CN102655879B - Vaccine combination - Google Patents
Vaccine combination Download PDFInfo
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- CN102655879B CN102655879B CN201080057152.5A CN201080057152A CN102655879B CN 102655879 B CN102655879 B CN 102655879B CN 201080057152 A CN201080057152 A CN 201080057152A CN 102655879 B CN102655879 B CN 102655879B
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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
- A61K39/12—Viral antigens
- A61K39/125—Picornaviridae, e.g. calicivirus
- A61K39/13—Poliovirus
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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
- A61K39/12—Viral antigens
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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
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/525—Virus
- A61K2039/5252—Virus inactivated (killed)
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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
- 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
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
- C12N2770/00011—Details
- C12N2770/32011—Picornaviridae
- C12N2770/32611—Poliovirus
- C12N2770/32634—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
This application provides the immunogenicity IPV preparation of high performance-price ratio.Described preparation contains the adjuvant of the inactivated poliomyelitis vaccine that can reduce by 5 to 10 multiple doses.
Description
Technical field
The present invention relates to the vaccine for resisting poliovirus 1,2 and 3 type, particularly comprising the unit price of decrement or the inactivated poliovirus D antigen of multivalent forms and adjuvant to cause the field to the vaccine of poliomyelitic protective immunity.
Background technology
The inactivated poliomyelitis vaccine (IPV) of current registration and use is based on non-attenuated (Salk) poliovirus vaccine and Strain: therefore they also refer to wild type IPV (wtIPV).IPV is transmitted by muscle (IM) or deeply subcutaneous (SC) injection.Current IPV both can be used as the independent formulations without adjuvant, also can multiple combination, comprise DT-IPV (with diphtheria and tetanus toxoid) and sexavalence DTPHepB-Hib-IPV vaccine (also having pertussis, hepatitis B in addition together with b type hemophilus influenza) obtains.After eradicating poliovirus, future can be increased to annual 400000000 5 thousand ten thousand doses by the level of current annual 8000 ten thousand doses to the global demand of IPV.Therefore, the method that IPV " extension " supplies may be needed.In addition, the price of the multiple IPV of making of needs assessment is easier to the strategy of acceptance.
When the undersupply of conventional vaccine maybe stops vaccine to be sold with the price that developing country can bear when the cost manufacturing conventional vaccine to meet global demand, need to use the IPV antigen of low dosage to anti-infective decrement bacterin preparation.
Decrement vaccine antigen being used for pandemic influenza vaccine is allowed to be known (for example, see WO2008/128939).
Oil-in-water emulsion originally in known in the art, and is proposed as adjuvant.(EP399843;WO95/17210)。
The current acceptable standard dose of poliomyelitis vaccine comprises D antigen (the such as Infanrix-IPV of inactivated poliovirus 3 type (Saukett) as inactivated poliovirus 1 type (Mahoney) of 40 units, inactivated poliovirus 2 type (MEF-I) of 8 units and 32 units
tM).
The preparation of existing independent IPV is not containing adjuvant.In combined vaccine, report that aluminum class adjuvant makes IPV dosage reduce 3 to 4 times, please refer to and the 8th of OPV/IPV manufacturer the WHO/UNICEF meeting and the 30th NRA, in October, 2009, Geneva, WHO/HQ.Estimate that this minimizing of 3 to 4 times is not enough to extend the supply of global vaccine and significantly reduces manufacturing cost.Therefore be badly in need of in the prior art allowing significantly to reduce dosage (more than 5 times) to increase the method for vaccine supply and reduction manufacturing cost.This reduction will manufacture the affordable vaccine of developing country.
The present inventor is surprised to find by being combined as adjuvant with deactivation polio antigen by oil-in-water emulsion, and the IPV of decrement can be used to cause the poliomyelitic level of antagonism that is enough or that improve.This vaccine has significant advantage, comprises the IPV vaccine to needing the individuality of this vaccine to provide more multiple dose.
Summary of the invention
The invention provides the multiple decrement IPV vaccine comprising antigen (only can have IPV component and maybe can have the IPV component be combined with other antigen) and oil-in-water emulsion.
Therefore, one aspect of the present invention provides and is greater than 1 D antigen unit and the IPV vaccine of the present invention being less than 1 type inactivated poliovirus of the dosage of 10 D antigen units a kind of comprising.
In one embodiment, the invention provides a kind of IPV vaccine of the present invention comprising 3 type inactivated poliovirus of dosage between 1 to 7 D antigen unit.
In another embodiment, the invention provides a kind of IPV vaccine of the present invention comprising 2 type inactivated poliovirus of dosage between 0.2 to 2 D antigen unit.
In a further aspect, the invention provides a kind of IPV vaccine of the present invention comprising inactivated poliovirus type and oil-in-water emulsion.
