CN100354297C - Adjuvanted meningococcus compositions - Google Patents

Adjuvanted meningococcus compositions Download PDF

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CN100354297C
CN100354297C CNB028241282A CN02824128A CN100354297C CN 100354297 C CN100354297 C CN 100354297C CN B028241282 A CNB028241282 A CN B028241282A CN 02824128 A CN02824128 A CN 02824128A CN 100354297 C CN100354297 C CN 100354297C
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antigen
plg
cpg
particulate
composition
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CN1599746A (en
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D·欧哈根
N·瓦里安特
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NOVARTIS VACCINES and DIAGNOSTIC Inc
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Chiron Corp
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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
    • A61K39/095—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
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    • 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
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • 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

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Abstract

A combination of CpG oligonucleotides and polymer microparticles is an extremely effective adjuvant for Neisserial antigens. The invention therefore provides a composition comprising: (a) a Neisserial antigen; (b) a CpG oligonucleotide; and (c) a biodegradable polymer microparticle.

Description

Auxiliary meningococcus composition
It is for reference that all documents that this paper quotes are all included this paper in.
Technical field
Invention relates to vaccine, more particularly anti-Neisseria meningitidis (Neisseria meningitidis) vaccine.
Background field
Reported Neisseria meningitidis (meningococcus) serologic group A[1] and B[2,3] genome sequence.Research serologic group B sequence is to identify vaccine antigen [as reference 4 to 9] and candidate antigens, and the operation candidate antigens is to improve heterogenous expression [reference 10 to 12].
Antigen generally need be used adjuvant altogether to improve their immunogenicities [13] in vaccine.Freund's adjuvant has been used for serologic group B meningococcus [9], the vaccine Menjugate of licensed-in antiserum(antisera) group C TMUse aluminium hydroxide [14].Reported and used the oligonucleotide adjuvant that contains the CpG motif to strengthen the antigenic fungicidal activity of neisserial (Neisseria) [15].
A purpose of invention provides the antigenic adjuvant of further and improved Neisseria.
The announcement of invention
The combination of having found CpG oligonucleotide and polymer particles is extremely effective neisserial antigens adjuvant, and the result of combination results is well more a lot of than arbitrary separate constituent.Therefore the composition that provides is provided comprises: (a) neisserial antigens; (b) CpG oligonucleotide; (c) biodegradable polymer particles.
Neisserial antigens
Neisserial antigens can be proteantigen, the antigenic nucleic acid of coded protein or sugar antigen.Antigen preferably causes sterilization or protective immune response (as antibody response) in the acceptor Mammals.
Antigen can derive from any neisserial bacterial strain, comprises neisseria gonorrhoeae (N.gonorrhoeae), lactose neisserial (N.lactamica) and Neisseria meningitidis.Preferred Neisseria meningitidis antigens and can be from any serologic group.When antigen during, preferably use proteantigen from serologic group B; When from serologic group A, C, W135 or Y, preferably use sugar antigen.When using sugar antigen, these generally derive from bacterial capsule polysaccharide (for example oligosaccharides, as the oligosaccharides that obtains by hydrolysis), they usually and carrier proteins put together (as with CRM 197).
The preferred protein antigen that derives from serologic group B Neisseria meningitidis is:
Each described protein in the reference 4,5,6,7,8 or 9 (particularly 446 even number SEQIDs shown in the reference 4 (promptly 2,4,6 ..., 890,892), 45 even number SEQ IDs shown in the reference 5 (promptly 2,4,6 ..., 88,90) and reference 6 shown in 1674 even number SEQIDs 2-3020, even number SEQ IDs 3040-3114 and all SEQ IDs 3115-3241);
A kind of protein, it comprises each described one or more proteinic immunogenic fragments in reference 4,5,6,7,8 or 9.
A kind of protein, each described one or more protein have sequence identity (being preferably greater than 50%, as 60%, 70%, 80%, 90%, 95%, 99% or higher) in contained sequence and reference 4,5,6,7,8 or 9.
Each described protein in the reference 10,11 or 12.
A kind of protein, each described one or more protein have sequence identity (being preferably greater than 50%, as 60%, 70%, 80%, 90%, 95%, 99% or higher) in contained sequence and reference 10,11 or 12.
Special preferred protein antigen from serologic group B Neisseria meningitidis is protein ' 287 '.This protein can the wild-type form use [as GenBank accession number gi:7228690; 287 multiformity is arranged the Tu5 ﹠amp that is shown in reference 8; 15], but can use the derivative of wild-type protein.For example spendable protein and gi:7228690 have 50% or higher sequence identity (as 60%, 70%, 80%, 90%, 95%, 99% or higher).Can use the protein that contains brachymemma or protein disappearance variant, the terminal clipped form of N-described in reference 10 to 12 (specificly be ' and Δ G287 ', wherein nearly and comprise that 6 protein N-ends that repeat glycine residues are lacked).Can use the fusion rotein that contains as 287 sequences.All these 287 forms more especially keep wild-type 287 proteinic immunogenic forms, are fit to used herein ' 287 ' connotation.
Another special preferred protein antigen from serologic group B Neisseria meningitidis is protein ' 961 ', is also referred to as ' NadA ' [16].This protein can the wild-type form use [as GenBank accession number gi:7227256; 961 allelotrope is disclosed in reference 17], but can use the derivative of wild-type protein.For example spendable protein and gi:7227256 have 50% or higher sequence identity (as 60%, 70%, 80%, 90%, 95%, 99% or higher).Can use the protein or the protein disappearance variant that contain brachymemma, described in reference 10 to 12 (particularly ' 961c ', it lacks the terminal film anchor of C-).Can use the fusion rotein that contains as 961 sequences.All these 961 forms particularly keep wild-type 961 proteinic immunogenic forms, are fit to used herein ' 961 ' connotation.
