EP1438323A2 - Compositions de meningocoque assorties d'un adjuvant - Google Patents

Compositions de meningocoque assorties d'un adjuvant

Info

Publication number
EP1438323A2
EP1438323A2 EP02800481A EP02800481A EP1438323A2 EP 1438323 A2 EP1438323 A2 EP 1438323A2 EP 02800481 A EP02800481 A EP 02800481A EP 02800481 A EP02800481 A EP 02800481A EP 1438323 A2 EP1438323 A2 EP 1438323A2
Authority
EP
European Patent Office
Prior art keywords
composition
antigen
protein
microparticles
neisserial
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02800481A
Other languages
German (de)
English (en)
Other versions
EP1438323A4 (fr
Inventor
Derek Chiron Corporation O'HAGAN
Nicholas Chiron Corporation VALIANTE
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis Vaccines and Diagnostics Inc
Original Assignee
Chiron Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/US2002/010869 external-priority patent/WO2002080648A2/fr
Application filed by Chiron Corp filed Critical Chiron Corp
Publication of EP1438323A2 publication Critical patent/EP1438323A2/fr
Publication of EP1438323A4 publication Critical patent/EP1438323A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K39/095—Neisseria
    • 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
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • 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
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55555—Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
    • 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
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55561—CpG containing adjuvants; Oligonucleotide containing adjuvants
    • 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
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55566—Emulsions, e.g. Freund's adjuvant, MF59
    • 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
    • A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
    • A61K2039/6093—Synthetic polymers, e.g. polyethyleneglycol [PEG], Polymers or copolymers of (D) glutamate and (D) lysine