In addition according to the present invention, the use of described adjuvant causes the effective dose of inactivated poliovirus D antigen to reduce 5,6,7,8,9 or 10 times.
Described oil-in-water emulsion of the present invention comprises can metabolism oil, emulsifying agent and optional tocopherol, as alpha-tocopherol.
Definition:
Term " vaccine " can be selected to be replaced by term " immunogenic composition ", and vice versa.
" D antigen unit " (also referred to as " iu " or IU): the D antigen forms of poliovirus brings out protectiveness neutralizing antibody.The D antigen unit (such as in vaccine of the present invention) of indication is the total D antigen unit recorded in each block IPV antigen before forming last vaccine herein, and this vaccine is added into (final volume of usual 0.5mL) in the preparation vaccine of per capita dose.
The method of reliable measurement D antigen unit is known in the art, and open by such as European Pharmacopoeia.Such as, D antigen unit is measured in the ELISA test that following examples 1 (" by the quantitative D antigen of ELISA ") can be used to describe.European Pharmacopoeia provides for by this methodological standardization (PharmeuropaSpecialIssue between manufacturer, test sample Bio96-2) (European Pharmacopoeia biological reference preparation-can purchased from Ph.Eur.Secretariat, as CodeP2160000).Therefore D antigen unit value in this area can be understood better.
Term " dosage " in literary composition " be generally the single administration amount of vaccine of the present invention, normally injection shot.Usual people's dosage is 0.5mL.Certainly can according to the multiple dosage of vaccine administration intended administration.
In literary composition, term " IPV " or the vaccine that comprises this component are intended to represent that inactivated poliovirus 1 type is (as the Mahoney preferably used, or the Brunhilde of the DiTeKiPol by name to be sold by Statens Seruminstitut) or 2 types (as MEF-I) or 3 types (as Saukett), or the combination of two or all three kinds in these types.Example for the IPV vaccine of complete (or standard) dosage (1,2 and 3 type IPV 40-8-32D antigen unit separately) of the object of the invention can be
(U.S.'s GlaxoSmithKline PLC biological product).Therefore, the multiple of the standard dose of the said IPV be present in vaccine of the present invention reduces herein, represent the minimizing of at least 5 times of preparing 40,8 and/or 32 the D antigen units (recording in each block IPV antigenic type) equaling 1,2 and/or 3 type IPV respectively in each dosage of described vaccine, and the preferred D antigen unit of minimizing of 10 times.
In literary composition, term is intended to represent the one or more of antigens from this pathogen from " the providing the component of protection to this pathogen " in " component " of pathogen or vaccine of the present invention.
In literary composition term " approximately " or " approx " represent to described numerical value ± 10%, but contextual use should be met.
Detailed description of the invention
The invention provides the vaccine of antigen and the oil-in-water emulsion comprised from poliovirus (IPV).
Antigen of the present invention can comprise IPV1 type or IPV2 type or IPV3 type, or IPV1 and 2 types, or IPV1 and 3 types, or IPV2 and 3 types, or IPV1,2 and 3 types.
The method preparing inactivated poliovirus (IPV) is known in the art.In one embodiment, IPV should comprise 1,2 and 3 types common in vaccines arts, and can be with the Salk poliomyelitis vaccine of formalin-inactivated (see such as, Sutter etc., 2000, Pediatr.Clin.NorthAm.47:287; Aimmerman & Spann1999, AmFamPhysician59:113; Salk etc., 1954, OfficialMonthlyPublicationoftheAmericanPublicHealthAssoc iation44 (5): 563; Hennesen, 1981, Develop.Biol.Standard47:139; Budowsky, 1991, Adv.VirusRes.39:255).
Poliovirus can grow in cell culture.Cell culture can be VERO cell line or comes from the continuous cell line PMKC of monkey kidney.VERO cell can be cultivated expediently on microcarrier.The cultivation of the VERO cell before and during viral infection can comprise cattle source property material as the use of calf serum, and the source that this material never should have the spongy pathological changes in Medulla Bovis seu Bubali portion (BSE) obtains.Cultivate the material that also can comprise as lactalbumin liquid.After growth, the technology purified virions as ultrafiltration, diafiltration and chromatograph can be used.Before patient's administration, necessary inactivation of viruses, and this realizes by using formaldehyde treated.
Virus can grow independently of one another, purification and deactivation, combines the concentrated block mixture being provided for IPV vaccine afterwards.
Antibody in vaccine of the present invention will exist with " immune effective dose ", namely be no matter using single dose or the amount effectively treating or prevent disease as the part in a series of to individual administration.Dosage treatment can be single dose plan or multiple dose plan (as comprising booster dose).
Now, the standard dose of poliomyelitis vaccine be tending towards comprising inactivated poliovirus 1 type of 40 D antigen units, inactivated poliovirus 2 type of 8 D antigen units and 32 D antigen units inactivated poliovirus 3 type (as Infanrix-IPV
tM).