Other preferred protein antigen is protein ' 741 ' and protein ' ORF46.1 ' and protein ' ORF1 ', ' ORF4 ', ' ORF25 ', ' ORF40 ', ' ORF83 ', ' NMB1343 ', ' 230 ', ' 233 ', ' 292 ', ' 594 ', ' 687 ', ' 736 ', ' 907 ', ' 919 ', ' 936 ', ' 953 ' and ' 983 '.Other preferred protein antigen is hybrid protein described in the reference 10 to 12, particularly comprises one or more: 287 protein, 953 protein, 963 protein and/or 741 proteinic hybrid proteins.
Proteantigen can derive from any Neisseria meningitidis bacterial strain.The preferred antigen that uses is from bacterial strain 2996, MC58,95N477 and 394/98.
Except the bacterial strain variant, single or multiple conservative amino acid replacements can change used immunogenicity of antigens according to the present invention and carry out.
Except or replace proteantigen, the antigenic nucleic acid of coded protein can be included in the inventive composition.In case be administered to mammalian receptors, proteantigen can be expressed and produce to nucleic acid in vivo.This nucleic acid immunization is known [as reference 18 to 23 etc.].Nucleic acid is the DNA plasmid normally.
The preferred sugar antigen that derives from serologic group C Neisseria meningitidis is Menjugate TMIn used oligosaccharides conjugate [24,25], it comprises 12 to 22 monosaccharide units from serologic group C capsular polysaccharide.
The preferred sugar antigen that derives from serologic group A is a kind of oligosaccharides, and one or more hydroxyls of wherein forming on the monosaccharide units are blocked group replacement [26].
Acquisition is disclosed in reference 27 from the more number carbohydrate antigen of serologic group A, W135 and Y.
Inventive composition can comprise the scorching neisserial antigens greater than.When the carbohydrate from Neisseria meningitidis serologic group A and C all comprised, preferred MenA sugar: the ratio of MenC sugar (w/w) was greater than 1 (as 2: 1,3: 1,4: 1,5: 1,10: 1 or higher)
Inventive composition is immunogenic composition or vaccine preferably.This composition comprises the antigen of immune significant quantity." immune significant quantity " refers to be administered to effective treatment or the preventative immunne response of improving of antigen amount (single dose or a series of part) that individual invention composition is comprised.The preparation, attending doctor of the health of individuality to be treated and physical condition, age, the sorted group (as inhuman primate, primate etc.) of individuality to be treated, the immunity system ability of individual synthetic antibody, required degree of protection, vaccine assessment and other correlative factor to medical condition depended in the variation of this amount.Amount can be in wide relatively scope, and scope can be determined by routine test.Antigen exists with the concentration of each 1 μ g/ml at least usually.
The metering treatment can be that (as comprising booster dose) arranged in single dose or many meterings.
The CpG oligonucleotide
Known CpG oligonucleotide brings out strong Th1 immunne response as vaccine adjuvant [as reference 28] and they.They are as parenteral and mucosal adjuvants [29].
CpG oligonucleotide used according to the invention is a kind of nucleic acid, and it comprises that at least one CpG dinucleotides is the cytidylic acid(CMP) that there is guanosine Nucleotide the back.Oligonucleotide can contain a plurality of CpG dinucleotides.
CG sequence in the oligonucleotide can have two purine of 5 ' flank and two pyrimidines, i.e. RRCGYY of 3 ' flank.
Cytidylic acid(CMP) in the CpG oligonucleotide can be methylated, but preferably they answer right and wrong methylated.
Cytosine(Cyt) and guanosine Nucleotide is deoxyribonucleotide and nucleic acid DNA preferably preferably.For improving the nuclease resistance, oligonucleotide can comprise the main chain of modification, as the thiophosphoric acid main chain.Except using DNA, may use PNA (peptide nucleic acid(PNA)).In addition, oligonucleotide can comprise the replacement of sugar moieties and nitrogenous base part.
Oligonucleotide preferably include about 6 and about 100 between Nucleotide, more preferably from about 8 and about 50 between Nucleotide, most preferably from about 10 and about 40 between Nucleotide.
The oligonucleotide that contains at least 1 CG dinucleotides can use conventional oligonucleotide synthesis method to prepare easily.
The example of CpG oligonucleotide adjuvant is found in reference 30 to 55.
Biodegradable polymeric particulate
Known biodegradable polymer particles is as vaccine adjuvant [as reference 56].They are as parenteral and mucosal adjuvants [29].
Remove biodegradablely, the polymkeric substance that is used to prepare particulate generally can be sterilized and nontoxic (physiologically acceptable).Suitable suitable biodegradable polymers can commercially be bought, and the polymkeric substance that comprises derives from multi-hydroxybutyrate; Polycaprolactone; Poe; Polyanhydride; Poly-(hydroxybutyric acid); With poly-(alpha-hydroxy acid).As poly-(L-rac-Lactide), poly-(D, L-rac-Lactide), D, the multipolymer of L-rac-Lactide and glycollide is (as poly-(D, L-lactide-co-glycolide) or D, the multipolymer of L-rac-Lactide and caprolactone from one or more poly-(alpha-hydroxy acids) for preferred polymer formation.Be preferably formed the particulate of autohemagglutination (D, L-lactide-co-glycolide) (' PLG ').
These polymers have various molecular weights, and the suitable molecular weight of specific antigen can easily be determined.For poly-(L-rac-Lactide), suitable molecular weight is equivalent to about 2000 to 250,000.For PLG, the suitable molecule weight range is generally from about 10,000 to 200,000, and preferred about 15,000 to about 150,000, and most preferably from about 50,000 to 100,000.
