CN101007167A - Mucosal meningococcal multivalence combined vaccines - Google Patents
Mucosal meningococcal multivalence combined vaccines Download PDFInfo
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- CN101007167A CN101007167A CN 200710007045 CN200710007045A CN101007167A CN 101007167 A CN101007167 A CN 101007167A CN 200710007045 CN200710007045 CN 200710007045 CN 200710007045 A CN200710007045 A CN 200710007045A CN 101007167 A CN101007167 A CN 101007167A
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- polysaccharide
- omp
- meningitis cocci
- combined vaccine
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Abstract
The invention discloses a polyvalent joint vaccine to prevent the coccus infection of epidemic meningitis of outer membrane proteins (OMP), which is one or more capsular polysaccharides of A, C, W135 and Y meningitis coccus, which lies in the joint coupled vaccine at protein carrier or non-coupled pattern to prevent child and adult infection of epidemic meningitis.
Description
Technical field
The present invention relates to the mucosal meningococcal multivalence combined vaccines of a kind of B of containing group meningitis cocci outer membrane protein composite (OMP).Particularly, the present invention relates to a kind of one or more and protein carrier coupling or non-link coupled capsular polysaccharide that will derive from B group meningitis cocci OMP and derive from A, C, W135, the Y group meningitis cocci and be mixed with the broad-spectrum multivalence combined vaccines.The multivalence combined vaccines of this broad-spectrum is used to prevent child and adult to infect meningitis and the septicemia that causes because of the epidemic cerebrospinal meningitis coccus.The invention still further relates to the preparation method of this multivalence combined vaccines.
Background of invention
Bacillary cerebrospinal meningitis is still the healthy serious problems in the harm whole world so far, it is estimated dead 170,000 examples of whole world year.In developed country, even antibiotics and good curing measure are arranged, case fatality rate is still up to 5-10%.And in developing country, case fatality rate is then higher.Permanent sequelae can appear in about 10-20% in the survivor, as epilepsy, mental retardation and nerve deafness etc.Meningococcus (Neisseria meningitidis) and streptococcus pneumoniae (Streptococcuspneumoniae) are to cause the modal cause of disease of bacillary cerebrospinal meningitis, wherein the unique especially pathogen that can cause epidemic cerebrospinal meningitis (epidemic encephalitis) of meningococcus (
Http:// www.who.int/vaccine research/diseases/soa bacterial / en/index2.html).
Meningococcus is a Gram-negative coccus, according to the difference of capsular polysaccharide immunochemistry character meningococcus is divided into A, B, C, D, X, Y, Z, 29E, W135, H, I, K, at least 13 sero-groups of L (Serogroup).Wherein A, B, C, Y and five groups of W135 can to cause the case that most epidemic encephalitis case, particularly A, three groups of B, C cause maximum, account for 90% of whole epidemic encephalitis cases.The A group meningitis cocci is mainly popular Africa, Asia and South America, and it once caused global several times being very popular.The B group meningitis cocci mainly causes localized epidemics in Europe and North America.Once some countries in " meningitis area " caused localized epidemics to the C group meningitis cocci in Brazil, the U.S., Canada and Africa.Cause that transition can take place the popular meningococcus sero-group of epidemic encephalitis, before the 1950's, U.S.'s epidemic encephalitis mainly be by the A group meningitis cocci cause popular, mainly cause morbidity from nineteen sixty by B group, after 1967 again based on C group.China is from the collected patient's meningococcus bacterial strain of 1975-1982, and A group accounts for 96.9%, B group accounts for 2.3%.1984-1989, A group accounts for 89.8%, and B group accounts for 10.2%.After nineteen ninety, A group accounts for 61.7%, B group account for 38.3% (Zhang Yanling, vaccinology, Science Press, 2004 936 pages).It is A group 52.0% that Shanghai City 1 984-1993 collects patient's meningococcus grouping result, and B group 42.0%.Clinical case load of infant below 2 years old and the shared ratio of non-epidemic season case load of relatively showing of B group's epidemic encephalitis and A group's epidemic encephalitis all obviously increases, and the state of an illness is heavy, easy concurrent subdural effusion and or ependymitis (Li Yuefang, China's infection chemotherapy magazine, 2004,4:6,321-323).Guangzhou 1996-2003 in healthy population in the isolating meningococcus, B group account for 62.5% (Liao Yuhuang, the south China preventive medicine, 2004,30:4,29-30).Another research thinks, the popular existence of Guangdong Province's epidemic encephalitis by A group to the trend of B group's transition (Zhou Huiqiong, the south China preventive medicine, 2002,28:3,6-8).China patient B group meningitis cocci strains separation occurs and increases, and indivedual regional child's epidemic encephalitis should cause highly vigilant of and attention based on B group's phenomenon.