But the present inventor is surprised to find by being combined with oil-in-water emulsion adjuvant by antigen, the IPV of decrement can be used to obtain good immunoreation.
In one embodiment, IPV vaccine dose of the present invention can be included between 1 to 10 D antigen unit of IPV1 type.
In another embodiment, vaccine dose of the present invention can comprise 1/10th of standard 40 D antigen units of IPV1 type approx or accurately.
In another embodiment, vaccine of the present invention can comprise the IPV2 type (being equivalent to standard 8 D antigen unit dosage of 10%) being less than 2 D antigen units, 0.2 ~ 2 about or accurate 0.8 D antigen unit of D antigen unit (being equivalent to standard 8 D antigen unit dosage of 2.5 ~ 25%).
In another embodiment, vaccine of the present invention can comprise and is greater than 1 and is less than 8 D antigen units, such as, be approximately or accurately the IPV3 type of 3.2 D antigen units.
In another embodiment, vaccine of the present invention can comprise 1/10th (being equivalent to approximate 3.2 D antigen units) of standard 32 D antigen units of IPV3 type approx or accurately.
In addition, according to the present invention, the use of described adjuvant can cause the minimizing of at least 10 times of IPV antigen dose.
In one aspect of the method, provide for causing the immunogenic composition of humoral response to the improvement of polio antigen in human body or antigen composition or the preparation method of test kit, said composition comprises (a) as a small amount of Polio virus antigens defined in literary composition or its antigen formulations and (b) oil-in-water emulsion adjuvant.
The described oil-in-water emulsion be applicable to comprises can metabolism oil, emulsifying agent and optional tocopherol, as alpha tocopherol.
In another embodiment, it is that at least one of 0.5% to 20% of cumulative volume can metabolism oil that described oil-in-water emulsion adjuvant comprises content, and have by intensitometer at least 70% and the diameter oil droplet that is less than 1 μm.
In one embodiment, polio antigen and oil-in-water emulsion adjuvant are included in same container.This is called " one bottle of method (Onevialapproach) ".In alternative embodiments, polio antigen and oil-in-water emulsion adjuvant are included in independently in container or bottle or unit, and before snibject or mixed at that time.This is referred to as " two bottles of methods (Twovialsapproach) ".For example, when this vaccine is 2 component vaccine of accumulated dose volume of the injected dose of 0.5mL, polio antigen can be used as (500 μ l) (antigen container in a bottle, as bottle) respectively containing being similar to the IPV1 of 40-8-32 D antigen unit, the standard poliomyelitis vaccine existence of 2 and 3 types, and another bottle comprises adjuvant (4500 μ l).Inclusions in antigen container is mixed with the inclusions in adjuvant container.Typically, poliomyelitis vaccine is the injected dose of 0.5mL, and multiple dose vials contains the bottle mixture of 1:10 before first experimenter.
Oil-in-water emulsion adjuvant
Adjunvant composition of the present invention comprises oil-in-water emulsion adjuvant, applicable described Emulsion comprise content be 0.5% to 20% of cumulative volume can metabolism oil, and have by intensitometer at least 70% and be less than the oil droplet of 1 μm of diameter.
In order to make any oil-in-water type compositions be suitable for mankind's administration, the oil phase of emulsion systems must comprise can metabolism oil.This oil can be any to nontoxic to receiver and can by the vegetable oil of metabolic conversion, fish oil, animal oil or artificial oil.Nut, seed and corn are the common source of vegetable oil.
Artificial oil is also a part of the present invention, and can comprise commercially available oil, as
and other.Particularly suitable can metabolism oil be zamene.Zamene (2,6,10,15,19,23-hexamethyl-2,6,10,14,18,22-tetracosa carbon six alkene) be a kind of to be found in a large number in shark liver oil and by the unsaturated oils found on a small quantity in olive oil, wheat germ oil, Testa oryzae oil and yeast, and be that one is specially adapted to oil of the present invention.Zamene is that one can metabolism oil, is because it is the fact (Merckindex, the tenth edition, call number 8619) of the intermediate in the biosynthesis of cholesterol.
Oil-in-water emulsion is known in the art itself, and is considered to effectively as adjunvant composition (EP399843; WO95/17210).
Can the applicable content of metabolism oil be 0.5% to 20% (ultimate density) of immunogenic composition cumulative volume, applicable content be 1.0% to 10% of cumulative volume, and applicable content is 2.0% to 6.0% of cumulative volume.
In a specific embodiment, can the final content of metabolism oil be about 0.5%, 1%, 3.5% or 5% of immunogenic composition cumulative volume.In another embodiment, can the final content of metabolism oil be 0.5%, 1%, 3.57% or 5% of the cumulative volume of immunogenic composition.The applicable content of zamene is the about 10.7mg of every vaccine dose, is suitably for every vaccine dose 10.4 to 11.0mg.
