WO2007081583A2 - Préparations anti-pneumococciques et méthodes d'utilisation - Google Patents
Préparations anti-pneumococciques et méthodes d'utilisation Download PDFInfo
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- WO2007081583A2 WO2007081583A2 PCT/US2006/049632 US2006049632W WO2007081583A2 WO 2007081583 A2 WO2007081583 A2 WO 2007081583A2 US 2006049632 W US2006049632 W US 2006049632W WO 2007081583 A2 WO2007081583 A2 WO 2007081583A2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/02—Bacterial antigens
- A61K39/09—Lactobacillales, e.g. aerococcus, enterococcus, lactobacillus, lactococcus, streptococcus
- A61K39/092—Streptococcus
Definitions
- the present invention relates to compositions and methods for preventing illnesses associated with pneumococcal infection.
- the compositions contain an antigen such as teichoic acid polymer of the pneumococcus (or a variant or derivative thereof, as described below), and they can be formulated for intramuscular administration.
- Pneumococcus is a pathogenic, Gram-positive bacterium that can be classified as having one of about 90 antigenic serotypes, depending on the capsular polysaccharide expressed external to the bacterial cell wall. Pneumococcus causes a variety of undesirable conditions, including pneumonia, middle ear infections (otitis media), bacteremia, and bacterial meningitis, and it can exacerbate other conditions, such as chronic bronchitis, sinusitis, arthritis, and conjunctivitis.
- pneumococcal vaccines based upon the capsular polysaccharides are available for use in humans.
- the vaccines intended for immunologically mature humans include a combination of unconjugated pneumococcal polysaccharides. These are PNEUMO V AX® 23 (Merck Sharp & Dohme, West Point, PA), which includes 23 different purified pneumococcal polysaccharides, and PNU-IMMUNE® 23, which is a similar vaccine produced by Wyeth- Lederle Vaccines (Pearl River, NY).
- a vaccine specifically designed for infants consists of seven serotypes of pneumococcal polysaccharides (4, 6B, 9V, 14, 18C, 19F, and 23F according to the Danish nomenclature) that have been conjugated to the protein CRM-197 (also produced by Wyeth-Lederle Vaccines).
- vaccines based upon capsular polysaccharides are not ideal.
- unconjugated pneumococcal polysaccharide vaccines are not very effective in young children.
- the conjugated vaccine is effective in infancy, the number of serotypes that can be included in those vaccines is limited; serotype replacement may occur (serotype replacement has been reported in clinical trials of PREVNAR® for otitis media); and production is costly.
- the present invention provides methods for inhibiting pneumococcal bacterial colonization, reducing the ability of the pneumococcus bacteria to cause disease in a subject and methods for inducing an immune response against pneumococci in a subject.
- the method comprises parenteral administration to the subject a composition comprising a teichoic acid-containing cell wall polysaccharide (CWPS) preparation of pneumococcus in a pharmaceutically acceptable carrier.
- CWPS teichoic acid-containing cell wall polysaccharide
- the disease is pneumonia. In one embodiment, the disease is otitis media. In one embodiment, wherein the disease is meningitis. In one embodiment, wherein the disease is bacteremia. In one embodiment, the subject is administered a dose of CWPS equal to or greater than 50 micrograms. In another embodiment, the subject is administered two parenteral doses of CWPS equal to or greater than 50 micrograms per dose.
- the immune response elicited by the techoic acid-containing CWPS composition may be CD4 + T cell mediated.
- the teichoic acid-containing CWPS preparation administered to a subject further comprises an adjuvant.
- the CWPS preparation administered to a subject includes fragments of the pneumococcal cell wall peptidoglycan.
- the CWPS preparation administered to a subject includes a glycolipid endgroup such as described for lipoteichoic acid, Forssman or F antigen.
- Figure 1 is a published representation of the teichoic acid polymeric structure of pneumococcal CWPS (reproduced from Szu et al., Infection and Immunity 54:448-455, 1986). Variants based upon the number of phosphorylcholine groups have recently been reported (Karlsson et al, Eur. J. Biochem. 275:1091) and are within the scope of the invention.
- Figure 2 shows reduced nasopharyngeal colonization in mice immunized with CWPS and CT compared to mice immunized with CT alone.
- the present invention is based, in part, on the surprising discovery that parenteral administration of CWPS compositions provide protection from pneumococcal colonization. Previous efforts documented in the prior art were unsuccessful in inducing protection from pneumococcal disease and did not study pneumococcal colonization.
- pneumococcus is a pathogenic, Gram-positive bacterium in which serotype is based on the capsular polysaccharide expressed external to the bacterial cell wall.