Definitions

  • the invention relates to vaccines, more particularly those against Neisseria meningitidis.
  • Antigens generally require the co-administration of adjuvants in order to enhance their immunogenicity in vaccines [13]. Freund's adjuvant has been used for serogroup B meningococcus
  • the invention therefore provides a composition comprising: (a) a Neisserial antigen; (b) a CpG oligonucleotide; and (c) a biodegradable polymer microparticle.
  • the Neisserial antigen may be a protein antigen, nucleic acid encoding a protein antigen, or a saccharide antigen.
  • the antigen preferably elicits a bactericidal or protective immune response ⁇ e.g. antibody response) in a recipient mammal.
  • the antigen may be derived from any species of Neisseria including N.gonorrhoeae, N.lactamica and N. meningitidis. It is preferably a N. meningitidis antigen and may be from any serogroup. Where the antigen is from serogroup B, it is preferred to use a protein antigen; where it is from serogroup A, C, W135 or Y then it is preferred to use a saccharide antigen. Where saccharide antigens are used, these will typically be derived from the bacterial capsular polysaccharide ⁇ e.g. oligosaccharides, such as those obtained by hydrolysis), and they will typically be conjugated to carrier proteins ⁇ e.g. to CRM ⁇ 97 ). Preferred protein antigens derived from serogroup B N. meningitidis are:
  • a protein comprising an immunogenic fragment of one or more of the proteins disclosed in any one of references 4, 5, 6, 7, 8 or 9.
  • a protein comprising a sequence having sequence identity (preferably greater than 50% e.g. 60%, 70%, 80%, 90%, 95%, 99% or more) to one or more of the proteins disclosed in any one of references 4, 5, 6, 7, 8 or 9.
  • a protein comprising a sequence having sequence identity (preferably greater than 50% e.g. 60%, 70%, 80%, 90%, 95%, 99% or more) to one or more of the proteins disclosed in any one of references 10, 11 or 12.
  • a particularly preferred protein antigen from serogroup B N. meningitidis is protein '287'.
  • This protein may be used in a wild-type form [e.g. GenBank accession gi:7228690; alignments of polymorphic forms of 287 are shown in figures 5 & 15 of ref. 8] but derivatives of the wild-type protein may be used. For instance, proteins having 50% or more sequence identity ⁇ e.g. 60%, 70%, 80%, 90%, 95%, 99% or more) to gi:7228690 may be used. Proteins comprising truncation or deletion variants of the protein may be used, such as the N-terminal truncated forms disclosed in references 10 to 12 (' ⁇ G287' in particular, in which the N-terminus of the protein up to and including the six repeated glycine residues is deleted).
  • Fusion proteins comprising such 287 sequences may be used. All of these forms of 287, and more particularly those which retain the immunogenicity of wild-type 287 proteins, fall within the meaning of '287' as used herein.
  • Another particularly preferred protein antigen from serogroup B N. meningitidis is protein
  • '961' also known as 'NadA' [16].
  • This protein may be used in a wild-type form [e.g. GenBank accession gi:7227256; alleles of 961 are disclosed in ref. 17] but derivatives of the wild-type protein may be used. For instance, proteins having 50% or more sequence identity ⁇ e.g. 60%, 70%, 80%, 90%, 95%, 99% or more) to gi:7227256 may be used. Proteins comprising truncation or deletion variants of the protein may be used, such as those disclosed in references 10 to 12 ('961c' in particular, which lacks the C-terminal membrane anchor). Fusion proteins comprising such 961 sequences may be used.
  • Other preferred protein antigens are the hybrid proteins disclosed in references 10 to 12, particularly those comprising one or more of: a 287 protein, a 953 protein, a 936 protein and/or a 741 protein.
  • Protein antigens may be derived from any strain of N. meningitidis. It is preferred to use antigens from strains 2996, MC58, 95N477 and 394/98.
  • strain variants single or multiple conservative amino acid substitutions may be made with altering the immunogenicity of antigens used according to the present invention.
  • nucleic acid encoding a protein antigen may be included within compositions of the invention.
  • the nucleic acid will be expressed in vivo once administered to a mammalian recipient and the protein antigen will be produced. Such nucleic acid immunization is well known [e.g. refs. 18 to 23 etc.].
  • the nucleic acid will typically be a DNA plasmid.
  • a preferred saccharide antigen derived from serogroup C N.meningitidis is the oligosaccharide conjugate used in MenjugateTM [24, 25], which contains 12 to 22 monosaccharide units from the serogroup C capsular polysaccharide.
  • a preferred saccharide antigen derived from serogroup A is an oligosaccharide in which one or more of the hydroxyl groups on the constituent monosaccharide units has been replaced by a blocking group [26].
  • oligosaccharide antigens from serogroups A, W135 and Y are disclosed in reference 27.
  • composition of the invention may comprise more than one Neisserial antigen. Where saccharides from both serogroups A and C of N.meningitidis are included, it is preferred that the ratio (w/w) of MenA saccharide :MenC saccharide is greater than 1 ⁇ e.g. 2:1, 3:1, 4:1, 5:1, 10:1 or higher).
  • composition of the invention is preferably an immunogenic composition or vaccine.
  • Such compositions comprise an immunologically effective amount of the antigen.
  • 'immunologically effective amount' it is meant that the administration to an individual of a composition of the invention comprising that amount of antigen (either in a single dose or as part of a series) is effective for raising a therapeutic or prophylactic immune response.
  • This amount varies depending upon the health and physical condition of the individual to be treated, age, the taxonomic group of individual to be treated (e.g. non-human primate, primate, etc.), the capacity of the individual's immune system to synthesise antibodies, the degree of protection desired, the formulation of the vaccine, the treating physician's assessment of the medical situation, and other relevant factors.