For the PLG particulate, can use multiple rac-Lactide: the glycollide ratio, and the ratio selection mainly is to depend in part on common administration of antigens and required degradation speed.For example, 50: 50 PLG polymkeric substance contains 50%D, L-rac-Lactide and 50% glycollide, and it adsorbs multipolymer fast again and 75: 25 PLG degraded is slower, because the rac-Lactide composition increases by 85: 15,90: 10 even slower.Rac-Lactide: the proper ratio of glycollide is discussed on the disease basis easily definite at antigenic property and institute.In addition, different rac-Lactides: the particle mixture of glycollide ratio is used for preparation with the release dynamics that obtains required specific antigen and first and secondary immune response are provided.The degradation speed of particulate of the present invention also can be controlled by factor such as polymericular weight and crystallinity.
As used herein, term ' particulate ' refers to the particle of the about 100nm of diameter to about 150 μ m, and more preferably the about 200nm of diameter is to about 30 μ m, and the about 500nm of most preferred diameters is to about 10 μ m.But preferred mean particle dia parenteral administration and do not need clog needle or kapillary.Particle size is determined by well known technology easily, surveys method and/or scanning electronic microscope as photon correlation spectroscopy method, laser diffraction.Term ' particulate ' comprises ' nano particle ' [57] in its scope.Preferred particulate is a microsphere, although also can use laminar particle [58].
Particulate can prepare [as reference 59] with any any certain methods well known in the art.For example, dual emulsion/solvent evaporation technology is [as reference 60﹠amp; 61] can be used for forming particulate.These technology comprise the original emulsion of formation, and emulsion is formed (if antigen is waited to be embedded in the particulate) by the droplet that contains antigenic polymer solution, mixes with the continuous water that contains particle stabilizers/tensio-active agent subsequently.
More particularly, (w-o-w) solvent evaporation system of water-in-oil oil-in-water (water-in-oil-in-water) can be used for forming particulate, as described in reference 62,63 and 64.In this technology, particular polymers is in conjunction with organic solvent, as ethyl acetate, dimethyl chlorination thing (being also referred to as methylene dichloride and methylene dichloride), acetonitrile, acetone, chloroform etc.Polymkeric substance is provided in about 2-15% solution, the organic solvent.Antigenic solution (as in water) and polymkeric substance/antigenic solution of adding about equivalent are used as homogenizer emulsification.Emulsion is then in conjunction with the aqueous solution of the emulsion stablizer of large volume, as polyvinyl alcohol (PVA) and polyvinylpyrrolidone.The emulsion stablizer is provided in about 2-15% solution usually, is more typically in about 4-10% solution.The homogenate mixture is to produce the two emulsions of stable w/o/w then.Evaporate organic solvent then.
Can operate formulation parameters little to prepare (＜5 μ m) and big (＞30 μ m) particulate [as 63,65].For example, reduce to stir producing big particulate, the increase of disperse phase volume is also like this.Small-particle produces by the high density PVA of low water volume.
The also available spraying of particulate-drying and cohesion are [as reference 66,67﹠amp; 68]; Turbid and the wurster's coating [69,70] of air-suspension packaging technique such as cooking-pot type dressing; Ion gelling [71] forms.
Before using particulate, thereby the particulate of generally determining the antigenic content appropriate amount can pass to the experimenter to cause suitable immunne response.
The antigenic content of particulate can be determined according to means known in the art, as the antigen of division particulate and extraction embedding.For example particulate dissolves in dimethyl chlorination thing and protein is extracted [as reference 72,73,74] in the distilled water.In addition, particulate can be dispersed among the 0.1M NaOH that contains 5% (w/v) SDS.Stirred sample, centrifugal and supernatant are with suitable assay method analysis.
Antigen and/or CpG oligonucleotide can be in particulate or on the location.Embedding exists antigen/oligonucleotide to finish in generally forming by particulate, and surface adsorption is finished by antigen/oligonucleotide being added the pre-particulate that forms.
Adsorption antigen/oligonucleotide is as follows to a kind of method on the preparation particulate.Particulate is rehydrated and be distributed to the essential monomer suspension of particulate, uses dialyzable negatively charged ion or cationic detergent.Useful washing composition includes but not limited to any different N-methyl glucose amide (glucamide) (being called MEGAs), as oenanthyl-N-methyl glucose amide (MEGA-7), decoyl-N-methyl glucose amide (MEGA-8), nonanoyl-N-methyl glucose amide (MEGA-9) and caprinoyl-N-methyl glucose amide (MEGA-10); Cholic acid; Sodium cholic acid; Septochol; Sodium desoxycholate; Taurocholate; Taurocholic acid sodium salt; Tauroursodeoxycholic acid; Sodium taurodeoxycholate; 3-3[(3-courage aminopropyl) dimethylamino]-1-propane-sulfonate (CHAPs); N-suffering lay a foundation glucoside, 3-3[(3-courage aminopropyl) dimethylamino]-2-hydroxyl-1-propane-sulfonate (CHAPSO); N-dodecyl-N, N-dimethyl-3-amino-1-propane-sulfonate (ZWITTERGENT 3-12); N, N-pair-(3-D-glucose aminopropyl)-deoxidation courage acid amides (DEOXY-BIGCHAP); Sucrose monolaurate; Glycocholic acid/NaGC; Bay sarkosine (laurosarcosine) (sodium salt); Glycodesoxycholic acid/glycodesoxycholic acid sodium; Sodium laurylsulfonate (SDS); Cetrimonium bromide (CTAB); The bromination dodecyl trimethyl ammonium; Cetrimonium bromide; Cetrimide; Bromination benzyl dodecyl dimethyl ammonium; Zephiran chloride hexadecyl two basic first ammoniums; Bromination benzyl tetradecyl Dimethyl Ammonium.Above washing composition can commercially be bought.Multiple cation lipid class known in the art also can be used as washing composition [76,77].
