Vaccination with Clumping Factor A and Fibronectin Binding Protein A to Prevent<i>Staphylococcus aureus</i>Infection of an Aortic Patch in Mice

Arrecubieta, Carlos; Matsunaga, Iwao; Asai, Tomohiro; Naka, Yoshifumi; Deng, Mario C.; Lowy, Franklin D.

doi:10.1086/590210

Cited by 50 publications

(35 citation statements)

References 15 publications

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“…C, surface plot of SEB shows mutated residues (red color) which are distinct from D the MHC surface (rotating 180 degrees around vertical axis) shows in cyan (residues 43, 44, 45, 46, 47, treatment of viral diseases including rabies and SARS, combination of mAbs against wild-type epitope and variant epitope can prevent the emergence of escape variants (47,48). Moreover several studies have shown that targeting more than one adhesion protein with mAb in S. aureus infection can be beneficial (49,50).…”

Section: Discussionmentioning

confidence: 99%

Generation, Characterization, and Epitope Mapping of Neutralizing and Protective Monoclonal Antibodies against Staphylococcal Enterotoxin B-induced Lethal Shock

Varshney

Wang

Cook

et al. 2011

Journal of Biological Chemistry

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T-cell stimulating activity of Staphylococcal enterotoxin B (SEB) is an important factor in the pathogenesis of certain staphylococcal diseases including SEB mediated shock. SEB is one of the most potent superantigens known and treatment of SEB induced shock remains a challenge. We generated and characterized murine monoclonal antibodies (mAbs) to SEB in mice. We tested mAbs neutralize mitogenic effects of SEB in vitro and in vivo with T-cell proliferation assays and 2 murine models for SEB induced lethal shock (SEBILS). Epitope mapping suggests that all these mAbs recognize conformational epitopes that are destroyed by deleting the C terminus of the protein. Further site-directed mutagenesis identified potential residues involved in binding to SEB that differ between Methicillin resistant and sensitive Staphylococcus aureus strains. Only mAb 20B1 was effective as a monotherapy in treating SEBILS in HLA DR3 transgenic mice, which exhibit enhanced sensitivity to SEB. It is noteworthy that mAbs, 14G8 and 6D3 were not protective when given alone in the HLA DR3 mice but their efficacy of protection could be greatly enhanced when mAbs were co-administered simultaneously. Our data suggest combinations of defined mAbs may constitute a better treatment strategy and provide a new insight for the development of passive immunotherapy. The Staphylococcal enterotoxins (SEs)2 comprise a family of distinct toxins (A-E) all of which are excreted by various strains of Staphylococcus aureus (S. aureus) (1). Staphylococcal enterotoxin B (SEB) is a well characterized 28 kDa protein that is related to SEC1-3 on the basis of sequence homology (1, 2). SEB is a superantigen that triggers cytokine production and T-cell proliferation by cross-linking MHC class II molecules on antigen presenting cells and T-cell receptors (TCR) (2-5). In humans, SEB can trigger toxic shock, profound hypotension and multi-organ failure. SEB is the major enterotoxin associated with non-menstrual toxic shock syndrome and accounts for the majority of intoxications that are not caused by toxic shock syndrome toxin 1 (TSST-1). In addition, some reports indicate that SEB induces an IgE response and thereby might contribute to the pathogenesis of asthma, chronic rhinitis, and dermatitis (6 -9). SEB is considered a select agent. The quantities needed to produce a desired effect are much lower than with synthetic chemicals. Also SEB can be easily produced in large quantities (10).Currently there are no therapies available for treating enterotoxin-induced shock, but clinical data suggests that immunoglobulins can alleviate disease (11). Moreover, passive administration of pooled human immunoglobulin, as well as murine and chicken antibodies (Abs) can protect against SEB induced lethal shock (SEBILS) in murine and primate animal models as well as against SEB triggered release of cytokines by SEB stimulated T-cells (12, 13). The efficacy of humoral immunity in protection against SEB was established by demonstrating an inverse relationship between susceptibility and an...