Meningococcus is invaded upper respiratory tract, at cavum nasopharyngeum mucosa growth and breeding through directly contact or air droplet transmission.Epidemic encephalitis can show as inapparent infection, any clinical symptoms do not occur, and only clinical symptoms takes place a few peoples.The mankind are generally to the epidemic encephalitis susceptible, and neonate obtains the bactericidin of parent to epidemic encephalitis by Placenta Hominis, and keeps effect level in 6 monthly ages, and during the 6-18 monthly age, the bactericidin level drops to minimum, and sickness rate then rises to the highest.
First AC group's capsular polysaccharide vaccine is since U.S.'s listing before 30 years, and the vaccine of several prevention epidemic encephalitiss has been developed in the whole world, to the popular enormous function of having brought into play of control epidemic encephalitis.These vaccines can be divided into three major types by antigenic property, one class is capsular polysaccharide vaccine (capsularpolysaccharide vaccines), another kind of is polysaccharide-protein combined vaccine (conjugatevaccines), and the 3rd class is 1 outer-membrane protein vaccine (outer membrane proteinsvaccines).
First kind capsular polysaccharide vaccine has A group's polysaccharide vaccine, AC group's two valency polysaccharide vaccines and ACW135Y group's tetravalence polysaccharide vaccine.It is as safe as a house and effective that polysaccharide vaccine has proved in crowd more than two years old, so polysaccharide vaccine recommended routine immunization that is used in crowd more than two years old.But A group's polysaccharide shows very weak immunogenicity and of short duration protection period in age group below two years old.And C group's polysaccharide does not just have immunogenicity at all in age group below two years old.If inoculate uncombined C group's polysaccharide vaccine to infant too early, can cause body tolerance to the C group antigen in the several years subsequently on the contrary, immunoreation is low.Therefore A group and C group's polysaccharide vaccine are unsuitable for the routine immunization of infant.
The second class polysaccharide-protein combined vaccine has C group's polysaccharide-protein combined vaccine, AC group's two valency polysaccharide-protein combined vaccines and ACW135Y group's tetravalence polysaccharide-protein combined vaccine.Because the same T cell dependent/non-dependent antigen that belongs to other bacterioid capsular polysaccharide antigens of meningococcal capsular polysaccharide antigen can not induce the immunological memory reaction, immunity inoculation can not play the effect of booster immunization once more, so poor to the infant immune effect.Studies have shown that, can obtain the dependent immune response of T cell after polysaccharide is attached to a protein carrier, produce enough high-caliber anti-pod membrane IgG antibody and the B cell of immunological memory is arranged.Therefore, combined vaccine provides the excellent protection effect for infant.
The 3rd class 1 outer-membrane protein vaccine mainly is B group's 1 outer-membrane protein vaccine.With respect to the meningococcus of other groups, the immunogenicity of B group meningitis cocci capsular polysaccharide is extremely faint, even it is attached on the protein carrier, does not still significantly change its immunne response.Its reason may be to have the n acetylneuraminic acid n polymerase similar to B group's polysaccharide in the human nerve tissue, makes the human immune system produce immunologic tolerance to B group's polysaccharide.Discover that B group meningitis cocci outer membrane protein has good immunogenicity, can induce the bactericidin of high titre.Based on the characteristic of outer membrane protein, Cuba and Norway research and develop out special vaccine at B group's epidemic encephalitis respectively.