The oil-in-water emulsion system that the present invention is applicable to has the little oil droplet size in sub-micrometer range.The oil droplet size be applicable to by the diameter range of 120 to 750nm, suitable size is in the diameter range of 120 to 600nm.
Usual oil-in-water emulsion contain by intensitometer at least 70% and diameter is less than the oil droplet of 500nm, specifically by strength agents at least 80% and diameter is less than 300nm, applicable press intensitometer at least 90% and diameter in the scope of 120 to 200nm.
The oil droplet size represented by intensity according to the present invention and diameter.There is several method by strength detection oil droplet size diameter.By using size measurement instruments (sizinginstrument), be applicable to by dynamic light scattering as MalvernZetasizer4000 or applicable MarvernZetasizer3000HS measured intensity.Detailed process provides in example II .2.First probability determines z average diameter ZAD by dynamic light scattering (PCS-photon correlation spectroscopy); The method also provides polydispersity index (PDI) in addition, and uses cumulant algorithm to calculate ZAD and PDI.These numerical value do not need the refractive index knowing granule.The second approach is by using another kind of algorithm, Contin, or NNLS, or " Malvern " algorithm (default algorithm provided by size measurement instruments) determines that whole particle size distribution is to calculate the diameter of oil droplet automatically.Time most of, because the granule refractive index of complex combination thing is unknown, only consider intensity distributions, and if necessary consider the mean intensity that got by this distribution.
Oil-in-water emulsion according to the present invention comprises tocopherol, as alpha-tocopherol.
There is applicable alpha tocopherol or derivatives thereof as alpha tocopherol succinate.The content of the alpha tocopherol be applicable to is between 0.2% to 5.0% (v/v) of the cumulative volume of immunogenic composition, applicable content is 2.5% (v/v) of the vaccine dose volume of 0.5ml, or 0.5% (v/v) of the vaccine dose volume of 0.5ml or 1.7 ~ 1.9% (v/v) of 0.7ml vaccine dose volume, be suitably for 1.8%.By illustrating, by using following conversion factor, the concentration provided with v/v is converted to the concentration of w/v: the alpha tocopherol concentration of 5% (v/v) equals the alpha-tocopherol concentration of 4.8% (w/v).The content of the alpha tocopherol be applicable to is that every vaccine dose is about 11.9mg, is suitably for every vaccine dose 11.6 to 12.2mg.
Oil-in-water emulsion comprises emulsifying agent.The content of this emulsifying agent can be 0.01 to the 5.0wt% (w/w) of immunogenic composition, and applicable content is 0.1 to 2.0wt% (w/w).The concentration be applicable to is 0.5 to the 1.5wt% of total composition.
Emulsifying agent can be suitably for polyoxyethylene 20 sorbitan monooleate (Tween80).In a specific embodiment, the vaccine dose volume of 0.5ml contains the Tween80 of 1% (w/w), and the vaccine dose volume of 0.7ml contains the Tween80 of 0.7% (w/w).In another embodiment, the concentration of Tween80 is 0.2% (w/w).The applicable content of polysorbate80 is that every vaccine dose is about 4.9mg, is suitably for 4.6 to the 5.2mg of every vaccine dose.
The vaccine dose be applicable to comprises the alpha tocopherol that every vaccine dose is about 11.9mg content, the zamene of every vaccine dose 10.7mg content, and every vaccine dose is about the polysorbate80 of 4.9mg content.
Oil-in-water emulsion adjuvant can use together with other adjuvant or immunostimulant, therefore important embodiment of the present invention be comprise zamene or another kind can metabolism oil, tocopherol is as the oil-in-water preparation of alpha tocopherol and Tween80.This oil-in-water emulsion also can contain span85 and/or lecithin.
Usually, oil-in-water comprise the zamene of 2 to 10% of immunogenic composition cumulative volume, the alpha tocopherol of 2 to 10% and 0.3 to 3% Tween80, and can to prepare according to method described in WO95/17210.The zamene be applicable to: the ratio of alpha tocopherol is equal to or less than 1, because which provide more stable Emulsion.Also can there is Span85 (polyoxyethylene 20 sorbitan trioleate), such as with 1% level.
Vaccine of the present invention can comprise containing poliovirus D antigen or the monovalent composition of antigen formulations that obtained by least one inactivated poliovirus type be selected from the group that is made up of poliovirus 1 type, 2 types and 3 types.
Vaccine in the present invention can comprise containing poliovirus D antigen or the multivalent composition of antigen formulations prepared by least 2 kinds or at least 3 kinds of inactivated poliovirus types.