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Section: Discussionmentioning

confidence: 99%

Generation, Characterization, and Epitope Mapping of Neutralizing and Protective Monoclonal Antibodies against Staphylococcal Enterotoxin B-induced Lethal Shock

Varshney

Wang

Cook

et al. 2011

Journal of Biological Chemistry

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“…Several studies have investigated the many surface proteins and virulence factors of S. aureus, many of which have been evaluated as potential vaccine targets (6)(7)(8)(9)(10)(11)(12)(13)(14)(15). Current and past S. aureus vaccines or therapeutic antibody strategies have focused mainly on capsular polysaccharide (CPS), virulence factors, surface proteins, and iron-regulated proteins.…”

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confidence: 99%

“…The leading candidate of this type of vaccine is StaphVAX, a bivalent polysaccharide and protein-conjugated vaccine (16,17). Other strategies for developing S. aureus vaccines have targeted virulence factors and surface proteins, including alpha-toxin (a nontoxic derivative of H35L) (7,18), clumping factor A (ClfA) (19), fibronectin binding protein A or B (FnBPA or FnBPB) (12), Panton-Valentine leukocidin (PVL) (20), and protein A (11). Iron-regulated proteins, such as Merck V710, which is based on iron-regulated surface determinant B (IsdB) (6,21), have also been investigated as other possible targets for vaccines against S. aureus.…”

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confidence: 99%

Recombinant ESAT-6-Like Proteins Provoke Protective Immune Responses against Invasive Staphylococcus aureus Disease in a Murine Model

Zhang

Hua

et al. 2015

Infect Immun

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bStaphylococcus aureus is a common pathogen found in the community and in hospitals. Most notably, methicillin-resistant S. aureus is resistant to many antibiotics, which is a growing public health concern. The emergence of drug-resistant strains has prompted the search for alternative treatments, such as immunotherapeutic approaches. To date, most clinical trials of vaccines or of passive immunization against S. aureus have ended in failure. In this study, we investigated two ESAT-6-like proteins secreted by S. aureus, S. aureus EsxA (SaEsxA) and SaEsxB, as possible targets for a vaccine. Mice vaccinated with these purified proteins elicited high titers of anti-SaEsxA and anti-SaEsxB antibodies, but these antibodies could not prevent S. aureus infection. On the other hand, recombinant SaEsxA (rSaEsxA) and rSaEsxB could induce Th1-and Th17-biased immune responses in mice. Mice immunized with rSaEsxA and rSaEsxB had significantly improved survival rates when challenged with S. aureus compared with the controls. These findings indicate that SaEsxA and SaEsxB are two promising Th1 and Th17 candidate antigens which could be developed into multivalent and serotype-independent vaccines against S. aureus infection.

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“…Several vaccine candidates have shown various levels of success in animal models (for reviews, see references 2 and 3). Clumping factor A (ClfA), an adhesin that can adhere to both fibrinogen and fibronectin, demonstrated some level of protection in sepsis (4,5), arthritis (5,6), prosthetic device infection (7), and mastitis (8) models. The fibrinogen-binding domain of ClfA (amino acids 40 to 559) is responsible for ligand binding.…”

mentioning

confidence: 99%

“…The fibrinogen-binding domain of ClfA (amino acids 40 to 559) is responsible for ligand binding. The entire domain and a slightly truncated version of the domain (amino acids 40 to 531) have been shown to elicit protection in animal models (5,7,9,10). A vaccine including a ClfA antigen based on the fibrinogen-binding domain fragment is currently in clinical trials (11,12).…”

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confidence: 99%

Immunogenicity Analysis of Staphylococcus aureus Clumping Factor A Genetic Variants

Brady

Mocca

Burns

2013

Clin Vaccine Immunol

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The staphylococcal adhesin clumping factor A (ClfA) has a variant amino acid sequence, generating the potential for alterations in epitope structure and immunogenicity of this vaccine candidate. We demonstrated for two recombinant ClfA 40 -531 (a slightly truncated version of the fibrinogen-binding domain of ClfA containing amino acids 40 to 531) genetic variants that strain-specific epitopes are immunodominant. This work indicates that immune responses elicited by ClfA may, at least in part, be dependent on the strain of origin of the ClfA.

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Vaccination with Clumping Factor A and Fibronectin Binding Protein A to PreventStaphylococcus aureusInfection of an Aortic Patch in Mice

Cited by 50 publications

References 15 publications

Generation, Characterization, and Epitope Mapping of Neutralizing and Protective Monoclonal Antibodies against Staphylococcal Enterotoxin B-induced Lethal Shock

Generation, Characterization, and Epitope Mapping of Neutralizing and Protective Monoclonal Antibodies against Staphylococcal Enterotoxin B-induced Lethal Shock

Recombinant ESAT-6-Like Proteins Provoke Protective Immune Responses against Invasive Staphylococcus aureus Disease in a Murine Model

Immunogenicity Analysis of Staphylococcus aureus Clumping Factor A Genetic Variants

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