  • the amount may fall in a relatively broad range that can be determined through routine trials.
  • Antigens will typically be present at a concentration of at least l ⁇ g/ml each.
  • Dosage treatment may be a single dose or a multiple dose schedule (e.g. including booster doses).
  • CpG oligonucleotides are known for use as vaccine adjuvants [e.g. ref. 28] and they induce strong Thl immune responses. They are useful as parenteral and mucosal adjuvants [29].
  • the CpG oligonucleotide used according to the present invention is a nucleic acid which includes at least one CG dinucleotide i.e. a cytosine nucleotide followed by a guanosine nucleotide.
  • the oligonucleotide may contain multiple CG dinucleotides.
  • a CG sequence in the oligonucleotide may be flanked by two purines at the 5' side and two pyrimidmes at the 3' side i.e. RRCGYY.
  • Cytosine nucleotides in the CpG oligonucleotide may be methylated, but it is preferred that they should be unmethylated.
  • the cytosine and guanosine nucleotides are preferably deoxynucleotides and the nucleic acid is preferably DNA.
  • the oligonucleotide may comprise a modified backbone, such as a phosphorothioate backbone.
  • PNA peptide nucleic acid
  • the oligonucleotides can comprise substitutions of the sugar moieties and nitrogenous base moieties.
  • the oligonucleotide preferably comprises between about 6 and about 100 nucleotides, more preferably between about 8 and about 50 nucleotides, most preferably between about 10 and about 40 nucleotides.
  • Oligonucleotides comprising at least one CG dinucleotide can conveniently be prepared using conventional oligonucleotide synthesis.
  • Biodegradable polymer microparticle Biodegradable polymer microparticles are known for use as vaccine adjuvants [e.g. ref. 56].
  • the polymer used to make the microparticles will generally be sterilizable and non-toxic (biocompatible).
  • Suitable biodegradable polymers are readily commercially available and include those derived from polyhydroxybutyric acid; polycaprolactone; polyorthoester; poly anhydride; poly (hydoxybutyr ate); and a poly( ⁇ -hydroxy acid).
  • Preferred polymers are formed from one or more poly( ⁇ -hydroxy acid) e.g.
  • Microparticles formed from ⁇ oly(D,L-lactide-co-glycolide) ('PLG') are preferred.
  • These polymers are available in a variety of molecular weights, and the appropriate molecular weight for a given antigen can readily be determined.
  • poly(L-lactide) a suitable molecular weight will be on the order of about 2000 to 250,000.
  • suitable molecular weights will generally range from about 10,000 to about 200,000, preferably about 15,000 to about 150,000, and most preferably about 50,000 to about 100,000.
  • lactide: glycolide ratios may be used and the ratio is largely a matter of choice, depending in part on the co-administered antigen and the rate of degradation desired.
  • a 50:50 PLG polymer, containing 50% D,L-lactide and 50% glycolide will provide a fast resorbing copolymer while 75:25 PLG degrades more slowly, and 85:15 and 90:10, even more slowly, due to the increased lactide component.
  • a suitable ratio of lactide: glycolide is easily determined based on the nature of the antigen and disorder in question.
  • microparticles with varying lactide: glycolide ratios will find use in the formulations in order to achieve the desired release kinetics for a given antigen and to provide for both a primary and secondary immune response.
  • Degradation rate of the microparticles of the present invention can also be controlled by such factors as polymer molecular weight and polymer crystallinity.
  • microparticle' refers to a particle of about 100 nm to about 150 um in diameter, more preferably about 200 nm to about 30 ⁇ m in diameter, and most preferably about 500 nm to about 10 ⁇ m in diameter.
  • the microparticle will be of a diameter that permits parenteral administration without occluding needles and capillaries.
  • Microparticle size is readily determined by techniques well known in the art, such as photon correlation spectroscopy, laser diffractometry and/or scanning electron microscopy.
  • the term 'microparticle' includes 'nanoparticles' [57] within its scope.
  • Preferred microparticles are microspheres, although lamellar particles [58] may also be used.
  • Microparticles may be prepared using any of several methods well known in the art [e.g. ref.
  • double emulsion/solvent evaporation techniques [e.g. refs. 60 & 61] can be used to form the microparticles. These techniques involve the formation of a primary emulsion consisting of droplets of polymer solution containing the antigen (if antigen is to be entrapped in the microparticle), which is subsequently mixed with a continuous aqueous phase containing a particle stabilizer/surfactant.
  • a water-in-oil-in-water (w/o/w) solvent evaporation system can be used to form the microparticles, as described in references 62, 63 and 64.
  • the particular polymer is combined with an organic solvent, such as ethyl acetate, dimethylchloride (also called methylene chloride and dichloromethane), acetonitrile, acetone, chloroform, and the like.
  • the polymer will be provided in about a 2-15% solution, in organic solvent.
  • An approximately equal amount of an antigen solution e.g. in water
  • the polymer/antigen solution emulsified using e.g. a homogenizer.
  • the emulsion is then combined with a larger volume of an aqueous solution of an emulsion stabilizer such as polyvinyl alcohol (PNA) or polyvinyl pyrrolidone.
  • PNA polyvinyl alcohol
  • the emulsion stabilizer is typically provided in about a 2-15% solution, more typically about a 4-10% solution.
  • the mixture is then homogenized to produce a stable w/o/w double emulsion. Organic solvents are then evaporated.
  • the formulation parameters can be manipulated to allow the preparation of small ( ⁇ 5 ⁇ m) and large (>30/ ⁇ m) microparticles [e.g. 63, 65]. For example, reduced agitation results in larger microparticles, as does an increase in internal phase volume. Small particles are produced by low aqueous phase volumes with high concentrations of PNA. Microparticles can also be formed using spray-drying and coacervation [e.g. refs. 66, 67 &
