A method of preventing or treating staphylococcal bacterial infection in an individual is disclosed. A vaccine based on a conjugate of PS1 polysaccharide antigen can be used for active protection in individuals who are to be subjected to conditions that place them at immediate risk of developing a bacterial infection, as would be case in the context of a catheterization or a surgical procedure. Alternatively, antibodies raised in response to the antigen can be used to treat or to provide passive protection to individuals. The method can be used in a population of patients at risk for infection by various species of Staphylococcus or various types of Staphylococcus epidermidis.

Description of the Invention

SUMMARY OF THE INVENTION

The present inventors have found that conjugates of an antigen isolated from one type of S. epidermidis are effective in protecting against bacterial infection by strains of bacteria other than those that are classified as the same type when serotyped. More particularly, a conjugate vaccine comprising the S. epidermidis antigen confers protection against infection by other S. epidermidis strains, other coagulase-negative Staphylococcus and against S. aureus. In particular, it confers protection against infection by both the Type 336 of S. aureus that is described in U.S. Pat. No. 5,770,208, and the mixed Type 336/5 and Type 336/8 strains of S. aureus that are described in co-pending application Ser. No. 11/101,386. It also provides protection against infection by other strains of S. epidermidis that are not of the same serotype as the strain from which the antigen is isolated. This was entirely unexpected as it was not known that conjugates of this S. epidermidis antigen could stimulate the production of antibodies that combat bacterial infection by strains other than the homologous strain. Absent such a teaching, the scope of protection offered by conjugate vaccines of the S. epidermidis antigen could not have been expected.

Type 336/5 and 336/8 are strains that type as Type 5 and Type 8 S. aureus, but which are serologically cross-reactive with antibodies that are raised against 336PS conjugate (336PS covalently bound to protein) vaccine. These strains therefore type serologically as both Type 336 and one of Type 5 or Type 8. They are denoted herein as "mixed Type 336/5" and "mixed Type 336/8," and account for approximately 29% of clinically significant isolates. Serotyping of S. aureus clinical isolates from bacteremic patients showed that the 336 phenotype was present on 37% of all the clinical isolates, with 8% 336, 13% 336/5, and 16% 336/8.

Based on the inventors' discovery, a method now is provided for preventing infection in a population of patients at risk for infection by various species of Staphylococcus comprising administering to a patient in the population a composition comprising a conjugate of an isolated S. epidermidis antigen that contains an N-acetyl-glucosamine linked to glycerol phosphate, wherein the antigen binds with antibodies to S. epidermidis deposited under ATCC 55254. The antigen is denoted herein as PS1. Upon administration to humans as well as animals the conjugate of the isolated S. epidermidis antigen induces production of antibodies that protect against the homologous serotype and species or serotype of Staphylococcus other than S. epidermidis homologous to ATCC 55254. The present invention further provides a method for preventing infection in a population of patients at risk for infection by coagulase-negative Staphylococcus and coagulase-positive Staphylococcus aureus, comprising administering to a patient in the population a composition comprising a conjugate of an isolated S. epidermidis antigen that contains an N-acetylglucosamine linked to glycerol phosphate, wherein the antigen binds with antibodies to S. epidermidis deposited under ATCC 55254. Conjugates of the isolated S. epidermidis antigen produce antibodies that protect against S. aureus. The antigen comprises a 1,3-poly(glycerol phosphate) polymer chain and N-acetyl-glucosamine residues attached to the 2-position of the glycerol.

Also provided is a method for preventing and treating infection in a population of patients at risk for developing infection by various species of Staphylococcus or various types of Staphylococcus epidermidis, comprising administering to a patient in the population a composition comprising antibodies to a conjugate containing an isolated S. epidermidis antigen that contains an N-acetyl-glucosamine linked to glycerol phosphate, wherein the antigen binds with antibodies to S. epidermidis deposited under ATCC 55254. The conjugate of the isolated S. epidermidis antigen produces antibodies that protect against various species of Staphylococcus other than strains homologous to S. epidermidis deposited under ATCC 55254. The present invention also provides a method for preventing and treating infection in a patient diagnosed as having a Staphylococcus infection, comprising administering to the patient a composition comprising antibodies to an isolated S. epidermidis antigen that contains an N-acetyl-glucosamine linked to glycerol phosphate, wherein the antigen binds with antibodies to S. epidermidis deposited under ATCC 55254.

DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS

It surprisingly has been discovered that vaccines based on conjugates of PS1 can effectively protect individuals against bacterial infection not only by homologous strains of bacteria that type as S. epidermidis strains, but also by strains of S. epidermidis that are not homologous to S. epidermidis deposited under ATCC 55254, as well as by strains of S. aureus. There are very few polysaccharide-based vaccines that provide protection against bacterial infection, and protection against non-homologous strains of bacteria has not been reported for any of these. Accordingly, it was quite surprising to discover that a conjugate vaccine based on antigen isolated from a strain homologous to ATCC 55254 of S. epidermidis provided protection against some non-homologous strains of S. epidermidis and against strains of S. aureus.

Quite unexpectedly, antibodies generated in response to a PS1 conjugate vaccine also possess the ability to protect against infections in which S. aureus is the causative organism. IgG derived from PS1 conjugate vaccine shows cross-reactivity with a S. aureus polysaccharide antigen that is found on clinical isolates. Furthermore, immunoglobulin raised in response to PS1 conjugate vaccine efficiently clears S. aureus bacteremia in a mouse model.

U.S. Pat. Nos. 5,866,140 and 5,961,975 describe a process for extracting antigen from S. epidermidis, and the contents of these documents are incorporated by reference in their entirety. These patents describe that the S. epidermidis antigens provide protection against infection by clinically significant S. epidermidis isolates. In this regard, a "clinically significant" isolate is an isolate that is pathogenic.

The antigen can be obtained in recoverable amounts, from certain S. epidermidis isolates cultured pursuant to the protocols described in further detail herein, in substantially pure form. In particular, purified antigen acceptable for human use contains minimal amounts of other materials such as proteins and nucleic acids, and is of vaccine-grade quality as defined by the FDA. A "recoverable" amount in this regard means that the isolated amount of the antigen is detectable by a methodology less sensitive than radiolabeling, such as immunoassay, and can be subjected to further manipulations involving transfer of the antigen per se into solution.

To obtain PS1, ATCC 55254 or a S. epidermidis isolate homologous thereto can be grown, for example, in Columbia Broth supplemented with 4% NaCl, although other media can be substituted. The preferred medium according to the present invention is a modified Columbia broth (Difco Laboratories, Detroit, Mich.), a medium in which the level of available phosphate is 76 .mu.g/ml. Such a medium simulates the in vivo level of available phosphate in humans, which is about 23-46 .mu.g/ml. Little or no slime is produced when S. epidermidis is grown in this medium.

Following fermentation, cells are killed, and then harvested by centrifugation. Antigen preferably is extracted from cell paste, although PS1 can be extracted from both the cells and the supernatant of clinical isolates of S. epidermidis grown in Columbia broth.

Enzyme treatments of cell paste with lysostaphin, DNase, RNase and optionally protease, followed by sequential precipitation with 25-75% cold ethanol/CaCl.sub.2, results in a crude antigen extract. The lyophilized material is dissolved in buffer and loaded onto an ion-exchange column equilibrated with the same buffer. The column is washed with NaCl loading buffer and then eluted with a NaCl gradient. Fractions containing antigen are pooled, dialyzed, and concentrated. Material is then loaded onto a size exclusion column and eluted using a buffer. Fractions containing antigen are pooled, dialyzed, concentrated, and lyophilized. The separation can be repeated to obtain better purification. The foregoing protocol is exemplary; various protocols can be followed to extract and purify PS1 in accordance with the present invention.

Analysis of purified PS1 shows that it comprises N-acetyl-glucosamine and glycerol phosphate. The antigen comprises a 1,3-poly(glycerol phosphate) chain and N-acetyl-glucosamine residues attached to the 2-position of the glycerol. The PS1 antigen thus is chemically distinct from Type 336 antigen, and also is chemically distinct from both the Type 5 and Type 8 S. aureus antigens and from S. aureus teichoic acid.

