The Provost Fellows and Scholars of the College of the Holy and Undivided Trinity of Queen Elizabeth, Near Dublin

The Texas A&m University System

Inhibitex, Inc.

Other

Universitá Degli Studi Di Pavia

Bioresearch Ireland

Glaxosmithkline Biologicals Sa

The Provost, Fellows and Scholars of the College of the Holy and Undivided Trinity of Queen Elizabeth

The Provost, Fellows and Scholars of the College of the Holy and

Provost Fellows & Scholars of the College of the Univ. of the Holy

The Provost Fellows and Scholars of the College of the Holy and Undivived Trinity of Queen Elizabeth Near Dublin

The Provost, Fellows, Foundation Scholars & the Other Members of Board, of the College of the Holy & Undiv. Trinity of Queen Elizabeth, Near Dublin

Timothy James Foster

Joseph M Patti

Magnus A O Hook

Elisabet Josefsson

Magnus A Hook

Damien Leo McDevitt

Samuel E Perkins

Deidre Ni Eidhin

Andrej Tarkowski

Joan Geoghegan

Orla Hartford

Kirk McCrea

Judy Higgins

Jeff T Hutchins

Pietro Speziale

Stacy Davis

Deirdre Ni Eidhin

Mark Pallen

Fiona Roche

Antonius Arnoldus Jacobs

Stacey Davis

Guy Dequesne

Elizabet Joseffson

Deirdre Nieidhin

Orla Mary Hartford

Andrej (deceased) Tarkowski

Magnus Hook

Fiona c/o The Provost Fellows & Scholars Roche

Elizabet Josefsson

The present invention is directed to improved microbial antigen vaccines, pharmaceutical compositions, immunogenic compositions and antibodies and their use in the treatment of microbial infections, particularly those of bacterial origin, including Staphylococcal origin. Ideally, the present invention is directed to a recombinant staphylococcal MSCRAMM or MSCRAMM-like proteins, or fragment thereof, with reduced binding to its host ligand, for use in therapy.

Treatment of microbial infections

Method of prophlactically treating infection using a recombinant fibrinogen binding protein clumping factor A (ClfA) or fragment thereof

Multicomponent vaccines are provided which aid in the prevention and treatment of staphylococcal infections and which include certain selected combinations of bacterial binding proteins or fragments thereof, or antibodies to those proteins or fragments. By careful selection of the proteins, fragments, or antibodies, a vaccine is provided that imparts protection against a broad spectrum ofand other bacterial strains and against proteins that are expressed at different stages of the logarithmic growth curve. In one embodiment of the invention, a composition is provided that includes a fibrinogen binding domain of a fibrinogen binding protein and a bacterial component such as a capsular polysaccharide, and both active and passive vaccines based on these components are also provided, along with methods of treating infection using these compositions and vaccines.

Multicomponent vaccines

Surface proteins are provided which generate polyclonal and monoclonal antibodies which are cross-reactive to both coagulase-positivebacteria, such asand to coagulase-negative bacteria, such asand. The antibodies may be generated from surface proteins that have been isolated on the basis of characteristics that may be common betweenand coagulase-negative staphylococci, or the A domains of those surface proteins, and these recombinant surface proteins are used to generate the cross-reactive antibodies. Vaccines comprising an immunologically effective amount of the proteins are also provided, and these vaccines are used in methods for the treatment or protection against a wide variety of staphylococcal infections.

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An isolated extracellular matrix-binding protein, designated as SdrE and its corresponding amino acid and nucleic acid sequences and motifs are described. The proteins, peptides, fragments thereof or antigenic portions thereof are useful for the prevention, inhibition, treatment and diagnosis ofinfection and as scientific research tools. Further, antibodies or antibody fragments to the proteins, peptides, fragments thereof or antigenic portions thereof are also useful for the prevention, inhibition, treatment and diagnosis ofinfection. In particular, the proteins or antibodies thereof may be administered to wounds or used to coat biomaterials to act as blocking agents to prevent or inhibit the binding ofto wounds or biomaterials.

The isolation of genes and proteins fromis provided, and the nucleic acids coding for specific regions of theprotein are described. The nucleic acids encode proteins that can be useful as vaccines or in pharmaceutical compositions for application to prevent infection, promotion of wound healing, blocking adherence to indwelling medical devices, or diagnosis of infection.

An isolated extracellular matrix-binding protein, designated as SdrD and its corresponding amino acid and nucleic acid sequences and motifs are described. The proteins, peptides, fragments thereof or antigenic portions thereof are useful for the prevention, inhibition, treatment and diagnosis ofinfection and as scientific research tools. Further, antibodies or antibody fragments to the proteins, peptides, fragments thereof or antigenic portions thereof are also useful for the prevention, inhibition, treatment and diagnosis ofinfection. In particular, the proteins or antibodies thereof may be administered to wounds or used to coat biomaterials to act as blocking agents to prevent or inhibit the binding ofto wounds or biomaterials.