- Compositions that contain a teichoic acid polymer present in pneumococci of all capsular serotypes has been evaluated as a protective antigen, and compositions including preparations of the polymer or its components have been tested as a possible vaccine in animal models (Briles et al, J. Exp. Med. 153:694-705, 1981; Wallick et al., J. Immunol.
- U.S. Pat No. 20030157133 issued to Drabick discloses lipotechoic acid compositions from Gram-positive bacteria for use as immunizing antigens. Yet, the lipotechoic acid structures from the different bacteria are widely different structures and pneumococcus-derived lipotechoic acid is not specifically disclosed. Furthermore, Drabick fails to disclose successful protection of mice from bacterial colonization.
- Tiar acid is a general term for a class of polymer in bacteria in which the common structural element is the presence of glycerol or ribitol residues within the polymer backbone.
- the polymers otherwise differ structurally and immunologically among species.
- Gram-positive species in general contain a form called lipoteichoic acid that contains a glycolipid end-group whereby the polymer is bound to the cell membrane; some species contain also a teichoic acid bound to the cell wall (in Microbiology, B.D. Davis et al., 4 th edition 1990, J.B. Lippencort Co., Philadelphia).
- Pneumococci can contain several morphologic forms of the polymer.
- One is associated with the cell wall and has been called cell wall polysaccharide or CWPS.
- Preparations of CWPS may thus contain residual fragments of the cell wall peptidoglycan.
- certain strains of pneumococci were experimentally generated in which the original serotype capsular polysaccharide was deleted and replaced with a capsule-like external layer consisting of the teichoic acid polymer, hyperproduced.
- Commercially available "CWPS" preparations are typically made from such strains, although the morphologic origin is the capsule and not the cell wall.
- the teichoic acid has a glycolipid end group that causes the polymer to associate with the (phospholipid) cell membrane of the pneumococcus; this form has more recently been called the pneumococcal lipoteichoic acid or LTA.
- the teichoic acid polymer (Fig. 1) of these several forms is identical (Fisher, "Pneumococcal Lipoteichoic Acid and Teichoic Acid” in S. pneumoniae - Molecular Biology and Mechanisms of Disease, pp. 155-177, A. Tomasz, Ed., Mary Ann Liebert, Inc., Larchmont NY, 2000).
- Typical preparations can contain polymer without and with the peptidoglycan fragments or the glycolipid group. For brevity, any such preparations are referred to herein as CWPS.
- Serum antibodies to phosphorylcholine may protect mice against parenteral challenge with capsulated serotype 3 pneumococci (Briles et al., supra).
- compositions including phosphorylcholine conjugated to a carrier protein and mixed with Freund's adjuvant may protect mice against an intravenous challenge with serotype 1 or serotype 3 pneumococci (Wallick et al., supra).
- serum transferred from treated mice passively protected untreated mice (Wallick et al., supra).
- compositions described above have been tested in animals, a few pneumococcal vaccines based upon the capsular polysaccharides are available for use in humans.
- the vaccines intended for immunologically mature humans include a combination of unconjugated pneumococcal polysaccharides. These are PNEUMOV AX® 23 (Merck Sharp & Dohme, West Point, PA), which includes 23 different purified pneumococcal polysaccharides, and PNU-IMMUNE® 23, which is a similar vaccine produced by Wyeth-Lederle Vaccines (Pearl River, NY).
- vaccines represent up to 90% of the serotypes that cause invasive pneumococcal infections in the United States, including the serotypes that most frequently cause invasive drug-resistant pneumococcal infection.
- a vaccine specifically designed for infants is PREVN AR®, which consists of seven serotypes of pneumococcal polysaccharides (4, 6B, 9 V, 14, 18C, 19F, and 23F according to the Danish nomenclature) that have been conjugated to the protein CRM- 197 (also produced by Wyeth-Lederle Vaccines).
- the current conjugate vaccine comprises only 7 of the 100 capsular types; while studies are being performed with 10- or 13- valent vaccines, it is clear that the number of serotypes that can be included in these complex vaccines is limited. This represents a potential limitation since serotype replacement, whereby pneumococcal strains with serotypes not included in the vaccine increase as a consequence of immunization of a population, has already been reported in clinical trials and epidemiologic studies.
- compositions and methods described herein are based, in part, on a CWPS- containing preparation of pneumococcus formulated for parenteral, e.g., intramuscular or subcutaneous, administration that when administered to a subject by that route, can reduce the risk of disease associated with pneumococcus.
- parenteral e.g., intramuscular or subcutaneous
- administration can begin before a subject has a pneumococcal disease, i.e., the preparation can be administered prophylactically, after suspected exposure to a pneumococcal disease, but while the patient is still apparently healthy, or after a subject has apparently recovered from a pneumococcal disease, i.e., the preparation can be administered to reduce the likelihood of recurrent infection or disease.