Particulate/detergent mixture is for example milled with porcelain mortar and pestle physics then, up to forming smooth slurry.Add suitable water damping fluid such as phosphate-buffered saline (PBS) or Tris buffer saline then, the gained mixture fully suspends up to particulate with ultrasonication or homogenate.Antigen/oligonucleotide adds microparticle suspending liquid then and system dialyses to remove washing composition.Preferred polymers particulate and detergent system make antigen/oligonucleotide be adsorbed onto microparticle surfaces and still keep active.The particulate that gained contains surface adsorption antigen/oligonucleotide can wash not to be had not conjugated antigen/oligonucleotide and preserves as the suspension in the suitable buffer preparation, or uses the suitable vehicle freeze-drying, as further described below.
Antigen/CpG/ particulate combination
Has multiple physical relation between three kinds of basal component of invention composition.These are that both can be used for locating CpG oligonucleotide and/or antigen because particulate has internal volume and surface.
Therefore antigen can be embedded in the particulate, and it is adsorbable to particulate, or can simply mix with particulate and do not have embedding or absorption.Preferred absorption.
Similarly, the CpG oligonucleotide can be embedded in the particulate, and it is adsorbable to particulate, or can simply mix with particulate.Sorptive power is finished with washing composition such as CTAB.
The CpG oligonucleotide all has identical physical relation with particulate each other with anti-, or they can be different.Same CpG oligonucleotide and antigen adsorbable to identical particulate or the CpG oligonucleotide adsorbable to different particulates with antigen.All possible combination is included in the present invention:
The CpG oligonucleotide
Embedding Absorption Mix
Anti- Embedding Be Be Be
Absorption Be Be Be
Mix Be Be Be
The invention composition can comprise top mixture, and as some the particulate embedding antigens in the composition, some are adsorption antigen then.
Pharmaceutical composition
For pharmaceutical use, the invention composition generally comprises pharmaceutically acceptable carrier.This has produced the pharmaceutical composition of invention.Pharmaceutically acceptable carrier can be any material, self does not induce generation to accepting the deleterious antibody of composition patient and not using with can having inappropriate toxicity.Suitable carrier can be big, slow metabolic macromole such as protein, polysaccharide, poly(lactic acid), polyglycolic acid, polymeric amino acid, amino acid copolymer and inactivation virion.This carrier is known for those of ordinary skills.Pharmaceutically acceptable carrier can comprise liquid such as water, salt solution, glycerine and ethanol.Auxiliary substance such as wetting agent or emulsifying agent, pH buffer substance etc. also can be present in this carrier.Liposome is a suitable carriers.Discussing fully in reference 78 of pharmaceutical carrier.
Inventive composition can prepare in a variety of forms.For example, composition can be prepared as injectable liquor or suspension.Also can prepare the solid form that is fit to be dissolved in or be suspended in liquid vehicle before the injection.Composition can prepare and be used for topical application, as ointment, creme or pulvis.Composition can prepare be used for oral, as tablet or capsule or as syrup (optional seasoning).Composition can prepare and be used for pulmonary administration as sucker, uses meticulous pulvis or spraying.Composition can be prepared as suppository or vaginal suppository.Composition can prepare and be used for nose, ear or eye is used, as drops, spraying or pulvis [as 79].
Pharmaceutical composition is preferably aseptic.It does not preferably have pyrogen.Its preferred buffered, as between pH6 and pH8, general pH about 7.
Pharmaceutical composition can freeze-drying.
Invention also provides the transfer device that contains the invention pharmaceutical composition.Device can be a syringe for example.
Therapeutic treatment and use
The invention composition can be used for treatment (promptly treating existing neisserial infects) or prevention (preventing that promptly neisserial in the future from infecting).
Invention provides the invention composition as medicine.
The antibody response that invention also provides method to be used for improving Mammals comprises that the pharmaceutical composition of using invention is to Mammals.Antibody response is IgA and IgG reaction and preferably germ-resistant preferably.
The Mammals that invention also provides method to be used for the treatment of infection of trouble neisserial and/or disease comprises that the pharmaceutical composition of using invention is to patient.
Invention provides method to be used to protect Mammals to avoid neisserial infection and/or disease equally, comprises that the pharmaceutical composition of using invention is to Mammals.
Invention also is provided in the drug manufacture uses (a) neisserial antigens, (b) the CpG oligonucleotide and (c) biodegradable polymer particles to prevent or to treat neisserial disease and/or infection in the Mammals.
Mammals is the people preferably.The people can be the adult, or preferred children.Inventive composition is used in particular for immune children and teenager.
The use of invention and method are used in particular for the anti-Neisseria meningitidis of treatment/protection and infect.Use and method be used in particular for preventing/treat disease, comprise bacterial meningitis.
Neisserial infected and tests after the effect of treatment can be used by monitoring invention composition.The immune response of anti-neisserial was tested after the effect of prophylactic treatment can be used by the monitoring composition.
Inventive composition generally directly is administered to patient.Finish direct transmission can pass through parenteral injection (as subcutaneous, intraperitoneal, intravenously, intramuscular, or the gap of tissue), rectum, oral, vagina, part, through skin, eye, nose, ear or pulmonary administration.Preferred injection and intranasal administration.
Dosage treatment can be single dose scheme or multiple doses scheme.