An isolated extracellular matrix-binding protein, designated as SdrC and its corresponding amino acid and nucleic acid sequences and motifs are described. The proteins, peptides, fragments thereof or antigenic portions thereof are useful for the prevention, inhibition, treatment and diagnosis ofinfection and as scientific research tools. Further, antibodies or antibody fragments to the proteins, peptides, fragments thereof or antigenic portions thereof are also useful for the prevention, inhibition, treatment and diagnosis ofinfection. In particular, the proteins or antibodies thereof may be administered to wounds or used to coat biomaterials to act as blocking agents to prevent or inhibit the binding ofto wounds or biomaterials.

Methods for treating or preventing infections from coagulase-negative staphylococci using proteins and polypeptides from coagulase-negative staphylococcal bacteria such as, including proteins designated SdrF, SdrG and SdrH, and their effective fragments such as their respective A domains, are provided. Methods are also provided wherein antibodies that recognize the SdrG protein or its ligand binding A region are used to treat or prevent staphylococcal infection, and these methods can also be utilized to prevent the formation of infections on indwelling medical devices.

Polypeptides and polynucleotides from coagulase-negative staphylococci

Multicomponent vaccines are provided which aid in the prevention and treatment of staphylococcal infections and which include certain selected combinations of bacterial binding proteins or fragments thereof, or antibodies to those proteins or fragments. By careful selection of the proteins, fragments, or antibodies, a vaccine is provided that imparts protection against a broad spectrum ofand other bacterial strains and against proteins that are expressed at different stages of the logarithmic growth curve. In one embodiment of the invention, a composition is provided that includes a fibrinogen binding domain of a fibrinogen binding protein and a bacterial component such as ca capsular polysaccharide, and both active and passive vaccines based on these components are also provided, along with methods of treating infection using these compositions and vaccines.

Proteins and polypeptides from coagulase-negative staphylococcal bacteria such as, including proteins designated SdrF, SdrG and SdrH, and their effective fragments such as their respective A domains, are provided which are useful in the prevention and treatment of infection caused by coagulase-negative staphylococcal bacteria such as. The SdrF, SdrG and SdrH proteins are cell-wall associated proteins that specifically bind host proteins and which each have a highly conserved motif of which the consensus sequence is TYTFTDYVD (SEQ ID NO: 16). The proteins and polypetides may be useful in generating antibodies for the diagnosis and treatment of coagulase-negative staphylococcal infections.

Proteins and polypeptides from coagulaslase-negative staphylococci

Isolated extracellular matrix-binding proteins, designated ClfB, SdrC, SdrD and SdrE, and their corresponding amino acid and nucleic acid sequences and motifs are described. The proteins, peptides, fragments thereof or antigenic portions thereof are useful for the prevention, inhibition, treatment and diagnosis ofinfection and as scientific research tools. Further, antibodies or antibody fragments to the proteins, peptides, fragments thereof or antigenic portions thereof are also useful for the prevention, inhibition, treatment and diagnosis ofinfection. In particular, the proteins or antibodies thereof may be administered to wounds or used to coat biomaterials to act as blocking agents to prevent or inhibit the binding ofto wounds or biomaterials. ClfB is a cell-wall associated protein having a predicted molecular weight of approximately 88 kDa and an apparent molecular weight of approximately 124 kDa, which binds both soluble and immobilized fibrinogen. ClfB binds both the alpha and beta chains of fibrinogen and acts as a clumping factor. SdrC, SdrD and SdrE are cell-wall associated proteins that exhibit cation-dependent ligand binding to the extracellular matrix. It has been discovered that in the A region of SdrC, SdrD, SdrE, ClfA and ClfB, there is a highly conserved amino acid sequence that can be used to derive a consensus motif of TYTFTDYVD.

The isolation of genes and proteins fromis provided, and the nucleic acids coding for specific regions of theCIfA protein are described. The nucleic acids encode proteins that can be useful as vaccines or in pharmaceutical compositions for application to prevent infection, promotion of wound healing, blocking adherence to indwelling medical devices, or diagnosis of infection.

A method and composition for the passive immunization of patients infected with or susceptible to infection frombacteria such asandinfection is provided that includes the selection or preparation of a donor plasma pool with high antibody titers to carefully selectedadhesins or MSCRAMMs, or fragments or components thereof, or sequences with substantial homology thereto. The donor plasma pool can be prepared by combining individual blood or blood component samples which have higher than normal titers of antibodies to one or more of the selected adhesins or other proteins that bind to extracellular matrix proteins, or by administering carefully selected proteins or peptides to a host to induce the expression of desired antibodies, and subsequently recovering the enhanced high titer serum or plasma pool from the treated host. In either case, the donor plasma pool is preferably purified and concentrated prior to intravenous introduction into the patient, and the present invention is advantageous in that a patient can be immunized against a wide variety of potentially dangerous staphylococcal infections. Kits for identifying potential donor with high titers of the selected adhesins are also provided. The present invention thus provides methods and compositions which can be highly effective against infections associated withbacteria.

Growing community of inventors

Dublin, Ireland

Timothy James Foster