- the CWPS-containing compositions can include, or can be administered with, an adjuvant, e.g., an adjuvant suitable for the type of patient being treated, e.g., human patients, and known to increase immunogenicity by parenteral routes, e.g., intramuscular, subcutaneous or intradermal routes.
- an adjuvant e.g., an adjuvant suitable for the type of patient being treated, e.g., human patients, and known to increase immunogenicity by parenteral routes, e.g., intramuscular, subcutaneous or intradermal routes.
- the antigens can be conjugated or conjugated to a carrier and, optionally, administered with an adjuvant.
- Antigens Pneumococci can contain several morphologic forms of the polymer teichoic acid, a published structure of which is shown in Figure 1.
- One form of teichoic acid is associated with the cell wall, and that form has been called cell wall polysaccharide (or CWPS).
- CWPS cell wall polysaccharide
- Preparations of CWPS, including those useful in the physiologically acceptable compositions of the present invention, may thus contain residual fragments of the cell wall peptidoglycan.
- the original serotype capsular polysaccharide was deleted and replaced with a capsule-like external layer including the teichoic acid polymer; some commercial sources of "cell wall polysaccharide" are in fact isolated from such capsular layers.
- the teichoic acid moiety includes a glycolipid end group that facilitates interaction between the polymer and the phospholipid cell membrane of pneumococcus. This form of CWPS has more recently been called lipoteichoic acid or LTA.
- LTA lipoteichoic acid polymer of these several forms is essentially identical.
- teichoic acid that is substantially identical to any of the forms described here can be a part of the CWPS -containing compositions of the present invention.
- typical preparations can contain teichoic acid polymers with or without the peptidoglycan fragments or the glycolipid groups.
- compositions of the invention include CWPS or a portion, fragment, or derivative thereof (such as described above) that is immunologically active.
- CWPS or a portion, fragment, or derivative thereof is "immunologically active" when, upon administration, e.g., parenteral administration, e.g., intramuscular administration, to a mammal, it evokes an immune response (either humoral or cellular) in the mammal (all that is required is an immune response sufficient to benefit the patient).
- the portion or fragment of CWPS may be all or a portion of the CWPS backbone (see, e.g., Figure 1) or all or a portion of the phosphoryl choline moiety that extends from the backbone (see, e.g., Figure 1).
- the teichoic acid-containing CWPS preparation comprises a repeating unit of
- R H or COCH 3 .
- CWPS can be obtained from a commercial source (e.g., Statens Seruminstitut, Copenhagen, Denmark) (some adjuvants, such as toxin-derived adjuvants are also commercially available)), or it may be extracted or purified from, for example, pneumococcal cells. Strains of bacteria (e.g., pneumococci and those that produce native toxins as well as detoxified derivatives) can be obtained from the American Type Culture collection (ATCC; Manassas, VA). Strains of pneumococcus that hyperproduce CWPS as a capsule-like structure can also be obtained from the ATCC, and CWPS can be purified by published techniques.
- ATCC American Type Culture collection
- VA Manassas
- CWPS can be isolated from culture supernatants as well as from bacterial cells from the base extraction technique described in U.S. Patent No. 6,248,570 (the contents of which is incorporated herein by reference).
- the CWPS produced by that method may lack covalent attachment to extraneous peptidoglycan.
- CWPS-containing compositions that include LTA can be extracted from pneumococci by a chloroform-methanol procedure and purified by hydrophobic affinity chromatography (Fischer, Pneumococcal Lipoteichoic Acid and Teichoic Acid In: S. pneumoniae — Molecular Biology and Mechanisms of Disease, pp. 155-177, A. Tomasz, Ed., Mary Ann Liebert, Inc., Larchmont, NY, 2000, which is hereby incorporated by reference in its entirety).
- antigenic components can be conjugated (i.e., linked by covalent bonds) to other molecules to increase immunogenicity.
- the antigenic components can also be conjugated to lipid or glycolipid molecules or to protein adjuvants or carrier proteins by methods known in the art ("proteins” and “peptides” are both polymers of amino acid residues and either may be used in the present invention; the term protein is used here only because it is more commonly applied to the higher molecular weight polymers used as adjuvants and carriers).
- CWPS or a portion, fragment, or derivative thereof that is immunologically active can be thus conjugated by methods that take account of the particular structure of CWPS which, like most proteins, contains free amino groups and which contains an easily hydrolyzed phosphodiester linkage (Fischer et al., Eur. J. Biochem. 215:851-857, 1993). Amino acids amenable to conjugation may also extend from a teichoic acid backbone.