  • antigen content Prior to use of the microparticles, antigen content is generally determined so that an appropriate amount of the microparticles may be delivered to the subject in order to elicit an adequate immune response.
  • Antigen content of the microparticles can be determined according to methods known in the art, such as by disrupting the microparticles and extracting entrapped antigen.
  • microparticles can be dissolved in dimethylchloride and the protein extracted into distilled water [e.g. refs. 72, 73, 74].
  • microparticles can be dispersed in 0.1 M ⁇ aOH containing 5% (w/v) SDS. The sample is agitated, centrifuged and the supernatant assayed for antigen using an appropriate assay [75].
  • Antigen and or CpG-oligonucleotides can be located within or on the microparticles. Entrapment will generally be achieved by having the antigen/oligonucleotide present during formation of the microparticles, whereas surface adsorption is achieved by adding antigen/oligonucleotide to pre-formed microparticles.
  • Microparticles are rehydrated and dispersed to an essentially monomeric suspension of microparticles using dialyzable anionic or cationic detergents.
  • Useful detergents include, but are not limited to, any of the various ⁇ -methylglucamides (known as MEGAs), such as heptanoyl- ⁇ - methylglucamide (MEGA-7), octanoyl- ⁇ -methylglucamide (MEGA-8), nonanoyl- ⁇ - methylglucamide (MEGA-9), and decanoyl- ⁇ -methyl-glucamide (MEGA-10); cholic acid; sodium cholate; deoxycholic acid; sodium deoxycholate; taurocholic acid; sodium taurocholate; taurodeoxycholic acid; sodium taurodeoxycholate; 3-[(3-cholamidopropyl)dimethylammonio]-l- propane-sulfonate (CHAPS); ⁇ -octylglucoside; 3-[(3-cholamidopropyl) dimethylammonio]-2- hydroxy-1-propane-sulfonate (CHAPSO); ⁇ -dodecyl- ⁇
  • the microparticle/detergent mixture is then physically ground e.g. using a ceramic mortar and pestle, until a smooth slurry is formed.
  • An appropriate aqueous buffer such as phosphate buffered saline (PBS) or Tris buffered saline, is then added and the resulting mixture sonicated or homogenized until the microparticles are fully suspended.
  • PBS phosphate buffered saline
  • Tris buffered saline Tris buffered saline
  • the antigen/oligonucleotide is then added to the microparticle suspension and the system dialyzed to remove detergent.
  • the polymer microparticles and detergent system are preferably chosen such that the antigen/oligonucleotide will adsorb to the microparticle surface while still maintaining activity .
  • microparticles containing surface adsorbed antigen/oligonucleotide may be washed free of unbound antigen/oligonucleotide and stored as a suspension in an appropriate buffer formulation, or lyophilized with the appropriate excipients, as described further below.
  • compositions of the invention Various physical relationships are possible between the three basic components of the compositions of the invention. These arise because the microparticles have an internal volume and a surface, either of which may be used to locate the CpG-oligonucleotide and/or the antigen.
  • the antigen may be entrapped within microparticles, it may be adsorbed to microparticles, or it may be in simple admixture with the microparticles without entrapment or adsorption. Adsorption is preferred.
  • the CpG-oligonucleotide may be entrapped within microparticles, it may be adsorbed to microparticles, or it may be in simple admixture with the microparticles. Adsorption can be achieved using detergents such as CTAB.
  • the CpG-oligonucleotide and the antigen may both have the same physical relationship to the microparticles as each other, or they may be different. Likewise the CpG-oligonucleotide and the antigen may be adsorbed onto the same microparticle or the CpG-oligonucleotide and the antigen may be adsorbed onto different microparticles. All possible combinations are encompassed within the present invention:
  • compositions of the invention may include mixtures of the above e.g. some microparticles within the composition have entrapped antigen and some have adsorbed antigen.
  • compositions of the invention will generally comprise a pharmaceutically acceptable carrier. This gives a pharmaceutical composition of the invention.
  • a pharmaceutically acceptable carrier can be any substance that does not itself induce the production of antibodies harmful to the patient receiving the composition, and which can be administered without undue toxicity.
  • Suitable carriers can be large, slowly-metabolised macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, and inactive virus particles. Such carriers are well known to those of ordinary skill in the art.
  • Pharmaceutically acceptable carriers can include liquids such as water, saline, glycerol and ethanol. Auxiliary substances, such as wetting or emulsifying agents, pH buffering substances, and the like, can also be present in such vehicles. Liposomes are suitable carriers. A thorough discussion of pharmaceutical carriers is available in ref. 78.
  • compositions of the invention may be prepared in various forms.
  • the compositions may be prepared as injectables, either as liquid solutions or suspensions. Solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection can also be prepared.
  • the composition may be prepared for topical administration e.g. as an ointment, cream or powder.
  • the composition be prepared for oral administration e.g. as a tablet or capsule, or as a syrup (optionally flavoured).
  • the composition may be prepared for pulmonary administration e.g. as an inhaler, using a fine powder or a spray.
  • the composition may be prepared as a suppository or pessary.
  • the composition may be prepared for nasal, aural or ocular administration e.g. as drops, as a spray, or as a powder [e.g. 79].
  • the pharmaceutical composition is preferably sterile. It is preferably pyrogen-free. It is preferably buffered e.g. at between pH 6 and pH 8, generally around pH 7.
  • the pharmaceutical composition may be lyophilised.
  • the invention also provides a delivery device containing a pharmaceutical composition of the invention.