Further composition
Except CpG oligonucleotide and polymer particles, inventive composition can comprise adjuvant.Preferably more adjuvants include but not limited to: (A) aluminum compound is (as aluminium hydroxide, aluminum phosphate, phosphoric acid hydrogen aluminium, oxyhydroxide, orthophosphoric acid salt, vitriol etc. [for example referring to the 8﹠amp of reference 13; 9 chapters]), or the mixture of different aluminum compound, compound is taked any suitable form (as gel, crystallization, amorphous etc.), preferred absorption; (B) MF59 (5% shark alkene, 0.5% tween 80 and 0.5%Span 85 are mixed with submicron particle with the Micro Fluid agent) [the 10th chapter referring to 13 is also referring to reference 80]; (C) liposome [referring to the 13rd and 14 chapters of reference 13]; (D) ISCOMs[is referring to the 23rd chapter of reference 13], can there be other washing composition [81]; (E) SAF contains 10 shark alkene, 0.4% tween 80 and 5%pluronic-blocking-up polymkeric substance L121 and thr-MDP, and miniflow changes into the emulsion [referring to the 12nd chapter of reference 13] of submicron emulsion or vortex generation larger grain size; (F) Ribi TMAdjuvant system (RAS) (Ribi Immunochem), contain 20% shark alkene, 0.2% tween 80 and one or more bacteria cell wall compositions, cell wall constituent is from monophosphoryl lipid A (MPL), trehalose two mycolic acids (TDM) and cell wall skeleton (CWS), preferred MPL+CWS (Detox TM); (G) Saponin/TSM adjuvant is as QuilA or QS21[the 12nd chapter referring to reference 13], be also referred to as Stimulon TM[82]; (H) chitosan [as 83]; (I) complete Freund's adjuvant (CFA) and incomplete Freund's adjuvant (IFA); (J) cytokine, as interleukin (as IL-1, IL-2, IL-4, IL-5, IL-6, IL-7, IL-12 etc.), Interferon, rabbit (as interferon-), macrophage colony stimulating factor, tumour necrosis factor etc. [referring to the 27﹠amp of reference 13; 28 chapters]; (K) monophosphoryl lipid A (MPL) or 3-O-deacylated tRNA MPL (3d MPL) [as the 21st chapter of reference 13]; (L) combination [84] of 3d MPL and for example QS21 and/or oil-in-water emulsion; (M) Soxylat A 25-7 or polyoxyethylene ester [85]; (N) the polyoxyethylene sorbitan esters tensio-active agent in conjunction with octoxinol [86] or Voranol EP 2001 or ester surfactant in conjunction with at least a other nonionogenic tenside such as octoxinol [87]; (O) particle of metal-salt [88]; (P) Saponin/TSM and oil-in-water emulsion [89]; (Q) Saponin/TSM (QS21)+3d MPL+IL-12 (optional+sterol) [90]; (R) heat-labile enterotoxin of E, coli (" LT ") or its detoxification mutant are as K63 or R72 mutant [as the 5th chapter of reference 91]; (S) Toxins,exo-, cholera (" CT ") or its detoxification mutant [as the 5th chapter of reference 91]; (T) double-stranded RNA and (U) other material are as the effectiveness [as the 7th chapter of reference 13] of immunostimulant enhancing composition.The further preferred adjuvant of aluminium (particularly aluminum phosphate and/or aluminium hydroxide) and MF59 as the parenteral immunity.The mutant toxin is preferred mucosal adjuvants.
Muramylpeptides comprises N-acetyl-muramyl-L-threonyl-D-isoglutamine (thr-MDP), N-acetyl-go first muramyl-L-alanyl-D-isoglutamine (removing first-MDP), the N-acetyl muramyl-different glutamy of L-alanyl-D---L-L-Ala-2 (1 '-2 '-two palmityls-sn-glycerine-3-hydroxyl phosphoryl oxygen)-ethamine MTP-PE) etc.
Except neisserial antigens, invention can further comprise the antigenicity composition.The antigen that can be included in the invention composition comprises:
From the antigen of helicobacter pylori (Helicobacter pylori), as CagA[92 to 95], VacA[96,96], NAP[98,99,100], HopX[is as 101], HopY[is as 101] and/or urase.
From adventitia vesicle (OMV) prepared product of Neisseria meningitidis serologic group B, shown in reference 102,103,104,105 etc.
Sugar antigen [as 106,107,108] from streptococcus pneumoniae (Streptococcus pneumoniae).
From the antigen of hepatitis A virus (HAV), as inactivation virus [as 109,110].
From the antigen of hepatitis B virus, as surface and/or cAg [as 110,111].
Antigen [as 112] from hepatitis C virus.
Antigen from Bordetella pertussis (Bordetella pertussis), as Whooping cough holotoxin (PT) with from the filamentous hemagglutinin (FHA) of Bordetella pertussis, optional also with PRN (pertactin) and/or agglutinogen 2 and 3 combinations [as reference 113﹠amp; 114].
Diphtheria antigen is as diphtheria toxoid [as the 3rd chapter of reference 115], for example CRM 197Mutant [as 116].
Tetanus antigen is as Toxoid,tetanus [as the 4th chapter of reference 115].
Sugar antigen [as 23] from the bloodthirsty fennel of influenza (Haemophilus infulenzae) B.
Antigen [as 117,118,119,120,121,122,123] from Chlamydia pneumoniae (Chlamydia pneumoniae).
Antigen [as 124] from chlamydia trachomatis (Chlamydia trachomatis).
Antigen [as 125] from bud gum porphyrin sporangium (Porphyromonas gingivalis).
Poliomyelitis antigen [as 126,127], for example IPV or OPV.
Rabies antigen [as 128], and for example freeze dried inactivation virus [as 129, RabAvert TM].
Measles, parotitis and/or rubella antigen [as reference 115 the 9th, 10﹠amp; 11 chapters].
From the antigen [as the 19th chapter of reference 115] of influenza virus, for example hemagglutinin and/or neuraminidase surface protein.
From the antigen of paramyxovirus, as respiratory syncytial virus (RSV[130,131] and/or parainfluenza virus (PIV3[132]).
Antigen [as 133] from morazella catarrhalis (Moraxella catarrhalis).
Antigen [as 134,135] from streptococcus agalactiae (streptococcus agalactiae) (B group B streptococcus B).
Antigen [as 135,136,137] from streptococcus pyogenes (Streptococcus pyogenes) (A group B streptococcus B).
Antigen [as 138] from streptococcus aureus (Staphylococcus aureus).