The reactivities of lipoteichoic acid (LTA) derived from five different G+bacteria other than S. epidermidis (Streptococcus pyogenes, Streptococcus sanguis, Bacillus subtilis, Streptococcus faecalis and S. aureus) PS1, S. aureus 336PS ("336PS") and S. aureus teichoic acid (SA TA) were compared with different monoclonal antibodies and polyclonal antisera using Ouchterlony method. PS1-conjugate antisera and 336PS-conjugate antisera did not precipitate with any of the five LTAs. Although some of these LTAs (S. aureus, S. pyogenes, and S. anguis) reacted with anti-PS1 monoclonal antibody, their reactivity disappeared following treatment of the LTAs with NaOH, whereas NaOH-treated PS1 retained its reactivity. The results clearly demonstrate that lipoteichoic acids are distinctly different compounds from both PS1 and 336PS.

Induction of bacteremia in mammals requires extremely high numbers of organisms or some previous maneuver to lower the host resistance. In vitro phagocytosis mediated by specific antibodies to bacterial polysaccharide, however, can be used as a correlate of protective immunity in vivo. In this model, the ability of PS1-specific monoclonal and polyclonal antibodies to opsonize S. aureus in vitro is measured by phagocytosis, according to the method described in Kojima et al., Infect. Dis. Immun. 58: 2367-2374 (1990). Antibodies induced by a PS1 vaccine facilitate type-specific phagocytosis, and antibodies to PS1 are protective against infection by S. aureus strains that carry 336PS. There was no previous suggestion that antibodies to the conjugate of PS1 would be protective against S. aureus 336 strains.

Bacterial polysaccharides are generally poor immunogens. Polysaccharide antigens normally generate a T-cell independent immune response and they induce humoral antibodies with no boost of the immune response observed upon reinjection. To generate a complete immune response polysaccharides are typically conjugated to T-cell dependent immunogens such as proteins. The direct results of chemical bonding between polysaccharide and protein are to increase the immunogenicity of the polysaccharide and memory response to the antigen potentiating their use in infants and immune-compromised patients. Therefore, for use in a vaccine, it is preferable to conjugate the antigen to an immunocarrier, usually a polypeptide or protein, thereby to improve qualitatively and quantitatively the host humoral immune response specific to the PS1 antigen by recruiting T cells and interaction between T and B cells for the induction of an immune response against the PS1 antigen. This is particularly important for vaccines intended for use in patients with reduced resistance.

An immunocarrier thus enhances immunogenicity both for active immunization, for preparing high-titered antisera in volunteers for passive immunization and for use as an immunogen in the process of making monoclonal antibodies. Suitable immunocarriers according to the present invention include tetanus toxoid, diphtheria toxoid, Pseudomonas aeruginosa Exotoxin A or its derivatives, recombinantly-produced non-toxic mutants of exotoxin A, as described, for example, in Fattom et al., Infect Immun 61: 1023-1032 (1993), as well as other proteins used as immunocarriers.

PS1 can be treated with carabodiimide such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and bound, through a linker containing nucleophilic group(s) or without a linker, to a suitable immunocarrier such as a protein, e.g., diphtheria toxoid (DTd), recombinant exoprotein A from Pseudomonas aeruginosa (rEPA), or tetanus toxoid (TTd) or their chemically modified derivatives such as succinylated rEPA. See, for example Kossaczka, et al., Infect Immun 65:2088-2093 (1997) The resulting conjugates are separated from unconjugated antigen.