- CWPS is selectively cleaved by periodate oxidation giving immunogenic fragments with aldehyde termini, the free amino groups of the fragments are reversibly blocked with the reagent "t-BOC", the aldehyde groups are coupled to the free amino acid groups of the protein by reductive amination (Anderson et al., J. Immunol. 137:1181- 1186, 1987), and the blocking groups are then removed. While specific conjugation methods are described herein, the invention is not so limited. Any suitable mode of conjugation may be employed to conjugate the CWPS component with an adjuvant or carrier.
- CWPS -containing conjugates include conjugates in which a protein or peptide is linked to the CWPS through one or more sites on the CWPS. Accordingly, the CWPS- containing compositions can include conjugate molecules that are monomers, dimers, trimers and/or more highly cross-linked molecules, the CWPS cross-linking multiple proteins.
- Adjuvants enhance the immunogenicity of an antigen but are not necessarily immunogenic themselves. Adjuvant may be administered prior to or subsequent to antigen administration, but generally, activation of antigen presenting cells by adjuvant occurs prior to presentation of antigen. Alternatively, adjuvant and antigen may be separately presented within a short interval of time but targeting the same anatomical region, e.g., the same draining lymph node field.
- the adjuvant selected will: (1) lack toxicity; (2) stimulate a long- lasting immune response; (3) remain stable despite long-term storage; (4) elicit humoral and perhaps cellular responses to CWPS; (5) act synergistically with other adjuvants; (6) selectively interact with populations of antigen presenting cells (APC); specifically elicit appropriate THl or TH2 cell-specific immune responses; and (8) electively increase appropriate antibody isotype levels (for example IgA) against antigens.
- APC antigen presenting cells
- IgA antibody isotype levels
- Adjuvants include, for example, chemokines (e.g., defensins, HCC-I , HCC4, MCP-I, MCP-3, MCP4, MIP-Ia, MIP-I ⁇ , MIP-I ⁇ , MIP-3 ⁇ , MIP-2, RANTES); other ligands of chemokine receptors (e.g., CCRl, CCR-2, CCR-5, CCR6, CXCR-I); cytokines (e.g., IL- l ⁇ , IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-15, IL-17 (A-F), IL-18; IFN ⁇ , IFN- ⁇ ; TNF- ⁇ ; GM-CSF); TGF)- ⁇ ; FLT-3 ligand; CD40 ligand; other ligands of receptors for those cytokines; ThI cytokines including,
- PCPP polymer poly[di(carboxylatophenoxy)phosphazene]
- RIBI RIBI
- MPL+TDM+CWS cell wall skeleton
- OM-174 a glucosamine disaccharide related to lipid A
- OM Pharma SA Meyrin, Switzerland
- heat shock proteins and derivatives thereof Leishmania homologs of elF4a and derivatives thereof
- bacterial ADP- ribosylating exotoxins and derivatives thereof e.g., genetic mutants, A and/or B subunit- containing fragments, chemically toxoided versions
- chemical conjugates or genetic recombinants containing bacterial ADP-ribosylating exotoxins or derivatives thereof C3d tandem array
- lipid ADP-ribosylating exotoxins or derivatives thereof C3d tandem array
- lipid ADP-ribosylating exotoxins or derivatives thereof C3d tandem array
- Adjuvant may be chosen to preferentially induce antibody or cellular effectors, specific antibody isotypes (e.g., IgM, IgD, IgAl, IgA2, secretory IgA, IgE, IgGl, IgG2, IgG3, and/or IgG4), or specific T-cell subsets (e.g., CTL, ThI, Th2, Th 17 and/or T D TH).
- antigen presenting cells may present Class Il-restricted antigen to precursor CD4+ T cells, and the ThI , Th2, or ThI 7 pathway may be entered.
- T helper cells actively secreting cytokine are primary effector cells; they are memory cells if they are resting.
- ThI characteristically secrete IFN- ⁇ TNF- ⁇ and IL-2 may also be secreted
- Th2 characteristically secrete IL4 IL-5 and IL- 13 may also be secreted
- Th 17 cells more recently described, characteristically secrete IL- 17 (A through F), and may enhance innate immune responses to a pathogen, by recruitment and activation of professional phagocytes.
- adjuvants may be chosen to prefer a ThI response (e.g., antigen-specific cytolytic cells) versus a Th2 response (e.g., antigen-specific antibodies) or a ThI 7 response.
- Unmethylated CpG dinucleotides or-similar-motifs are known to activate B lymphocytes and macrophages (see, U.S. Pat. No. 6,218,371).
- Other forms of bacterial DNA can be used as adjuvants.
- Bacterial DNA is among a class of structures which have patterns allowing the immune system to recognize their pathogenic origins to stimulate the innate immune response leading to adaptive immune responses. These structures are called pathogen-associated molecular patterns (PAMP) and include lipopolysaccharides, teichoic acids, unmethylated CpG motifs, double-stranded RNA, and mannins.