Antigen [as 139,140,141] from anthrax bacillus (Bacillus anthracis).
From the antigen of flaviviridae family (Flavivirus) virus, as from yellow fever virus, japanese encephalitis virus, the serotype of 4 kinds of dengue fever viruss, tick-brone encephalitis virus, west Nile virus.
Pestivirus antigen, Tathagata is from classical Pig Fever virus, bovine viral diarrhea virus and/or border disease virus.
Parvovirus antigen is as from assays for parvovirus B 19.
Prion protein (as the CJD prion protein).
Amyloid protein is as β peptide [142].
Cancer antigen is as the table 1 of reference 143 or the table 3﹠amp of reference 144; 4 is listed.
Composition can comprise one or more these further antigens.
Toxic protein antigen can be by detoxification (as making the Toxins, pertussis detoxification by chemistry and/or genetic method) when needing.
When diphtheria antigen is included in the composition, also preferably include tetanus antigen and Toxins, pertussis.Similarly, when comprising tetanus antigen, also preferably include diphtheria antigen and Toxins, pertussis.Similarly, when comprising Toxins, pertussis, also preferably include diphtheria antigen and tetanus antigen.
Antigen preferably is adsorbed onto aluminium salt.
Antigen in the composition exists with the concentration of each 1 μ g/ml at least usually.Generally, the concentration of specific antigen is enough to cause anti-this antigenic immunne response.
Except using the proteantigen in the invention composition, can use the nucleic acid of coding for antigens.Therefore the protein component of invention composition this proteic nucleic acid (preferred DNA, as with the plasmid form) that can be encoded replaces.
Definition
Term " comprise " refer to " comprising " and " by ... form ", " comprise " X as composition and can form maybe by X fully and can comprise other composition such as X+Y.
Per-cent sequence identity refers to that when arranging, relatively the amino acid per-cent of two sequences is identical between two aminoacid sequences.This arrangement and per-cent homology or sequence identity can determine that for example the 7.7.18 part of reference 145 is described with software program known in the art.Preferred arrangement determines with the search of affine gap by Smith-Waterman homology searching algorithm, and at interval open point penalty is 12 and to extend point penalty at interval be 2, and the BLOSUM matrix is 62.Smith-Waterman homology searching algorithm is taught in reference 146.
Finish the pattern of invention
Strengthen with Neisseria meningitidis serologic group B antigen parenteral sensitization and mucous membrane
Reference 6 has disclosed the protein from Neisseria meningitidis serologic group B, is called ' 287 '.Reference 10 to 12 has disclosed the method for improving its expression.A kind of method comprises disappearance protein N-end and comprises that 6 are repeated glycine residue.This protein is called ' Δ G287 '.
Mouse is used MenB Δ G287 antigen (the 20 μ g/ dosage) sensitization from bacterial strain 2996 and strengthens, and this antigen is made and is used for intramuscular (IMU) and uses by being adsorbed onto the PLG particulate, and this can be with or without CpG oligonucleotide (also being adsorbed onto particulate).The preparation that (IN) uses in the another kind of nose uses the LT-K63 adjuvant.Mouse is accepted 3 IM dosage or 2 IM 2 IN dosage (dosage: 0 day then; The 28th day; The 84th day; Optional the 98th day).
Group Preparation Approach Dosage Antibody GMT is after 2 weeks
Dosage 2 Dosage 3 Dosage 4
1 PLG/287 IM 1，2，3 10,729 2,853 -
2 PLG/287+PLG/CpG IM 1，2，3 15,673 4,163 -
3 PLG/287 IM 1，2 9,064 7,948 9,412
287+LT-K63 IN 3，4
4 PLG/287+PLG/CpG IM 1，2 34,891 15,167 16,556
287+LT-K63 IN 3，4
Therefore, comprise the CpG oligonucleotide and improve antibody titers (the comparative group 1﹠amp that anti-intramuscular is used MenB protein 287; 2).Antibody titers can improve (comparative group 1﹠amp by replacing the 3rd intramuscular dosage with 2 intranasal doses; 3).The CpG raising also is found in scheme (comparative group 3﹠amp in intramuscular/nose; 4).
The adjuvant that relatively is used for MenB protein 287
Δ G287 makes and is administered to mouse with multiple adjuvant.Serum from mouse is as follows with assessment of bactericidin (BCA) mensuration and titre:
Adjuvant Behind the BCA-2 Behind the BCA-3
Freund's adjuvant 2048 8192
Aluminium ＜4 256
Aluminium+CpG oligonucleotide 256 4097
MF59 ＜4 ＜4
The CpG oligonucleotide ＜4 128
PLG particulate (absorption) 8 1024
PLG particulate (absorption)+CpG 2048 16384
Therefore the CpG oligonucleotide only appropriateness effectively as adjuvant, almost can with aluminum ratio.The PLG particulate is more effective than aluminium and CpG, but does not have freund's adjuvant effective.Yet significantly opposite is, CpG and PLG mixture matched with the adjuvanticity of freund's adjuvant after two immunity stages, and surpasses freund's adjuvant in immunity back for the third time.
Improving the PLG adjuvanticity with CpG is also finding in the research (02-0279) separately:
Adjuvant Behind the GMT 2 Behind the GMT 3
MF59 6967 13417
PLG particulate (absorption) 7070 11367
PLG particulate (absorption)+CpG 15099 26833
Absorption is to the effect of adjuvanticity
Studied the effect of absorption to adjuvanticity.Protein Δ G287 is adsorbed onto on the PLG particulate or with particle with DSS tensio-active agent or SDS and simply mixes.Immunity was carried out at the 0th, 21 and 35 day and titre was assessed at the 35th and 49 day.The result is as follows:
Preparation BCA Antibody titers after 2 weeks
Dosage 2 Dosage 3
CpG+PLG (DSS) goes up 287 of absorption 4096 45817 67921
CpG+PLG (SDS) goes up 287 of absorption 4096 39730 29911
CpG+287+PLG (not absorption) ＜16 62 1065
Adsorb on the DSS+ aluminium 287 ＜16 1209 1249
Adsorb on the CpG+ aluminium 287 1024 4054 12236
Adsorb on the aluminium 287 128 646 2454
So when antigen is adsorbed onto particulate, CpG and the adjuvanticity the best that is used for the particle mixture of Δ G287.