There are other conjugation methods known in the art, e.g., cyanogen bromide (CNBr) (see Schneerson et al., J. Exp Med 152:361-376, 1980; Chu et al., Infect Immun 40:245-256, 1983) or a-cyano-4-dimethylamino-pyridinium tetrafluoroborate (CDAP) activation of carbohydrates (see Kohn, et al., FEBS Lett 154:209-210, 1983 or Kossaczka et al., Infect Immun 69:5037-5043, 2000), or periodate oxidation of carbohydrates followed with reductive amination, carbodiimide treatment, and other methods and/or their different combinations that can provide direct or indirect (through a linker) covalent binding of PS1 and carrier protein and thus yield the conjugate. Regardless of the method used to conjugate the antigen to the carrier protein, the covalent binding of PS1 to carrier protein converts PS1 from a T cell independent antigen to a T cell dependent antigen. As a result, PS1-protein conjugate elicits PS1-specific antibody response in immunized animals in contrast to no such response observed upon administering PS1 alone.

Preferably the conjugate is administered without an adjuvant in order to avoid adjuvant-induced toxicity. If an adjuvant is used, it is preferred to use one that promotes humoral immune response and is acceptable for human use, e.g., aluminum hydroxide, aluminum phosphate, QS-21. Efficient adjuvants to be used experimentally include complete Freund's adjuvant (CFA) and incomplete Freund's adjuvant (IFA). A vaccine according the invention additionally may comprise a yeast or a fungal derived .beta.-glucan or its derivatives, in particular, a baker yeast .beta.-glucan as described in U.S. Pat. No. 6,355,625.

The PS1 conjugate according to the present invention is the active ingredient in a composition, which additionally may comprise a pharmaceutically acceptable excipient for the active ingredient. In this regard, a pharmaceutically acceptable excipient is a material that can be used as a vehicle for administering a medicament because the material is inert or otherwise medically acceptable, as well as compatible with the active agent, in the context of vaccine administration. In addition to a suitable excipient, the composition can contain conventional vaccine additives like diluents, adjuvants, antioxidants, preservatives and solubilizing agents. The vaccine can induce production in vivo of antibodies that combat S. aureus, S. epidermidis and other coagulase-negative Staphylococcal infections.

Preferably, a composition of the antigen/immunocarrier conjugate according to the present invention "consists essentially of" the conjugate. In this context, the phrase "consists essentially of" means that the composition does not contain any material that negatively impacts the elicitation of an immune response to the antigen (and to other antigens, if present) when the composition is administered to a subject as a vaccine. Preferably the composition does not contain a substantial amount of unconjugated antigen.

The present invention is particularly based on the ability of anti-PS1 antibodies that are elicited in response to PS1 conjugate, to mediate protection against not only homologous strains of bacteria but also against heterologous strains. This results from the heretofore unrealized cross-reactive capacity of antibodies elicited by PS1 conjugate to other surface polysaccharides of other staphylococcal species, strains and serotypes.

The present invention also relates to the use of the PS1 conjugate to produce polyclonal antibodies or monoclonal antibodies (mouse or human) that bind to various Staphylococcal strains that carry PS1 and/or similar antigens that cross-react with antibodies to PS1, thereby mediating their clearance. Protocols for producing these antibodies are described in Ausubel, et al. (eds.), Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.)., Chapter 11; in METHODS OF HYBRIDOMA FORMATION 257-271, Bartal & Hirshaut (eds.), Humana Press, Clifton, N.J. (1988); in Vitetta et al., Immunol. Rev. 62:159-83 (1982); and in Raso, Immunol. Rev. 62:93-117 (1982).

Inoculum for polyclonal antibody production typically is prepared by dispersing the conjugate in a physiologically-tolerable diluent such as phosphate buffered saline (PBS). An immunostimulatory amount of inoculum, with or without adjuvant, is administered to a mammal and the inoculated mammal is then maintained for a time period sufficient for the antigen to induce protecting PS1 specific antibodies. Boosting doses of the conjugate may be used in individuals that are not already primed to respond to the antigen.

Antibodies can include antibody preparations from a variety of commonly used animals, e.g., goats, primates, donkeys, swine, rabbits, horses, hens, guinea pigs, rats, and mice, and even human antibodies after appropriate selection, fractionation and purification. Animal antisera may also be raised by inoculating the animals with formalin-killed strains of S. epidermidis that carry PS1, by conventional methods, bleeding the animals and recovering serum or plasma for further processing.