- PAMP pathogen-associated molecular patterns
- exotoxins are organized as A:B heterodimers with a B subunit containing the receptor binding activity and an A subunit containing the ADP- ribosyltransferase activity.
- exotoxins include cholera toxin (CT), E. coli heat-labile enterotoxin (LT), diphtheria toxin, Pseudomonas exotoxin A (ETA), pertussis toxin (PT), C. botulinum toxin C2, C. botulinum toxin C3, C. limosum exoenzyme, B. cereus exoenzyme, Pseudomonas exotoxin S, S.
- CT cholera toxin
- LT E. coli heat-labile enterotoxin
- ETA Pseudomonas exotoxin A
- PT pertussis toxin
- C. botulinum toxin C2 C. botulinum toxin C
- mutant bARE for example containing mutations of the trypsin cleavage site (e.g., Dickenson et al., Infect Immun, 63:1617-1623, 1995) or mutations affecting ADP-ribosylation (e.g., Douce et al., Infect Immun, 65:28221-282218, 1997) may be used.
- Exotoxin subunit-containing fragments may be used, e.g., CTA, CTB, LTA or LTB.
- toxins can be chemically inactivated to form toxoids which are less toxic but remain immunogenic.
- An adjuvant may be chemically conjugated to other antigens including, for example, carbohydrates, polypeptides, glycolipids, and glycoprotein antigens. Chemical conjugation with toxins, their subunits, or toxoids with these antigens would be expected to enhance the immune response to these antigens.
- toxins e.g., diphtheria toxin is known to be so toxic that one molecule can kill a cell
- several workers have taken a recombinant approach to producing genetically-produced toxoids. This is based on inactivating the catalytic activity of the ADP-ribosyl transferase by genetic deletion.
- toxins retain the binding capabilities, but lack the toxicity, of the natural toxins. Additionally, several techniques exist to chemically modify toxins and can address the same problem. These techniques could be important for certain applications, especially pediatric applications, in which ingested toxins might possibly elicit adverse reactions.
- Undesirable properties or harmful side effects may be reduced by modification without destroying its effectiveness in immunization.
- Modification may involve, for example, removal of a reversible chemical modification (e.g., proteolysis) or encapsulation in a coating which reversibly isolates one or more components of the formulation from the immune system.
- a reversible chemical modification e.g., proteolysis
- encapsulation in a coating which reversibly isolates one or more components of the formulation from the immune system.
- one or more components of the formulation may be encapsulated in a particle for delivery (e.g., microspheres, nanoparticles).
- Phagocytosis of a particle may, by itself, enhance activation of an antigen presenting cell by upregulating expression of MHC Class I and/or Class II molecules and/or costimulatory molecules (e.g., CD40, B7 family members like is CD80 and CD86).
- MHC Class I and/or Class II molecules and/or costimulatory molecules e.g., CD40, B7 family members like is CD80 and CD86.
- Alternative methods of upregulating such molecules by activating an antigen presenting cell are also known to the skilled artisan.
- An adjuvant may be used that creates causes an antigen or allergen to be slowly released in the body thus prolonging the exposure of immune cells to the antigen or allergen, i.e., one that creates a depot effect.
- This class of adjuvants includes but is not limited to alum (e.g., aluminum hydroxide, aluminum phosphate); or emulsion-based formulations including mineral oil, non-mineral oil, water-in-oil or oil-in-water-in-oil emulsion, oil-in-water emulsions such as Seppic ISA series of Montanide adjuvants (e.g., Montanide ISA 720, AirL ⁇ quide, Paris, France); MF-59; and PROVAX (an oil-in-water emulsion containing a stabilizing detergent and a micelle- forming agent; IDEC Pharmaceuticals Corporation, San Diego, Calif.).
- alum e.g., aluminum hydroxide, aluminum phosphate
- An adjuvant that both creates a depot effect and stimulates the immune system may be used.
- This class of adjuvants includes but is not limited to ISCOMS (Immunostimulating complexes which contain mixed saponins, lipids and form virus-sized particles with pores that can hold antigen; CSL, Melbourne, Australia); SB-AS2 (SmithKline Beecham adjuvant system #2 which is an oil-in-water emulsion containing MPL and QS21; SmithKline Beecham Biologicals [SBB], Rixensart, Belgium); SB-AS4 (SmithKline Beecham adjuvant system #4 which contains alum and MPL; SBB, Belgium); non-ionic block copolymers that form micelles such as CRL 1005 (these contain a linear chain of hydrophobic polyoxpropylene flanked by chains of polyoxyethylene; Vaxcel, Inc., Norcross, Ga.); and Syntex Adjuvant Formulation (SAF, an oil-in-water emulsion containing Tween
- certain bacterial protein toxins and their derivatives or subcomponents are utilized as adjuvants.