  • the device may be, for example, a syringe.
  • compositions of the invention may be used therapeutically (i.e. to treat an existing Neisserial infection) or prophylactically (i.e. to prevent future Neisserial infection).
  • the invention provides a composition of the invention for use as a medicament.
  • the invention also provides a method for raising an antibody response in a mammal, comprising administering a pharmaceutical composition of the invention to the mammal.
  • the antibody response is preferably an IgA or IgG response and it is preferably bactericidal.
  • the invention also provides a method for treating a mammal suffering from a Neisserial infection and/or disease, comprising administering to the patient a pharmaceutical composition of the invention.
  • the invention also provides a method for protecting a mammal against a Neisserial infection and/or disease, comprising administering to the mammal a pharmaceutical composition of the invention.
  • the invention also provides the use of (a) a Neisserial antigen, (b) a CpG oligonucleotide, and (c) a biodegradable polymer microparticle, in the manufacture of a medicament for preventing or treating disease and/or infection in an mammal.
  • the mammal is preferably a human.
  • the human may be an adult or, preferably, a child.
  • Compositions of the invention are particularly useful for immunising children and teenagers.
  • the uses and methods of the invention are particularly useful for treating/protecting against infections of N.meningitidis.
  • the uses and methods are particularly useful for preventing/treating diseases including bacterial meningitis.
  • Efficacy of therapeutic treatment can be tested by monitoring Neisserial infection after administration of the composition of the invention.
  • Efficacy of prophylactic treatment can be tested by monitoring ⁇ -Neisseria immune responses after administration of the composition.
  • compositions of the invention will generally be administered directly to a patient.
  • Direct delivery may be accomplished by parenteral injection (e.g. subcutaneously, intraperitoneally, intravenously, intramuscularly, or to the interstitial space of a tissue), or by rectal, oral, vaginal, topical, transdermal, ocular, nasal, aural, or pulmonary administration. Injection or intranasal administration is preferred.
  • Dosage treatment can be a single dose schedule or a multiple dose schedule.
  • compositions of the invention may include adjuvants in addition to CpG-oligonucleotides and polymer microparticles.
  • Preferred further adjuvants include, but are not limited to: (A) aluminium compounds (e.g. aluminium hydroxide, aluminium phosphate, aluminium hydroxyphosphate, oxyhydroxide, orthophosphate, sulphate etc. [e.g. see chapters 8 & 9 of ref. 13]), or mixtures of different aluminium compounds, with the compounds taking any suitable form (e.g.
  • RibiTM adjuvant system Ribi Immunochem
  • Ribi Immunochem Ribi Immunochem
  • MPL monophosphorylipid A
  • TDM trehalose dimycolate
  • CWS cell wall skeleton
  • saponin adjuvants such as QuilA or QS21 [see Chapter 22 of ref. 13], also known as StimulonTM [82]
  • H chitosan [e.g.
  • CFA complete Freund's adjuvant
  • IFA incomplete Freund's adjuvant
  • J cytokines, such as interleukins (e.g. L-1, L-2, IL-4, IL-5, IL-6, IL-7, IL-12, etc.), interferons (e.g. interferon- ⁇ ), macrophage colony stimulating factor, tumor necrosis factor, etc. [see Chapters 27 & 28 of ref. 13];
  • K monophosphoryl lipid A (MPL) or 3-O-deacylated MPL (3dMPL) [e.g. chapter 21 of ref.
  • Muramyl peptides include N-acetyl-muramyl-L-threonyl-D-isoglutamine (thr-MDP), N- acetyl-normuramyl-L-alanyl-D-isoglutamine (nor-MDP), N-acetylmuramyl-L-alanyl-D-isoglutaminyl- L-alanine-2-(l '-2'-dipalmitoyl-5 ⁇ -glycero-3-hydroxyphosphoryloxy)-ethylamine MTP-PE), etc.
  • thr-MDP N-acetyl-muramyl-L-threonyl-D-isoglutamine
  • nor-MDP N- acetyl-normuramyl-L-alanyl-D-isoglutamine
  • composition may comprise further antigenic components.
  • Antigens which can be included in the composition of the invention include:
  • Helicobacter pylori such as CagA [92 to 95], Vac A [96, 97], NAP [98, 99, 100], HopX [e.g. 101], HopY [e.g. 101] and/or urease.
  • OMV outer-membrane vesicle
  • an antigen from hepatitis A virus such as inactivated virus [e.g. 109, 110].
  • an antigen from hepatitis B virus such as the surface and/or core antigens [e.g. 110, 111].
  • an antigen from hepatitis C virus [e.g. 112].
  • an antigen from Bordetella pertussis such as pertussis holotoxin (PT) and filamentous haemagglutinin (FHA) from B.pertussis, optionally also in combination with pertactin and/or agglutinogens 2 and 3 [e.g. refs. 113 & 114].
  • diphtheria antigen such as a diphtheria toxoid [e.g. chapter 3 of ref. 115] e.g. the CRM 197 mutant [e.g. 116].
  • tetanus antigen such as a tetanus toxoid [e.g. chapter 4 of ref. 115].
  • Chlamydia pneumoniae an antigen from Chlamydia pneumoniae [e.g. 117, 118, 119, 120, 121, 122, 123].
  • - polio antigen(s) e.g. 126, 127
  • UN or OPV polio antigen
  • rabies antigen(s) e.g. 128
  • lyophilised inactivated virus e.g.129, RabAvertTM
  • influenza virus e.g. chapter 19 of ref. 115
  • antigen(s) from influenza virus e.g. chapter 19 of ref. 115
  • haemagglutinin and/or neuraminidase surface proteins such as the haemagglutinin and/or neuraminidase surface proteins
  • a - antigen(s) from a specific mammal such as respiratory syncytial virus (RSV [130, 131]) and/or parainfluenza virus (PIV3 [132]).
  • RSV respiratory syncytial virus
  • PSV3 parainfluenza virus
  • Bacillus anthracis an antigen from Bacillus anthracis [e.g. 139, 140, 141].
  • an antigen from a virus in the flaviviridae family such as from yellow fever virus, Japanese encephalitis virus, four serotypes of Dengue viruses, tick-borne encephalitis virus, West Nile virus.
  • pestivirus antigen such as from classical porcine fever virus, bovine viral diarrhoea virus, and/or border disease virus.
  • parvovirus antigen e.g. from parvovirus B19.
  • a prion protein e.g. the CJD prion protein
  • an amyloid protein such as a beta peptide [142]
  • composition may comprise one or more of these further antigens.