Hyperimmune PS1-rEPA polyclonal antisera can be raised in rabbits by multiple immunizations with PS1-rEPA conjugate vaccine. Similarly, murine monoclonal antibodies can be developed from primed murine splenocytes, immunized with PS1-rPEA conjugates. Both the rabbit hyperimmune polyclonal antisera and the monoclonal antibodies (ascites and concentrated supernatants) are purified by protein G affinity column chromatography and quantitated either by UV absorbance or BCA methodologies.

The antibodies induced in this fashion can be harvested and isolated to the extent desired by well known techniques, such as by alcohol fractionation and column chromatography, or by immunoaffinity chromatography; that is, by binding antigen to a chromatographic column, passing the antiserum through the column, thereby retaining specific antibodies and separating out other immunoglobulins (IgGs) and contaminants, and then recovering purified antibodies by elution with a chaotropic agent, optionally followed by further purification, for example, by passage through a column of bound blood group antigens or other non-pathogen species. This procedure may be preferred when isolating the desired antibodies from the sera or plasma of humans that have developed an antibody titer against the pathogen in question, thus assuring the retention of antibodies that are capable of binding to the antigen. They can then be used in preparations for passive immunization against strains homologous to ATCC 55254 as well as against heterologous strains of S. epidermidis, and even against other species of Staphylococcus, in particular against S. aureus Type 336.

A monoclonal PS1 specific antibody composition contains, within detectable limits, only one antibody specificity capable of binding to an epitope on PS1 or an epitope of a cross-reactive antigen. Suitable antibodies in monoclonal form can be prepared using conventional hybridoma technology.

To form hybridomas from which a monoclonal antibody composition of the present invention is produced, a myeloma or other self-perpetuating cell line is fused with lymphocytes obtained from peripheral blood, lymph nodes or the spleen of a mammal hyperimmunized with PS1 conjugate. It is preferred that the myeloma cell line be from the same species as the lymphocytes. Splenocytes are typically fused with myeloma cells using polyethylene glycol 1500. Fused hybrids are selected by their sensitivity to hypoxanthine-aminopterin-thymidine (HAT). Hybridomas secreting the antibody molecules of this invention can be identified using an ELISA.

A BALB/c mouse spleen, human peripheral blood, lymph nodes or splenocytes are the preferred materials for use in preparing murine or human hybridomas. Suitable mouse myelomas for use in the present invention include the HAT cell lines, a preferred myeloma being P3X63-Ag8.653. The preferred fusion partner for human monoclonal antibody production is SHM-D33, a heteromyeloma available from ATCC, Manassas, Va. under the designation CRL 1668.

A monoclonal antibody composition of the present invention can be produced by initiating a monoclonal hybridoma culture comprising a nutrient medium containing a hybridoma that secretes antibody molecules of the appropriate specificity. The culture is maintained under conditions and for a time period sufficient for the hybridoma to secrete the antibody molecules into the medium. The antibody-containing medium is then collected. The antibody molecules then can be isolated further by well known techniques.

Media useful for the preparation of these compositions are both well known in the art and commercially available, and include synthetic culture media, inbred mice and the like. An exemplary synthetic medium is Dulbecco's Minimal essential medium supplemented with 20% fetal calf serum. An exemplary inbred mouse strain is the BALB/c.

Other methods of preparing monoclonal antibody compositions are also contemplated, such as interspecies fusions, since it is primarily the antigen specificity of the antibodies that affects their utility in the present invention. Human lymphocytes obtained from infected individuals can be fused with a human myeloma cell line to produce hybridomas that can be screened for the production of antibodies that recognize PS1. More preferable in this regard, however, is a process that does not entail the use of a biological sample from an infected human subject. For example, a subject immunized with a vaccine as described herein can serve as a source for antibodies suitably used in an antibody composition within the present invention.

In a particularly preferred embodiment, monoclonal antibodies are produced to PS1 using methods similar to those described for type-specific antibodies to S. aureus Type 5, Type 8 and Type 336. The purified monoclonal antibodies are characterized by bacterial agglutination assays using a collection of clinical isolates.