The optional freedom of described multivalent composition: a) as inactivated poliovirus 1 type of 8 unit, the D antigen of inactivated poliovirus 3 type of inactivated poliovirus 2 type of 1.6 unit and 6.4 unit; B) as inactivated poliovirus 1 type of 6.6 unit, the D antigen of inactivated poliovirus 3 type of inactivated poliovirus 2 type of 1.3 unit and 5.3 unit; C) as inactivated poliovirus 1 type of 5.7 unit, the D antigen of inactivated poliovirus 3 type of inactivated poliovirus 2 type of 1.1 unit and 4.5 unit; D) as inactivated poliovirus 1 type of 5 unit, the D antigen of inactivated poliovirus 3 type of inactivated poliovirus 2 type of 1 unit and 4 unit; E) as inactivated poliovirus 1 type of 4.4 unit, the D antigen of inactivated poliovirus 3 type of inactivated poliovirus 2 type of 0.88 unit and 3.5 unit; Or f) as inactivated poliovirus 1 type of 4 unit, in the group of the D antigen composition of inactivated poliovirus 3 type of inactivated poliovirus 2 type of 0.8 unit and 3.2 unit.
Except above-mentioned antigen and adjuvant component, vaccine of the present invention also comprises one or more " pharmaceutically acceptable carrier or excipient " usually, comprises any excipient of the generation self do not caused the antibody that the individuality accepting said composition is harmful to.The excipient be applicable to is generally large, that metabolism is slow macromole, as protein, saccharide, polylactic acid, polyglycolic acid, polyamino acid, amino acid copolymer, sucrose (Paoletti etc., 2001, Vaccine, 19:2118), trehalose (WO00/56365), lactose and lipid aggregates (as oil droplet or liposome).This carrier is known to those of ordinary skill in the art.This vaccine also can contain diluent, as water, saline, glycerol etc.In addition, auxiliary substance can be there is, as wetting agent or emulsifying agent, pH buffer substance etc.Aseptic pyrogen-free phosphate buffered saline is typical carrier.Can see Gennaro to the detailed description of the acceptable excipient of pharmacy, 2000, Remington: science and pharmacy practice, the 20th edition, ISBN:0683306472.
Compositions can be present in bottle, or they can be present in the syringe preparing to fill.This syringe can have or not have syringe needle.Syringe can comprise the compositions of single dose, and bottle can comprise single dose or multiple dose (as 2 dosage).This dosage is for the mankind in one embodiment.In another embodiment this dosage be for being grown up, teenager, child, baby or be less than the one-year-old mankind and by drug administration by injection.
Vaccine of the present invention can in a unit or multiple dose form (as 2 dosage) packaging.In the group of described multi-dose compositions optional freedom 2 dosage, 5 dosage and 10 dosage composition.
Concerning multiple dose form, bottle is preferable over pre-filled syringe.Effective dose volume can be set up routinely, but for the typical human dose of the said composition of injecting, there is the volume of 0.5mL.
Compositions of the present invention is isotonic concerning the mankind.Vaccine of the present invention can comprise antibacterial, particularly when with multiple dose packaged.Thimerosal should be avoided, because it can cause the forfeiture of IPV component effect.Other antibacterial can be used, as 2-phenyl phenol or benzoate (essence of Niobe, ethyl ester, propyl ester).Any antiseptic is all preferred to be existed with low-level.Antiseptic can add in addition and/or be that mixing is to form the component (as the antiseptic as pertussis antigen exists) of the block antigen of compositions.
In one embodiment, vaccine of the present invention is not containing thimerosal or substantially not containing thimerosal." not containing thimerosal " or " substantially not containing thimerosal " refers to the thimerosal that there is not the enough effect to affect IPV component negatively in the final formulation.
Vaccine of the present invention can comprise cleaning agent, as Tween (polysorbate), as Tween80.Cleaning agent exists, as <0.01% with low-level usually.Vaccine of the present invention can comprise sodium salt (as sodium chloride) to provide osmotic pressure.Said composition can comprise sodium chloride.
In one embodiment, in compositions of the present invention the concentration of sodium chloride in the scope of 0.1 to 100mg/mL (as 1 ~ 50mg/mL, 2 ~ 20mg/mL, 5 ~ 15mg/mL), and in another embodiment, the concentration of sodium chloride is 10 ± 2mg/mLNaCl, according to appointment 9mg/mL.
Vaccine of the present invention generally includes buffer.Typically phosphate, citrate or histidine buffering liquid.Vaccine of the present invention can comprise free phosphate anion (as by using phosphate buffer) in the solution to prevent from promoting not absorbing of antigen.The concentration of present composition Free Phosphorus acid ion is between 0.1 to 10.0mM in one embodiment, or is between 1 to 5mM in another embodiment, or is about 2.5mM in another embodiment.