  • Toxic protein antigens may be detoxified where necessary (e.g. detoxification of pertussis toxin by chemical and/or genetic means [114]). Where a diphtheria antigen is included in the composition it is preferred also to include tetanus antigen and pertussis antigens. Similarly, where a tetanus antigen is included it is preferred also to include diphtheria and pertussis antigens. Similarly, where a pertussis antigen is included it is preferred also to include diphtheria and tetanus antigens.
  • Antigens are preferably adsorbed to an aluminium salt.
  • Antigens in the composition will typically be present at a concentration of at least l ⁇ g/ml each. In general, the concentration of any given antigen will be sufficient to elicit an immune response against that antigen.
  • nucleic acid encoding the antigen may be used.
  • Protein components of the compositions of the invention may thus be replaced by nucleic acid (preferably DNA e.g. in the form of a plasmid) that encodes the protein.
  • composition comprising X may consist exclusively of X or may include something additional e.g. X + Y.
  • references to a percentage sequence identity between two amino acid sequences means that, when aligned, that percentage of amino acids are the same in comparing the two sequences.
  • This alignment and the percent homology or sequence identity can be determined using software programs known in the art, for example those described in section 7.7.18 of reference 145.
  • a preferred alignment is determined by the Smith- Waterman homology search algorithm using an affine gap search with a gap open penalty of 12 and a gap extension penalty of 2, BLOSUM matrix of 62.
  • the Smith- Waterman homology search algorithm is taught in reference 146. MODES FOR CARRYING OUT THE INVENTION
  • Reference 6 discloses a protein from serogroup B N.meningitidis called '287'.
  • References 10 to 12 disclose ways of improving its expression. One way involves deleting the N-terminus of the protein up to and including the six repeated glycine residues. This protein is referred to as ' ⁇ G287'.
  • Mice were primed and boosted with MenB ⁇ G287 antigen (20 g/dose) from strain 2996, formulated for intramuscular (IM) administration by adsorption to PLG microparticles, with or without CpG oligonucleotide (also adsorbed to the microparticles).
  • An additional formulation for intranasal (IN) administration used LT-K63 adjuvant. Mice received either 3 IM doses or 2 IM then 2 IN doses (doses at: day 0; day 28; day 84; and, optionally, day 98).
  • CpG-oligonucleotide enhanced antibody titers against intramuscularly administered MenB protein 287 (compare groups 1 & 2). Titers could be enhanced by replacing a third intramuscular dose with two intranasal doses (compare groups 1 & 3). The CpG enhancement was also seen in the intramuscular/intranasal regime (compare groups 3 & 4).
  • ⁇ G287 was formulated with various adjuvants and administered to mice. Sera from the mice were assessed using the bactericidal antibody (BCA) assay and titers were as follows:
  • CpG-oligonucleotide was thus only mildly effective as an adjuvant, almost comparable to alum.
  • the PLG microparticles were more effective than both alum and CpG, but not as effective as Freund's adjuvant.
  • the mixture of CpG and PLG matched the adjuvanticity of Freund's adjuvant at the post-second immunization stage and exceeded Freund's adjuvant post-third immunization.
  • Protein ⁇ G287 was either adsorbed onto PLG microparticles using DSS surfactant or SDS or was simply mixed with the particles. Immunisations were performed on days 0, 21 and 35 and titers were assessed on days 35 and 49. Results were as follows:
  • the adjuvanticity of CpG and microparticle mixtures for ⁇ G287 is thus optimal when the antigen is adsorbed to microparticles.
  • Reference 6 discloses a protein from serogroup B N.meningitidis called '961' (now known as 'NadA' [16,17]).
  • References 10 to 12 disclose ways of improving the expression of NadA. One way involves deleting the C-terminus of the protein to remove its membrane anchor (i.e. remove amino acids 351-405 for strain 2996), as well as natural removal of its leader peptide. This protein is referred to as '961c'. The effect of adsorption on PLG adjuvanticity when co-administered with CpG was studied for 961c, as described above for 287:
  • the adjuvanticity of CpG and microparticle mixtures for 961c is optimal when the antigen is adsorbed to microparticles. This is true for the antigen on its own and the antigen when combined with ⁇ G287.
  • MF59 and alum can further enhance efficacy of CpG/PLG mixtures, adsorption of CpG to PLG microparticles is not necessary for adjuvanticity, but adsorption of antigen to microparticles is again seen to be optimal.
  • the adjuvanticity of CpG and microparticle mixtures for protein 961c is optimal when the antigen is adsorbed to microparticles.
  • Reference 12 discloses a combination of three proteins which, between them, include five different N.meningitidis antigens: (1) 961c 2996 ; (2) ⁇ G287 NZ -953 2 96 ; and (3) 936 2996 - ⁇ G741 MC58 -
  • the antigen mixture was tested in reference 12 using aluminum hydroxide adjuvant.
  • the antigen mixture is adjuvanted by adso ⁇ tion to a biodegradable polymer microparticle plus a CpG oligonucleotide. Titers after the third dose were as follows:
  • the PLG+CpG mixture leads to lower overall antibody titers (except for protein 287) but, importantly, gives higher bactericidal titers against a wide range of strains. Although absolute titers are lower, therefore, the adjuvant of the invention therefore advantageously shifts antibody production towards bactericidal antibodies.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Immunology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Oncology (AREA)
  • Microbiology (AREA)
  • Virology (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Mycology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • AIDS & HIV (AREA)
  • Molecular Biology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Biological Depolymerization Polymers (AREA)
  • Compositions Of Macromolecular Compounds (AREA)