The monoclonal and polyclonal antibody compositions produced according to the present description can be used in passive immunization to introduce antibodies that mediate opsonophagocytosis for the treatment of infection by strains of Staphylococcus that carry PS1 and/or an antigen that cross-reacts with antibodies raised to PS1 conjugate. Such strains include, but are not necessarily limited to, Type 336, Type 336/5, and Type 336/8 S. aureus. In this regard, the antibody preparation can be a polyclonal composition. Such a polyclonal composition may include, in addition to the antibodies that bind to PS1 and/or antigens that cross-react with antibodies raised to the PS1 conjugate, antibodies that bind to the antigens that characterize Type 5 and Type 8 strains of S. aureus. Such a composition can be obtained by immunizing a population with a multivalent vaccine or by mixing antibodies raised in separate populations in response to monovalent vaccines. Thus, the polyclonal antibody component can be a polyclonal antiserum, preferably affinity purified, from an animal that has been immunized with the PS1 conjugate, and preferably also immunized with Type 5 and Type 8 antigen conjugates and GP1 antigen conjugates described in U.S. Pat. No. 6,936,258 Alternatively, an "engineered oligoclonal" mixture may be used, such as a mixture of monoclonal antibodies to PS1, and monoclonal antibodies to the Type 5 and/or Type 8 antigens, and monoclonal antibodies to GP1.

In both types of mixtures, it can be advantageous to link antibodies together chemically to form a single polyspecific molecule capable of binding to PS1 or to a cross-reactive antigen, and to one or both of Type 5 and Type 8 antigens. One way of effecting such a linkage is to make bivalent F(ab').sub.2 hybrid fragments by mixing two different F(ab').sub.2 fragments produced, e.g., by pepsin digestion of two different antibodies, reductive cleavage to form a mixture of Fab' fragments, followed by oxidative reformation of the disulfide linkages to produce a mixture of F(ab').sub.2 fragments including hybrid fragments containing a Fab' portion specific to each of the original antigens. Methods of preparing such hybrid antibody fragments are disclosed in Feteanu, Labeled Antibodies In Biology And Medicine 321-23, McGraw-Hill Int'l Book Co. (1978); Nisonoff, et al., Arch Biochem. Biophys. 93: 470 (1961); and Hammerling, et al., J. Exp. Med. 128: 1461 (1968); and in U.S. Pat. No. 4,331,647.

Other methods are known in the art to make bivalent fragments that are entirely heterospecific, e.g., use of bifunctional linkers to join cleaved fragments. Recombinant molecules are known that incorporate the light and heavy chains of an antibody, e.g., according to the method of Boss et al., U.S. Pat. No. 4,816,397. Analogous methods of producing recombinant or synthetic binding molecules having the characteristics of antibodies are included in the present invention. More than two different monospecific antibodies or antibody fragments can be linked using various linkers known in the art.

An antibody component produced in accordance with the present invention can include whole antibodies, antibody fragments, or subfragments. Antibodies can be whole immunoglobulin of any class, e.g., IgG, IgM, IgA, IgD, IgE, chimeric antibodies or hybrid antibodies with dual or multiple antigen or epitope specificities, or fragments, e.g., F(ab').sub.2, Fab', Fab and the like, including hybrid fragments, and additionally includes any immunoglobulin or any natural, synthetic or genetically engineered protein that acts like an antibody by binding to a specific antigen to form a complex. In particular, Fab molecules can be expressed and assembled in a genetically transformed host like E. coli. A lambda vector system is available thus to express a population of Fab's with a potential diversity equal to or exceeding that of subject generating the predecessor antibody. See Huse, W. D. et al., Science 246: 1275-81 (1989).