- CT cholera toxin
- LT heat-labile toxin
- pertussis toxin shiga toxin
- anthrax toxin pseudomonas exotoxin A
- nontoxic derivatives of such toxins See Mrsny et al., Drug Discovery Today 7:247-258, 2002.
- Pneumolysin a toxin from the pneumococcus itself, may likewise act as an adjuvant.
- Derivatives can be rendered nontoxic by, for example, mutating the nucleic acid sequence that encodes them; some amino acid substitutions are known to reduce toxicity while retaining adjuvant action ⁇ e.g., LT(Rl 02G) or LT(S63K)).
- adjuvant action e.g., LT(Rl 02G) or LT(S63K)
- Such adjuvants can simply be combined or admixed with the antigens to be parenterally, e.g., intramuscularly, administered.
- protein adjuvants can be conjugated to (a broad term that encompasses any coupling or association) the antigen (i.e., to CWPS or a portion, fragment, or derivative thereof).
- the antigen i.e., to CWPS or a portion, fragment, or derivative thereof.
- CWPS and a protein adjuvant can be chemically coupled as described by Szu et al. (supra).
- the adjuvant can be a liposome, a lipid-based composition such as RHINOV AX® (an adjuvant formulation based on caprylic-capric glycerides dissolved in polysorbate 20 and water, Lyfjathroun, Reykjavik, Iceland), or a glycolipid such as derivitives of the lipid A component of Gram-negative bacterial endotoxin).
- the formulation may comprise a vehicle.
- the formulation may comprise an Aquaphor, Freund, Ribi, or Syntex emulsion; water- in-oil emulsions (e.g., aqueous creams, ISA-720), oil-in-water emulsions (e.g., oily creams, ISA-51, MF59), microemulsions, anhydrous lipids and oil-in-water emulsions, other types of emulsions; gels, fats, waxes, oil, silicones, and humectants (e.g., glycerol).
- water- in-oil emulsions e.g., aqueous creams, ISA-720
- oil-in-water emulsions e.g., oily creams, ISA-51, MF59
- microemulsions e.g., anhydrous lipids and oil-in-water emulsions, other types of emulsions
- the CWPS- containing compositions of the invention can include heterologous carrier proteins that are chemically coupled to the antigen. These include proteins that may or may not lack adjuvant activity when admixed but that, when coupled, enhance the presentation of the CWPS-containing compositions to antigen-processing cells, particularly useful in immunologically immature subjects.
- CWPS (or a portion, fragment, or derivative thereof) can be conjugated to the outer membrane protein complex of a Gram-negative bacterium such as Neisseria meningitidis (or proteins within those complexes), to various bacterial toxins and toxoids ⁇ e.g., diphtheria or tetanus toxins or their respective conventional toxoids or genetically detoxified toxins referred to as cross-reacting material, e.g., CRM 197), or haemocyanins (some of these materials are mentioned elsewhere herein).
- a Gram-negative bacterium such as Neisseria meningitidis (or proteins within those complexes)
- toxoids e.g., diphtheria or tetanus toxins or their respective conventional toxoids or genetically detoxified toxins referred to as cross-reacting material, e.g., CRM 197
- haemocyanins (some of these materials are mentioned elsewhere herein).
- a carrier protein can be conjugated to CWPS and administered with (e.g., admixed with) one of the adjuvants described herein.
- a pharmaceutical composition is formulated to be compatible with its intended route of administration.
- routes of administration include parenteral, intravenous, intraarterial, intraperioneal, intradermal, transdermal, or subcutaneous administration.
- Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
- the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
- compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
- suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS).
- the composition must be sterile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
- the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof.
- the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
- Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
- Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
- dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
- the methods of preparation include vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
- the dose of CWPS (or any portion, fragment, or derivative thereof) will be a dose that is safe and effective ⁇ i.e., able to generate a protective immune response in a patient upon the completion of the treatment protocol) and appropriate for a particular type of formulation.
- Suitable dosages of antigens are determined by those of ordinary skill in the art by routine methods, and the dosage can range from micrograms to milligrams. For example, an average adult human can be given 1 ⁇ g - 10 mg of CWPS (or a portion, fragment, or derivative thereof) ⁇ e.g., 1 ⁇ g - 1 mg; 1 ⁇ g - 200 ⁇ g).
- the recitations of numerical ranges by endpoints include all numbers subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.).
- These doses can be administered on one or several ⁇ e.g., two, three, or four successive occasions) and can be varied appropriated based on the patient's age, body weight and other known criteria used to determine dosages of various drugs and antigens.
- the antibody response in an individual can be monitored by assaying for antibody titer or bactericidal activity and boosted if necessary to enhance the response.
- compositions containing anti-CWPS antibodies can be similarly formulated and administered to confer passive immunity, as known in the art.