Poliomyelitis effect by recording the serum neutralization test of rat: for the purposes of the present invention, should single dose vaccine be used and by the ratio of the geometric mean titer (GMT) of determining test vaccine and the GMT of control vaccine, the vaccine containing IPV of the present invention be carried out to the analysis of the IPV qualitative assessment of vaccine potency, and representing with relative response (RR) or relative effectivenes (RP).Contrast GMT can be and uses any respectively containing the GMT of any IPV vaccine acquisition of the IPV1-2-3 type of 40-8-32 D antigen unit, and can be and passes through known vaccine
the GMT obtained.Usually, RP test is carried out as follows:
By serum neutralization test determination poliovirus 1,2 and 3 type to the effect of rat: to 10 groups of healthy rats (Sprague-Dawley (OFA) or any kind verified in advance) intramuscular injection test sample or the diluent (1/1.25 of control material in phosphate buffered saline (PBS); 1/3.125; 1/7.81).If necessary, by injecting undiluted vaccine and three kinds of above-mentioned diluents expand dilution range to 4 kinds of diluents.Using ten rats of injection diluent as negative control.Observe weekly a rat to detect any abnormal response.After injection after 20 to 22 days, to rat deep anaesthesia and blood-letting, collect serum with by serum and test analyze.Concerning in serum and test, by 56 DEG C in a water bath incubation 30 minutes to inactivating blood serum.Use suitable diluent media in microwell plate, prepare three kinds of dilution series of serum, often kind of poliomyelitis type is a kind of.Microwell plate is stored at+4 DEG C.To three kinds of poliovirus types, the virus (30-300CCID50) of predetermined content is added in serum dilution.This three kinds of viral suspensions are diluted according to their respective titres.Final diluent is called " effective diluent ".Often kind of effective diluent is added in corresponding microwell plate.Incubation 16 hours by plate sealing and at 37 DEG C ± 1 DEG C afterwards, adds Hep-2 cell and afterwards by microwell plate incubation 7 days at 37 DEG C ± 1 DEG C.After coomassie brilliant blue staining, use inverted microscope to read the cytopathic effect (CPE) of virus.The existence of poliomyelitis antibody inhibits the growth of virus and the appearance of corresponding CPE.Poliomyelitis virus titer (1,2 and 3 type) corresponds to the titre of the last diluent without any CPE.In each group, record has the animal of neutralizing antibody and determines the antibody titer of poliovirus dissimilar in each blood serum sample.NAT is represented with the log2 of the inverse suppressing the most high dilution of the blood serum sample of the cytopathic effect of poliovirus in Hep-2 cell completely.
Determine equally often to organize each dilution factor of rat and the geometric mean titer (GMT) of each Virus Type.
The packaging of vaccine of the present invention
Polytype container package vaccine of the present invention can be used, as bottle, syringe etc.Multiple dose vials comprises the plastics mouth that can seal again usually, can insert aseptic syringe needle to take away the vaccine of dose, again sealed by plastics mouth after removing syringe needle by this plastics mouth.
Can multiple container (as 2 or 3 kind) in vaccine is provided.Can with single injection on-the-spot mixer inclusions before main body administration, or at different loci concomitant dosing.The dosage of vaccine, if or the dosage of test kit concomitant dosing (in two or more containers) often kind of vaccine be generally 0.5mL.
The administration of vaccine of the present invention
The invention provides and cause immunoreactive method in mammalian body, comprise the step of the vaccine of the present invention of administration effective content.Preventability ground this vaccine of administration (namely protecting from infection).That immunoreation is preferably protectiveness and preferably comprise antibody.The method may cause booster reaction.
After primary vaccination, reinforcement (subsequently) inoculation at abundant interval can be had once or several times to experimenter.Dosage treatment can be single dose schedule or multiple dose plan.Multiple dose can be used on main inoculation plan and/or booster shot in the works.Booster dose plan can may be being carried out after the major dose plan of effect one year.Time (as between 4-16 week) between the startup dosage be applicable to and startup and the time adding Qianghian can be determined routinely.In one embodiment, this mammal is the mankind.When this vaccine is for preventing, these mankind are preferably child (as child or baby) or teenager; When this vaccine is used for the treatment of, these mankind are preferably adult.Be intended to also can be used for adult for the vaccine of child, such as, determine safety, dosage, immunogenicity etc.Bacterin preparation of the present invention can be used by described vaccine directly being delivered medicine to patient to protect or treats the mammal being easy to infect.By parenteral administration (space between muscle, abdominal cavity, Intradermal, subcutaneous, vein or tissue); Or by rectum, oral cavity, vagina, locally, transdermal, nasal cavity, glasses, lung or other mucosa delivery complete direct administration.In one embodiment, by intramuscular injection to thigh or upper arm administration.Undertaken injecting (as entry needle) by syringe needle, but also use Needleless injection alternatively.Typical intramuscular injection dosage is 0.5mL.Multiple positions of Bacterial infections affect human body, therefore can compositions of the present invention can prepare in a variety of forms.Such as, said composition can be made into injectable liquid solution or suspension.Said composition can be prepared for the pulmonary administration using fine powder or spraying, as inhaler.Said composition can be made into suppository or medicine is fastened.Said composition can be prepared for nasal cavity, ear or dosing eyes, as spraying, drop, colloid or powder (see such as Almeida & Alpar, 1996, JDrugTargeting, 3:455; Bergquist etc., 1998, APMIS, 106:800).One-tenth beneficence nasal-cavity administration (Ryan etc., 1999, Infect.Immun., the 67:6270 of DTP vaccine are reported; Nagaietal., 2001, Vaccine, 19:4824).In one embodiment, simultaneously by the vaccine in first and second (and suitable 3rd) container in different parts administration, and in alternative embodiments the present inventor's imagination before as single vaccine administration by the inclusions mixing (alternatively on-the-spot mixing) in the first and second containers.The present invention can be used for initiating system and/or mucosal immunity.