The present invention comprehends protecting a human at risk for infection by various species of Staphylococcus including various types of Staphylococcus epidermidis, other coagulase-negative Staphylococci and Staphylococcus aureus The method comprises administering to a patient in such a population a composition comprising a conjugate of PS1. The PS1 conjugate induces the production of antibodies that also protect against a species or type of Staphylococcus other than strains that are homologous to S. epidermidis ATCC 55254. The vaccine is administered in a dose that produces a serotype-specific antibody level in the individual that is sufficient to provide immunity against challenge.

The method can be used to protect against bacterial infection in immune-compromised individuals, and produces in immune-compromised individuals a level of serotype-specific antibody to the antigens contained in the vaccines that is the same, within the limits of expected experimental variation, to the level that is achieved in normal healthy subjects when they are immunized. This was entirely unexpected in light of conventional theory to the effect that immune-compromised individuals cannot be expected to mount an effective immune response against poorly immunogenic antigens such as polysaccharide antigens, which are known for their generally low immunogenicity. There are a large number of immune-compromised populations that benefit from the administration of vaccines according to the present invention. Immune-compromised individuals include end stage renal disease (ESRD) patients; cancer patients on immunosuppressive therapy, AIDS patients, diabetic patients, the elderly in extended care facilities, patients with autoimmune disease on immunosuppressive therapy, transplant patients, and burn patients.

Preferably the PS1-conjugate vaccine or adjuvanted vaccine is formulated to contain a target dose of at least about 5 .mu.g of conjugate and up to about 500 .mu.g of conjugate. Preferably at least 25 .mu.g of conjugate, and more preferably 50, 75, 100 or 200 .mu.g of conjugate is used. A higher initial dose and/or a second dose of the vaccine given after the first dose may be used, particularly in immune-compromised populations because of the anticipated weaker immune response in this chronically-ill population. The vaccine provides a level that is at least two fold greater, and preferably four fold greater, than the prevaccination level.

The vaccine can be used for active protection in immune-compromised individuals that are about to be subjected to conditions that place them at immediate risk of developing a bacterial infection. These conditions would include, for example, catheterization or a surgical procedure. Notably, even immune-compromised individuals may mount an effective immune response when vaccinated with a vaccine according to the present invention.

Pursuant to the present invention, such a vaccine can be administered to a subject not already infected with Staphylococcus, thereby to induce a staphylococcal-protective immune response in that subject. Alternatively, a vaccine within the present invention can be administered to a subject in whom staphylococcal infection already has occurred but is at a sufficiently early stage that the immune response produced to the vaccine effectively inhibits further spread of infection. Notably, the PS1 conjugate vaccine can prevent bacteremia from developing.

By another approach, a vaccine of the present invention can be administered to a subject who then acts as a source for globulin, produced in response to PS1 conjugate vaccine ("hyperimmune globulin"), which contains antibodies directed against Staphylococcus. subject thus treated would donate plasma from which hyperimmune globulin would then be obtained, via conventional plasma-fractionation methodology, and administered to another subject in order to impart resistance against or to treat staphylococcal infection. Hyperimmune globulins according to the invention are particularly useful for immune-compromised individuals, for individuals undergoing invasive procedures or where time does not permit the individual to produce his own antibodies in response to vaccination.

Similarly, monoclonal or polyclonal antibodies to PS1 of S. epidermidis produced according to the present invention can be conjugated to an immunotoxin, and administered to a subject in whom staphylococcal infection has already occurred but has not become widely spread. To this end, antibody material produced pursuant to the present description would be administered in a pharmaceutically acceptable carrier, as defined herein.

Claim 1 of 11 Claims

1. A method for reducing the incidence of Staphylococcus aureus bacteremia in a patient in a population of patients at risk for infection by Staphylococcus comprising administering to a patient in the population a composition comprising a conjugate of an isolated S. epidermidis antigen with an immunocarrier, wherein the antigen binds with antibodies to S. epidermidis deposited under ATCC 55254, wherein the conjugate of the isolated S. epidermidis antigen produces antibodies that protect against a species or type of Staphylococcus other than S. epidermidis deposited under ATCC 55254, and wherein the antigen comprises a 1,3-poly(glycerol phosphate) polymer chain and N-acetyl-glucosamine residues attached to the 2-position of the glycerol.

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