Reference 6 has disclosed a kind of protein from Neisseria meningitidis serologic group B, is called ' 961 ' (being also referred to as ' NadA ' [16,17] now).Reference 10 to 12 has disclosed the method that NadA expresses of improving.A kind of method comprises that the proteinic C-end of disappearance is to remove its film anchor (promptly removing the amino acid 341-405 of bacterial strain 2996) and its leading peptide of natural removal.This protein is called ' 961c '.About as described in 287, when using CpG altogether, studied the effect of absorption as top to the PLG adjuvanticity:
Preparation BCA The antibody titers in 32 weeks of back of dosage
PLG (SDS) goes up 961 of absorption 2048 20661
961+PLG (not absorption) 256 1706
287 of the last absorption of PLG 4096 63057
The 287+ solvable 961 of the last absorption of PLG 4096 287：86052；961：1924
The 287+PLG of the last absorption of PLG goes up 961 of absorption 8192 287：107142；961：11717
287 (not absorption)+961 (not absorption)+' blank ' PLG 1024 287：1266；961：145
287 (absorption)+961 (absorption)+' blank ' PLG 8092 287：78176；961：20876
So for Δ G287, when antigen is adsorbed onto particulate, CpG and the adjuvanticity the best that is used for the particle mixture of 961c.This also is suitable for during in conjunction with Δ G287 for antigen itself and antigen.
So for independent and bonded Δ G287 and 961c, when antigen is adsorbed onto on the PLG particulate, adjuvanticity the best of CpG and PLG mixture.
PLG, CpG, aluminium and MF59
The various combination of test PLG, CpG, aluminium and MF59 is used to be expressed as the protein Δ G287 of His-marked product.3 times immunity back serum sterilizing titre is as follows:
Adjuvant Titre
Aluminium 2048
Aluminium+CpG 32768
MF59 8192
MF59+CpG 32768
PLG (antigen is adsorbed onto PLG) 1024
PLG+CpG (antigen and CpG are adsorbed onto PLG) 4096
PLG+MF59 (antigen is adsorbed onto PLG) 2048
PLG+MF59+CpG (antigen is adsorbed onto PLG) 8192
Complete Freund's adjuvant 32768
PLG+ complete Freund's adjuvant (antigen is adsorbed onto PLG) 2048
Similarly test and the result as follows:
Adjuvant Titre
PLG (antigen is adsorbed onto PLG) 1024
PLG+CpG (antigen is adsorbed onto PLG) 16384
PLG+CpG (antigen and CpG are adsorbed onto PLG) 16384
PLG+ aluminium (antigen is adsorbed onto PLG) 1024
PLG+ aluminium+CpG (antigen is adsorbed onto PLG) 16384
PLG+ aluminium+CpG (antigen and CpG are adsorbed onto PLG) 8192
PLG+MF59 (antigen is adsorbed onto PLG) 4096
PLG+MF59+CpG (antigen is adsorbed onto PLG) 16384
Aluminium (antigen is adsorbed onto aluminium) 256
CpG 128
Aluminium+CpG 1024
(antigen is adsorbed onto aluminium to aluminium+CpG+PLG; CpG is adsorbed onto PLG) 4096
(CpG is adsorbed onto PLG to CpG+PLG; Antigen is absorption not) 64
Therefore MF59 and aluminium can further improve the effect of CpG/PLG mixture, and it is optional for adjuvanticity that CpG is adsorbed onto the PLG particulate, but see that once more antigen is adsorbed onto particulate the best.
Antigen mixture
For independent and bonded protein Δ G287 and 961c, studied the effect of absorption to adjuvanticity.Antibody titers is as follows behind 3 dosage:
Preparation Antibody GMT is anti-
287 961
961 of the last absorption of CpG+PLG - 20661
CpG+961+PLG (not absorption) - 1706
287 of the last absorption of CpG+961+PLG 86052 1924
The 961+PLG of the last absorption of CpG+PLG goes up 287 of absorption 107142 11717
287 of the last absorption of CpG+PLG 63057 -
CpG+PLG last co-adsorption 287 and 961 57306 6251
The 961+PLG of the last absorption of CpG+PLG goes up the 287+PLG of absorption 78176 20876
287+961+PLG (not having adsorption antigen) 1266 145
So for Δ G287, when antigen is adsorbed onto particulate, CpG and the adjuvanticity the best that is used for the particle mixture of protein 961c.
