produced by Staphylococcus aureus. The serologically and genetically distinct SEs (A, A1, A2, B, C, C1, C2, C3, D, E, G, H, and I) bind to major histocompatibility complex class II (MHC-II) proteins and to T-cell antigen receptors (TCRs), bypassing processing by antigen-presenting cells (1). Since T-cell engagement with SAgs is independent of clonal specificity, picomolar concentrations of a SAg can result in the polyclonal activation of large subsets of peripheral T cells (up to 20%) (2-4). The nonspecific activation of lymphocytes and the subsequent overwhelming production of cytokines make the clinical effects of SAgs potentially lethal. During the 1960s, staphylococcal enterotoxin B (SEB) became a focus of interest because aerosolization of minute amounts could be used to produce an incapacitating biological weapon (5).Strategies to counteract the effects of SAgs are currently limited to treatment of the infection, which thereby limits toxin production. There are currently no approved vaccines for Staphylococcus aureus or SEB. There is evidence that anti-SEB antibodies capable of neutralizing the effect of the SAg can abrogate the superantigenic activation of the immune system and be protective for the host (6, 7). Nonetheless, efforts to develop SEB vaccines require caution because biological inactivation must be complete and the critical antigenic structural epitopes must be preserved.An Escherichia coli-expressed recombinant SEB (rSEB) mutant containing mutations in the hydrophobic binding loop (L45R), the polar binding pocket (Y89A), and the disulfide loop (Y94A) was developed using a structure-based rational approach (8) wherein site-specific mutagenesis was used to direct mutations at the MHC-II binding site (9-11). In a limited number of animal challenge studies, parenteral immunization with a nonadjuvanted rSEB mutant elicited anti-SEB IgG antibodies in mice and rhesus monkeys that could be measured by enzyme-linked immunosorbent assay (ELISA) and that correlated with protection (9). Nasal and oral immunization with the rSEB mutant, given with cholera toxin (CT) as an adjuvant, also elicited anti-SEB antibodies and protected against lethal challenge (10). In expanded studies, mice and rhesus monkeys parenterally immunized with the rSEB mutant plus an alum adjuvant demonstrated anti-SEB antibodies that correlated with protection; animals that achieved anti-SEB titers of Ն10 4 were 100% protected, those with titers of ϳ10 3 had partial

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Structurally Designed Attenuated Subunit Vaccines for S. aureus LukS-PV and LukF-PV Confer Protection in a Mouse Bacteremia Model

Cited by 44 publications

References 43 publications

The Bicomponent Pore-Forming Leucocidins of Staphylococcus aureus

The Bicomponent Pore-Forming Leucocidins of Staphylococcus aureus

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 Parenterally Administered, Structure-Based Rationally Modified Recombinant Staphylococcal Enterotoxin B Protein Vaccine, STEBVax

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