Abstract

L'invention concerne une combinaison d'oligonucléotides CpG et de microparticules polymères qui constitue un adjuvant extrêmement efficace pour des antigènes de Neisseria. L'invention concerne donc une composition comprenant (a) un antigène de Neisseria; (b) un oligonucléotide CpG; et (c) une microparticule polymère biodégradable.
EP02800481A 2001-10-03 2002-10-03 Compositions de meningocoque assorties d'un adjuvant Withdrawn EP1438323A4 (fr)

Applications Claiming Priority (13)

Application Number Priority Date Filing Date Title
US254438 1988-10-06
US32692901P 2001-10-03 2001-10-03
US326929P 2001-10-03
PCT/US2002/010869 WO2002080648A2 (fr) 2001-04-05 2002-04-05 Augmentation de l'immunite des muqueuses a la suite d'un amorçage parenteral
WOPCT/US02/10869 2002-04-05
US37354702P 2002-04-17 2002-04-17
US373547P 2002-04-17
US38067702P 2002-05-13 2002-05-13
US380677P 2002-05-13
US25443802A 2002-09-24 2002-09-24
WOPCT/US02/30423 2002-09-24
US0230423 2002-09-24
PCT/US2002/031726 WO2003028661A2 (fr) 2001-10-03 2002-10-03 Compositions de meningocoque assorties d'un adjuvant

Publications (2)

Publication Number Publication Date
EP1438323A2 true EP1438323A2 (fr) 2004-07-21
EP1438323A4 EP1438323A4 (fr) 2007-08-01

Family

ID=32601151

Family Applications (1)

Application Number Title Priority Date Filing Date
EP02800481A Withdrawn EP1438323A4 (fr) 2001-10-03 2002-10-03 Compositions de meningocoque assorties d'un adjuvant

Country Status (8)

Country Link
EP (1) EP1438323A4 (fr)
JP (1) JP4522699B2 (fr)
CN (1) CN100354297C (fr)
AU (1) AU2002334844B2 (fr)
BR (1) BR0213119A (fr)
CA (1) CA2462646C (fr)
NZ (1) NZ532274A (fr)
WO (1) WO2003028661A2 (fr)

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0115176D0 (en) 2001-06-20 2001-08-15 Chiron Spa Capular polysaccharide solubilisation and combination vaccines
GB0302218D0 (en) * 2003-01-30 2003-03-05 Chiron Sri Vaccine formulation & Mucosal delivery
MXPA04011249A (es) * 2002-05-14 2005-06-06 Chiron Srl Vacunas mucosales con adyuvante de quitosano y antigenos meningococicos.
KR101239242B1 (ko) * 2002-08-02 2013-03-11 글락소스미스클라인 바이오로지칼즈 에스.에이. 항원 조합물을 포함하는 나이세리아 백신 조성물
JP2006520746A (ja) 2002-12-27 2006-09-14 カイロン コーポレイション リン脂質を含む免疫原性組成物
WO2004067030A2 (fr) * 2003-01-30 2004-08-12 Chiron Srl Vaccins injectables contre les multiples serogroupes du meningocoque
DE602004020189D1 (de) * 2003-01-30 2009-05-07 Novartis Vaccines & Diagnostic Adjuvante influenza-vakzine
US7731967B2 (en) * 2003-04-30 2010-06-08 Novartis Vaccines And Diagnostics, Inc. Compositions for inducing immune responses
PL1631264T5 (pl) 2003-06-02 2018-09-28 Glaxosmithkline Biologicals Sa Kompozycje immunogenne oparte na biodegradowalnych mikrocząstkach zawierających toksoid błonicy i tężca
WO2005081847A2 (fr) * 2004-02-20 2005-09-09 Hybridon, Inc. Reponse immunitaire mucosale puissante induite par des oligonucleotides immunomodulateurs modifies
US9107813B2 (en) 2004-11-15 2015-08-18 Derek T. O'Hagan Immunogenic compositions containing anthrax antigen, biodegradable polymer microparticles, and polynucleotide-containing immunological adjuvant
BRPI0607254A2 (pt) 2005-01-28 2009-08-25 Susan Szathmary composições imunologicamente ativa, método in vitro para identificação de peptìdeo ou proteìna, uso da composição e célula dendrìtica
JP2008531672A (ja) * 2005-03-02 2008-08-14 イギリス国 医薬組成物
AU2008335457B2 (en) 2007-12-07 2015-04-16 Glaxosmithkline Biologicals S.A. Compositions for inducing immune responses
CN101559225B (zh) * 2008-04-18 2012-07-11 北京生物制品研究所 脑膜炎球菌疫苗
RU2669346C2 (ru) 2012-06-21 2018-10-10 Норсвестерн Юниверсити Частицы, конъюгированные с пептидами