- the patient can be any animal susceptible to pneumococcal infection.
- the patient can be a mammal, such as a human, a domesticated animal (e.g., a dog or cat; or a farm animal such as a horse, pig, or cow), a rodent, or a nonhuman primate.
- a mammal such as a human, a domesticated animal (e.g., a dog or cat; or a farm animal such as a horse, pig, or cow), a rodent, or a nonhuman primate.
- the "patient” may also be referred to herein as a "host” or "subject.”
- compositions and methods of the invention can be used alone or in combination with existing or experimental conjugated vaccines.
- compositions of the invention can be administered to patients of any age, including patients whose immune systems are not fully mature (e.g., children under the age of two).
- conjugated antigens may be administered at, for example, about two months of age, and conjugated or unconjugated antigens can be administered subsequently (at, for example, about four, six, 12, and/or 18 months of age.
- CWPS-based compositions can also be administered to elderly patients (e.g., patients over the age of 65). While otherwise healthy patients may also be treated, the ability to mount an immune response against the immunogen need not be perfect for the CWPS-based compositions described here to confer some degree of protection against pneumococcus. Physicians, veterinarians, and others who routinely care for patients will be able to determine whether a patient is apparently in good enough health to consider administering a CWPS-based composition.
- the CWPS-based compositions and methods of the present invention are also useful as components of multivalent vaccines, which are capable of eliciting an immune response against a plurality of infectious agents.
- the invention is illustrated further by the following non-limiting examples, which demonstrate that intraparenteral, and in particular intramuscular, administration of CWPS, with cholera toxin (CT) as an adjuvant, exhibits a significant and impressive protection against pneumococcal infection.
- CT cholera toxin
- mice were thus immunized with CWPS (50 ⁇ g) + CT (1 ⁇ g) or CT alone, intramuscularly (in the calf muscle), twice at a one week interval.
- mice were challenged intranasally with a strain of serotype 6B. Density of nasopharyngeal colonization was determined one week later by serial dilutions of tracheal washes on BAP+Gent.
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Abstract
L’invention a pour objet des méthodes pour traiter, réduire ou empêcher des maladies et des infections causées par un pneumocoque. Les méthodes s'appuient sur l'utilisation d'une composition contenant un polysaccharide- (CWPS -) de paroi cellulaire (par exemple, une préparation de polymère d’acide teichoïque CWPS) de pneumocoque et un adjuvant qui peuvent être conjugués chimiquement ou simplement mélangés. Les méthodes sont particulièrement utiles contre une colonisation nasopharyngée et une maladie envahissante due à un pneumocoque encapsulé.
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US75598406P | 2006-01-04 | 2006-01-04 | |
US60/755,984 | 2006-01-04 |
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WO2007081583A3 WO2007081583A3 (fr) | 2007-11-08 |
WO2007081583A8 WO2007081583A8 (fr) | 2008-05-08 |
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Cited By (12)
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EP2108656A1 (fr) | 2008-03-19 | 2009-10-14 | Beninati, Concetta | Fragments de protéines antigéniques de streptococcus pneumoniae |
EP2252326A1 (fr) * | 2008-02-01 | 2010-11-24 | Newcastle Innovation Limited | Compositions de vaccin |
EP2293815A1 (fr) * | 2008-05-22 | 2011-03-16 | Children's Medical Center Corporation | Conjugué immunogène synergique protéine de fusion-polysaccharide |
EP2303888A2 (fr) * | 2008-06-12 | 2011-04-06 | President and Fellows of Harvard College | Procédés et composés pour intervention antimicrobienne |
WO2012155007A1 (fr) * | 2011-05-11 | 2012-11-15 | Children's Medical Center Corporation | Composition immunogène présentant de multiples antigènes, procédés et utilisations associés |
EP2589387A1 (fr) * | 2011-11-04 | 2013-05-08 | Lunamed AG | Utilisation d'acide téichoïque pour le traitement du liquide maligne cérébro-spinal dans le cerveau |
US11013793B2 (en) | 2018-09-12 | 2021-05-25 | Affinivax, Inc. | Multivalent pneumococcal vaccines |
US11305001B2 (en) | 2017-03-28 | 2022-04-19 | The Children's Medical Center Corporation | Multiple antigen presenting system (MAPS)-based Staphylococcus aureus vaccine, immunogenic composition, and uses thereof |