Reference and the publication of all references are incorporated herein by reference.
Embodiment
Only provide embodiment for illustrative purposes, and be not intended to limit the scope of the invention.
Embodiment 1:
Prepare oil-in-water emulsion and the method be combined with IPV vaccine by this Emulsion
According to file [Ott etc., TheadjuvantMF59:a10-yearperspective.In-vaccineadjuvants: preparationmethodsandresearchprotocols.MethodsinMolecula rmedicine, vol42, chapter12, p211-228.EditedbyD.T.O ' Hagan (2000)] in describe method prepare oil-in-water emulsion.Briefly, 9.75g zamene (Sigma, from shark liver) is mixed with 1.175g sorbitan trioleate.Separately the citrate buffer of 1.175g polysorbate80 with the 10mMpH6.5 of 240ml is mixed, add afterwards in zamene-sorbitan trioleate solution.Desk-top homogenizer (Silverson) is used to be homogenized further 1 minute by this mixture.MicrofluidicsM110H microfluidizer (Microfluidics, MA, USA) is used this material to be carried out to the high pressure microjet of Five-channel afterwards at once.The size using Malvern laser particle analyzer to demonstrate oil droplet is less than 150nm.Aseptic filtration is carried out to gained Emulsion and stores at 2 ~ 8 DEG C.
Use PBS by 1 bottle of (1 people's dosage) IPV (NVI, Holland) dilution five times, add the Emulsion of equivalent volumes afterwards wherein, obtain 10 times of diluents altogether of this vaccine.
Embodiment 2:
The immunity of rat and immunogenic evaluation
Use the A of 0.1ml) IPV of full strength; B) PBS is used to dilute IPV and C of 10 times) the IPV intramuscular injection twice (the 0th and 28 days) that uses above-mentioned Emulsion to dilute 10 times makes rat (n=5) immunity.The 42nd day time, collect serum and carry out in poliovirus and the evaluation of titre to all three kinds in IPV vaccine.
The geometric mean titer of virus neutralization is as shown in the table
Table 1 geometric mean titer (N=5)
(in bracket numeric representation geometric average deviation)
This illustrates when combine with oil-in-water emulsion, and it is equally effective that the immunoreation of the IPV vaccine of 1/10 dosage initiation at least causes with the full dose vaccine not containing adjuvant.
Therefore in IPV vaccine, add adjuvant allow the minimizing of vaccine dose and the antigen inoculation allowing to use more low dosage.
Claims (16)
1. one kind for causing the immunogenic composition of the humoral immune reaction of the improvement to polio antigen, described immunogenic composition comprises the combination of a) antigen or antigen formulations and b) adjuvant, wherein, described antigen or antigen formulations are a small amount of Polio virus antigens or antigen formulations, and described adjuvant is oil-in-water emulsion adjuvant, the dosage of described a small amount of Polio virus antigens or antigen formulations is the dosage of 1/10th of the vaccine not containing adjuvant, wherein said oil-in-water emulsion adjuvant has oil droplet, the average oil droplet size of described oil droplet is less than 150nm, wherein said oil-in-water emulsion adjuvant comprise can metabolism oil, and described can metabolism oil be zamene.
2. immunogenic composition as claimed in claim 1, wherein said can exist with the content of per capita dose 0.5 ~ 10,0.5 ~ 9,1 ~ 10,2 ~ 10,4 ~ 8,1 ~ 2,2 ~ 3,4.5 ~ 5.5,5 ~ 6 or 9 ~ 10 or 10 ~ 11mg by metabolism oil.
3. immunogenic composition as claimed in claim 1, wherein said oil-in-water emulsion adjuvant comprises emulsifying agent, and described emulsifying agent is nonionic surfactant.