For protein Δ G287 and 961c, further test the combination of adjuvant and PLG particulate.CpG is solvable or be adsorbed onto the PLG particulate.The result is as follows:
Preparation+PLG particulate BCA GMT is anti-
287 961
287 (the last absorption of PLG)+961 (the last absorption of PLG) 256 5719 2412
287 (the last absorption of PLG)+961 (the last absorption of PLG)+CpG 512 17553 8627
287 (the last absorption of PLG)+961 (the last absorption of PLG)+CpG (the last absorption of PLG) 1024 16906 6720
287 (the last absorption of PLG)+961 (the last absorption of PLG)+MF59 64 4636 3969
287 (the last absorption of PLG)+961 (the last absorption of PLG)+MF59+CpG 2048 23642 48446
10 CD-1 mouse groups are similarly worked, use the every IM dosage of the every PLG-adsorption antigen of 20 μ g (0,21 and 35 day).When CpG exists, give 10 μ g every dosage.ELISA titre (GMT) is calculated as OD 450nm0.5 the dilution of mutual serum, test two kinds of antigenic serum.Serum bactericidal activity titre (SBA) is calculated as the mutual serum dilution of killing 50% target bacteria, the activity of anti-2996 bacterial strains of test sera and anti-allos bacterial strain MC58.49 days titre (2 weeks behind the dosage for the third time) is as follows:
287 961 Extra adjuvant GMT SBA
287 961 2996 M58
X - - 8375 - 512 ＜4
X - Solvable CpG 33736 - 1024 128
X The CpG of PLG-absorption 32058 - 1024 64
- X - - 3818 nd nd
- X Solvable CpG - 14149 2048 ＜4
- X The CpG of PLG-absorption - 18526 2048 ＜4
X X - 13557 2476 nd nd
X X Solvable CpG 21664 6557 8192 64
X X The CpG of PLG-absorption 27259 7510 2048 128
X X Solvable CpG+MF59 27981 26826 2048 256
Contrast: solvable 287 and CFA 37889 - 1024 ＜32
Contrast: solvable 961 and CFA - 50453 4096 ＜4
Contrast: solvable 287 and 961 and CFA 16781 27069 512 ＜32
Nd does not detect
Reference 12 has disclosed three kinds of proteinic combinations, comprises 5 different Neisseria meningitidis antigens between them: (1) 961c 2996(2) Δ G287 NZ-953 2996(3) 936 2996-Δ G741 MC58Antigen mixture is tested with aluminum hydroxide adjuvant in the reference 12.According to the present invention, antigen mixture adds that by being adsorbed onto biodegradable polymer particles oligonucleotide assists a ruler in governing a country.Titre is as follows behind the dosage for the third time:
Immunity ELISA GMT SBA (anti-7 bacterial strains)
961 287 741 953 2996 MC58 BZ133 394/98 NGH38 F6124 44/76
(1) 961 on the aluminium 12346 - - - 4096 ＜4 ＜4 ＜4 ＜4 64 ＜4
(2) 287-953 on the aluminium - 6415 - 585 1024 1024 256 1024 4096 256 1024
(2) 936-741 on the aluminium - - 10625 - ＜4 32678 16384 1024 128 16384 32768
(1) on the aluminium, (2) and (3) 42302 18206 33881 4549 8192 32768 32768 2048 4096 32768 65536
(1) 961 on the aluminium 14185 - - - 2048 4 ＜4 ＜4 16 256 ＜4
(2) 287-953 on the aluminium - 43515 - 478 2048 128 2048 2048 8192 4096 128
(2) 936-741 on the aluminium - - 16150 - ＜4 32768 16384 1024 512 8192 262144
(1) on the aluminium, (2) and (3) 6735 24304 13801 1214 4096 65536 32768 2048 4096 32768 65536
(1) on the aluminium, (2) and (3)+CpG 10896 40697 26966 2301 8192 262144 65536 4096 8192 32768 262144
Compare with reference 12 used aluminium adjuvants, the PLG+CpG mixture produces lower total antibody titers (except protein 287), but importantly provides the higher sterilization titre of anti-wide scope bacterial strain.Although therefore absolute titre is lower, the adjuvant of invention makes the antibody generation advantageously tend to bactericidin.
Should be understood that invention only describes in the example mode, can in invention scope and spirit, modify.
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Claims (12)

1. an immunogenic composition is characterized in that, described composition comprises (a) neisserial antigens; (b) CpG oligonucleotide; (c) the biodegradable polymer particles that contains poly-(D, L-lactide-co-glycolide).
2. composition as claimed in claim 1 is characterized in that neisserial antigens is a proteantigen.
3. composition as claimed in claim 2 is characterized in that, the Neisseria meningitidis protein that neisserial antigens comprises is selected from NadA albumen; 287 protein; 741 protein; 953 protein.
4. as each described composition of front claim, it is characterized in that the CpG oligonucleotide comprises 6 to 100 deoxyribonucleotides.
5. as each described composition of front claim, it is characterized in that neisserial antigens is embedded in the particulate.
6. as each described composition of front claim, it is characterized in that neisserial antigens is adsorbed onto on the particulate.
7. as each described composition of front claim, it is characterized in that the CpG oligonucleotide is embedded in the particulate.
8. as each described composition of front claim, it is characterized in that the CpG oligonucleotide is adsorbed onto on the particulate.
9. composition as claimed in claim 1 is characterized in that described composition comprises the MF59 adjuvant.
10. composition as claimed in claim 1 is characterized in that described composition comprises the silver salt adjuvant.
11., it is characterized in that described composition further comprises pharmaceutically acceptable carrier as each described composition of front claim.
12. the described composition of claim 1 is used for making the purposes of the medicine that prevents or treat that the Mammals neisserial infects.
CNB028241282A 2001-10-03 2002-10-03 Adjuvanted meningococcus compositions Expired - Fee Related CN100354297C (en)

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US32692901P 2001-10-03 2001-10-03
US60/326,929 2001-10-03
PCT/US2002/010869 WO2002080648A2 (en) 2001-04-05 2002-04-05 Mucosal boosting following parenteral priming
USPCT/US02/10869 2002-04-05
US37354702P 2002-04-17 2002-04-17
US60/373,547 2002-04-17
US38067702P 2002-05-13 2002-05-13
US60/380,677 2002-05-13
US25443802A 2002-09-24 2002-09-24
USPCT/US02/30423 2002-09-24
US0230423 2002-09-24
US10/254,438 2002-09-24
USPCT/US02/31486 2002-10-03
US10/265,083 2002-10-03

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WO2003028661A3 (en) 2003-10-09
AU2002334844B8 (en) 2003-04-14
EP1438323A4 (en) 2007-08-01
BR0213119A (en) 2004-12-28
EP1438323A2 (en) 2004-07-21
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WO2003028661A2 (en) 2003-04-10

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