US11576958B2 (en) | 2013-02-07 | 2023-02-14 | Children's Medical Center Corporation | Protein antigens that provide protection against pneumococcal colonization and/or disease |
US11612647B2 (en) | 2017-06-23 | 2023-03-28 | University Of Maryland, Baltimore | Immunogenic compositions |
US12036276B2 (en) | 2021-09-09 | 2024-07-16 | Affinivax, Inc. | Multivalent pneumococcal vaccines |
US12129283B2 (en) | 2018-09-12 | 2024-10-29 | The Children's Medical Center Corporation | Pneumococcal fusion protein vaccines |
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2006
- 2006-12-29 WO PCT/US2006/049632 patent/WO2007081583A2/fr active Application Filing
Non-Patent Citations (5)
Cited By (26)
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EP2252326A1 (fr) * | 2008-02-01 | 2010-11-24 | Newcastle Innovation Limited | Compositions de vaccin |
EP2252326A4 (fr) * | 2008-02-01 | 2012-08-29 | Newcastle Innovation Ltd | Compositions de vaccin |
EP2108656A1 (fr) | 2008-03-19 | 2009-10-14 | Beninati, Concetta | Fragments de protéines antigéniques de streptococcus pneumoniae |
EP2293815A1 (fr) * | 2008-05-22 | 2011-03-16 | Children's Medical Center Corporation | Conjugué immunogène synergique protéine de fusion-polysaccharide |
EP2293815A4 (fr) * | 2008-05-22 | 2013-04-03 | Childrens Medical Center | Conjugué immunogène synergique protéine de fusion-polysaccharide |
US9125863B2 (en) | 2008-05-22 | 2015-09-08 | Children's Medical Center Corporation | Synergistic immunogenic fusion protein-polysaccharide conjugate |
US8598342B2 (en) | 2008-06-12 | 2013-12-03 | President And Fellows Of Harvard College | Methods and compounds for antimicrobial intervention |
EP2303888A2 (fr) * | 2008-06-12 | 2011-04-06 | President and Fellows of Harvard College | Procédés et composés pour intervention antimicrobienne |
EP2303888A4 (fr) * | 2008-06-12 | 2012-02-29 | Harvard College | Procédés et composés pour intervention antimicrobienne |
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US11981708B2 (en) | 2011-05-11 | 2024-05-14 | Children's Medical Center Corporation | Multiple antigen presenting immunogenic composition, and methods and uses thereof |
US9499593B2 (en) | 2011-05-11 | 2016-11-22 | Children's Medical Center Corporation | Modified biotin-binding protein, fusion proteins thereof and applications |
WO2012155007A1 (fr) * | 2011-05-11 | 2012-11-15 | Children's Medical Center Corporation | Composition immunogène présentant de multiples antigènes, procédés et utilisations associés |
US10611805B2 (en) | 2011-05-11 | 2020-04-07 | Children's Medical Center Corporation | Modified biotin-binding protein, fusion proteins thereof and applications |
US10766932B2 (en) | 2011-05-11 | 2020-09-08 | The Children's Medical Center Corporation | Multiple antigen presenting immunogenic composition, and methods and uses thereof |
US11976097B2 (en) | 2011-05-11 | 2024-05-07 | Children's Medical Center Corporation | Modified biotin-binding protein, fusion proteins thereof and applications |
US11560410B2 (en) | 2011-05-11 | 2023-01-24 | Children's Medical Center Corporation | Modified biotin-binding protein, fusion proteins thereof and applications |
EP2589387A1 (fr) * | 2011-11-04 | 2013-05-08 | Lunamed AG | Utilisation d'acide téichoïque pour le traitement du liquide maligne cérébro-spinal dans le cerveau |
US11576958B2 (en) | 2013-02-07 | 2023-02-14 | Children's Medical Center Corporation | Protein antigens that provide protection against pneumococcal colonization and/or disease |
US12083173B2 (en) | 2013-02-07 | 2024-09-10 | Children's Medical Center Corporation | Protein antigens that provide protection against pneumococcal colonization and/or disease |
US11305001B2 (en) | 2017-03-28 | 2022-04-19 | The Children's Medical Center Corporation | Multiple antigen presenting system (MAPS)-based Staphylococcus aureus vaccine, immunogenic composition, and uses thereof |
US11612647B2 (en) | 2017-06-23 | 2023-03-28 | University Of Maryland, Baltimore | Immunogenic compositions |
US11701416B2 (en) | 2018-09-12 | 2023-07-18 | Affinivax, Inc. | Multivalent pneumococcal vaccines |
US11013793B2 (en) | 2018-09-12 | 2021-05-25 | Affinivax, Inc. | Multivalent pneumococcal vaccines |
US12129283B2 (en) | 2018-09-12 | 2024-10-29 | The Children's Medical Center Corporation | Pneumococcal fusion protein vaccines |
US12036276B2 (en) | 2021-09-09 | 2024-07-16 | Affinivax, Inc. | Multivalent pneumococcal vaccines |
Also Published As
Publication number | Publication date |
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WO2007081583A3 (fr) | 2007-11-08 |
WO2007081583A8 (fr) | 2008-05-08 |
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