4. immunogenic composition as claimed in claim 3, wherein said emulsifying agent is polyoxyethylene 20 sorbitan monooleate or sorbitan trioleate or both mixture.
5. immunogenic composition as claimed in claim 4, wherein said polyoxyethylene 20 sorbitan monooleate is polysorbate80, and described sorbitan trioleate is Span85.
6. immunogenic composition as claimed in claim 3, wherein said emulsifying agent exists with the content of per capita dose 0.1 ~ 5,0.2 ~ 5,0.3 ~ 5,0.4 ~ 5,0.4 ~ 1.2,0.5 ~ 4,1 ~ 2,2 ~ 3 or 4 ~ 5.5mg.
7. immunogenic composition as claimed in claim 1, wherein said adjuvant also comprises tocol.
8. immunogenic composition as claimed in claim 7, wherein said tocol is alpha tocopherol.
9. immunogenic composition as claimed in claim 7, wherein said tocol exists with the content of per capita dose 0.5 ~ 12,1 ~ 11,2 ~ 10,4 ~ 9,5 ~ 6,5 ~ 7,2.5 ~ 3.5,1 ~ 2,1 ~ 3 or 10 ~ 11 or 11-12mg.
10. immunogenic composition as claimed in claim 1, wherein said adjuvant be selected from by
I) when there is 11.5 ~ 12.5mg tocol of per capita dose, 10 ~ 11mg of per capita dose can metabolism oil, 4.5 ~ 5.5mg emulsifying agent,
Ii) when there is 11.6 ~ 12.2mg tocol of per capita dose, 10.5 ~ 11mg of per capita dose can metabolism oil, 4.6 ~ 5.2mg emulsifying agent
In the group of composition.
11. immunogenic compositions as claimed in claim 1, wherein said compositions is the monovalent composition of the antigen formulations comprising poliovirus D antigen or obtained by least one inactivated poliovirus type be selected from the group that is made up of poliovirus 1 type, 2 types and 3 types.
12. immunogenic compositions as claimed in claim 1, wherein said compositions is the multivalent composition of the antigen formulations comprising poliovirus D antigen or prepared by least 2 kinds or at least 3 kinds of inactivated poliovirus types.
13. immunogenic compositions as claimed in claim 12, the dosage of wherein said multivalent composition is selected from by the following group formed
I) as the D antigen of inactivated poliovirus 2 type of inactivated poliovirus 1 type of 8 units, 1.6 units and inactivated poliovirus 3 type of 6.4 units,
Ii) as the D antigen of inactivated poliovirus 2 type of inactivated poliovirus 1 type of 6.6 units, 1.3 units and inactivated poliovirus 3 type of 5.3 units,
Iii) as the D antigen of inactivated poliovirus 2 type of inactivated poliovirus 1 type of 5.7 units, 1.1 units and inactivated poliovirus 3 type of 4.5 units,
Iv) as the D antigen of inactivated poliovirus 2 type of inactivated poliovirus 1 type of 5 units, 1 unit and inactivated poliovirus 3 type of 4 units,
V) as the D antigen of inactivated poliovirus 2 type of inactivated poliovirus 1 type of 4.4 units, 0.88 unit and inactivated poliovirus 3 type of 3.5 units,
Vi) as the D antigen of inactivated poliovirus 2 type of inactivated poliovirus 1 type of 4 units, 0.8 unit and inactivated poliovirus 3 type of 3.2 units.
14. immunogenic compositions as claimed in claim 1, the per capita dose of wherein said immunogenic composition is selected from: 0.5ml or less, between 0.5 to 1.5ml, between 0.2 to 1.2ml, with accurate 0.25 or 0.5 or 0.7 or 1ml or less between 0.2 to 0.7ml.
15. immunogenic compositions as claimed in claim 1, it is characterized by described compositions is single dose or multi-dose compositions.
16. immunogenic compositions as claimed in claim 15, is characterized by described multi-dose compositions and are selected from the group be made up of 2 dosage, 5 dosage and 10 dosage.
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| MX2017004534A (en) * | 2014-10-07 | 2017-10-11 | Serum Institute Of India Pvt Ltd | Improved methods for enterovirus inactivation, adjuvant adsorption and dose reduced vaccine compositions obtained thereof. |
| CN106290886A (en) * | 2016-07-28 | 2017-01-04 | 北京科兴生物制品有限公司 | A kind of method of detection III type poliovirus D antigenic content |
| CN108241058A (en) * | 2018-01-13 | 2018-07-03 | 中国医学科学院医学生物学研究所 | A kind of pre-coated detection method of III type D antigens of poliovirus and its detection kit and application |
| CN108387726A (en) * | 2018-01-13 | 2018-08-10 | 中国医学科学院医学生物学研究所 | I, II, III type D antigens of poliovirus simultaneously and rapidly differentiate, quantitative detecting method and its detection kit and application |
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