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6239116B1 (en) * 1994-07-15 2001-05-29 University Of Iowa Research Foundation Immunostimulatory nucleic acid molecules
CA2308606A1 (fr) * 1997-11-06 1999-05-20 Chiron S.P.A. Antigenes de neisseria
AU1979599A (en) * 1998-01-14 1999-08-02 Chiron S.P.A. (neisseria meningitidis) antigens
BR9910089A (pt) * 1998-05-01 2004-06-08 Chiron Corp Composições e antìgenos de neisseria meningitidis
DE69930642T2 (de) * 1998-07-29 2006-12-28 Chiron Corp., Emeryville Mikropartikel mit adsorbenten oberflächen, verfahren zu ihrer herstellung und ihrer verwendung
JP2004511201A (ja) * 1998-10-09 2004-04-15 カイロン　コーポレイション ナイセリアゲノム配列およびそれらの使用方法
EP1574210B1 (fr) * 1999-02-26 2016-04-06 Novartis Vaccines and Diagnostics, Inc. Microemulsions à macromolécules adsorbées
US8221761B1 (en) * 1999-02-26 2012-07-17 Novartis Ag Enhancement of bactericidal activity of neisseria antigens with oligonucleotides containing CG motifs
RU2245366C2 (ru) * 1999-04-30 2005-01-27 Чирон С.Р.Л. Антиген neisseria, кодирующая его нуклеиновая кислота, их использование
PT2270030E (pt) * 2000-02-28 2012-07-24 Novartis Vaccines & Diagnostic Expressão heteróloga de proteínas de neisseria

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
O'HAGAN D T ET AL: "POLY(LACTIDE-CO-GLYCOLIDE) MICROPARTICLES FOR THE DEVELOPMENT OF SINGLE-DOSE CONTROLLED-RELEASE VACCINES" ADVANCED DRUG DELIVERY REVIEWS, AMSTERDAM, NL, vol. 32, 1998, pages 225-246, XP000944990 ISSN: 0169-409X *
See also references of WO03028661A2 *
SINGH M ET AL: "ADVANCES IN VACCINE ADJUVANTS" NATURE BIOTECHNOLOGY, NATURE PUBLISHING GROUP, NEW YORK, NY, US, vol. 17, no. 11, November 1999 (1999-11), pages 1075-1081, XP000941305 ISSN: 1087-0156 *
SINGH M ET AL: "Cationic microparticles are an effective delivery system for immunie stimulatory CpG DNA" PHARMACEUTICAL RESEARCH, NEW YORK, NY, US, vol. 18, no. 10, October 2001 (2001-10), pages 1476-1479, XP002976979 ISSN: 0724-8741 *

Also Published As

Publication number Publication date
AU2002334844B8 (en) 2003-04-14
BR0213119A (pt) 2004-12-28
JP4522699B2 (ja) 2010-08-11
CA2462646C (fr) 2013-02-12
AU2002334844B2 (en) 2007-08-02
JP2005526697A (ja) 2005-09-08
CN1599746A (zh) 2005-03-23
WO2003028661A2 (fr) 2003-04-10
NZ532274A (en) 2006-02-24
EP1438323A4 (fr) 2007-08-01
CN100354297C (zh) 2007-12-12
CA2462646A1 (fr) 2003-04-10
WO2003028661A3 (fr) 2003-10-09

Similar Documents

Publication Publication Date Title
USRE45137E1 (en) Adjuvanted meningococcus compositions
EP1409013B1 (fr) Vaccins comprenant des adjuvants aluminium et histidine
US7754218B2 (en) Vaccines comprising aluminum adjuvants and histidine
EP1587538B1 (fr) Vaccins contre le meningocoque administres par la muqueuse
US20110150923A1 (en) Mucosal meningococcal vaccines
JP2017178971A (ja) 血清型ＢおよびＣ由来のＮｅｉｓｓｅｒｉａ ｍｅｎｉｎｇｉｔｉｄｉｓ抗原、ならびにさらなる抗原を含む組成物
AU2002330681A1 (en) Vaccines comprising aluminium adjuvants and histidine
CA2462646C (fr) Compositions de meningocoque assorties d'un adjuvant
AU2002334844A1 (en) Adjuvanted meningococcus compositions
US7838015B2 (en) Adjuvanted meningococcus compositions
WO2002045741A2 (fr) Vaccination de sensibilisation et d'exaltation contre helicobacter pylori
AU2007231677A1 (en) Adjuvanted meningococcus compositions
MXPA04003186A (es) Composiciones de meningococo coadyuvantes.
RU2360699C2 (ru) Композиции менингококковых вакцин с адъювантами

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20040420

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LI LU MC NL PT SE SK TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: NOVARTIS VACCINES AND DIAGNOSTICS, INC.

A4 Supplementary search report drawn up and despatched

Effective date: 20070704

RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 39/385 20060101ALI20070628BHEP

Ipc: A61K 39/095 20060101ALI20070628BHEP

Ipc: A61K 39/02 20060101AFI20070628BHEP

17Q First examination report despatched

Effective date: 20101020

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20140501