Existing based on meningococcal polysacharide or polysaccharide-protein combined vaccine, multipotency prevention A, C, W135, four groups' of Y epidemic encephalitis, and the epidemic encephalitis that only can prevent a group of B group based on the vaccine of outer membrane protein.Therefore, just need be a kind of at the meningococcal wide spectrum of five sero-groups (A, B, C, W135, Y), the multivalence combined vaccines that can cause whole epidemic encephalitis cases, or a kind of at the meningococcal wide spectrum of three sero-groups (A, B, C), the polyvalent vaccine that can cause 90% epidemic encephalitis case.Along with B group meningitis cocci proportion in the epidemic encephalitis case more and more increases, just further need such multivalence combined vaccines should comprise the antigen that can prevent the B group meningitis cocci to infect.Mucosal meningococcal multivalence combined vaccines of the present invention by will deriving from or be selected from A, C, W135, four groups of Y polysaccharide or the polysaccharide-protein conjugate with derive from B group's outer membrane protein and be mixed with bacterin preparation and solved this needs.
Summary of the invention
The invention provides derive from A, C, W135, the Y group meningitis cocci with protein carrier coupling or non-link coupled polysaccharide and derive from the combined vaccine that the outer membrane protein composite (OMP or claim OMV) of B group meningitis cocci is formed.In other words, the present invention comprises the compositions of the meningococcal polysacharide that derives from A, C, W135, four groups of Y and derives from the multivalence combined vaccines that OMP formed of B group meningitis cocci, described polysaccharide is present in the combined vaccine with form independently, perhaps is present in the combined vaccine with the combining form that is coupled at respectively on the protein carrier.Combined vaccine provided by the invention is used for the disease of child and the meningococcal infection initiation of adult's prevention.
The invention provides derive from A, the C group meningitis cocci with protein carrier coupling or non-link coupled polysaccharide and derive from the combined vaccine that the outer membrane protein composite (OMP) of B group meningitis cocci is formed.Therefore, the present invention comprises the compositions of the meningococcal polysacharide that derives from A, two groups of C and derives from the multivalence combined vaccines that OMP formed of B group meningitis cocci, described polysaccharide is present in the combined vaccine with form independently, perhaps is present in the combined vaccine with the combining form that is coupled at respectively on the protein carrier.
The invention provides be selected from A, C, W135, the Y group meningitis cocci with protein carrier coupling or non-link coupled polysaccharide and derive from the combined vaccine that the outer membrane protein composite (OMP) of B group meningitis cocci is formed.Therefore, the present invention comprises the compositions of the meningococcal polysacharide that is selected from A, C, W135, four groups of Y and derives from the multivalence combined vaccines that OMP formed of B group meningitis cocci, described polysaccharide is present in the combined vaccine with form independently, perhaps is present in the combined vaccine with the combining form that is coupled at respectively on the protein carrier.
The invention provides derive from A, C, W135, the Y group meningitis cocci with the link coupled polysaccharide of protein carrier and derive from the combined vaccine that the outer membrane protein composite (OMP) of B group meningitis cocci is formed, wherein each conjugate comprises the meningococcal polysacharide that derives from different sero-groups with carrier protein couplet.Therefore, the present invention comprises the compositions of the meningococcal polysacharide that derives from A, C, W135, four groups of Y and derives from the multivalence combined vaccines that OMP formed of B group meningitis cocci, and described polysaccharide is coupled on the protein carrier respectively.
The invention provides derive from A, the C group meningitis cocci with the link coupled polysaccharide of protein carrier and derive from the combined vaccine that the outer membrane protein composite (OMP) of B group meningitis cocci is formed.Wherein each conjugate comprises the meningococcal polysacharide that derives from different sero-groups with carrier protein couplet.Therefore, the present invention comprises the compositions of the meningococcal polysacharide that derives from A, two groups of C and derives from the multivalence combined vaccines that OMP formed of B group meningitis cocci, and described polysaccharide is coupled on the protein carrier respectively.
The invention provides be selected from A, C, W135, the Y group meningitis cocci with the link coupled polysaccharide of protein carrier and derive from the combined vaccine that the outer membrane protein composite (OMP) of B group meningitis cocci is formed.Wherein each conjugate comprises the meningococcal polysacharide that derives from different sero-groups with carrier protein couplet.Therefore, the present invention comprises the compositions of the meningococcal polysacharide that is selected from A, C, W135, four groups of Y and derives from the multivalence combined vaccines that OMP formed of B group meningitis cocci, and described polysaccharide is coupled on the protein carrier respectively.
The invention provides the combined vaccine that the outer membrane protein composite (OMP) that derives from the polysaccharide in A, C, W135, the Y group meningitis cocci and derive from the B group meningitis cocci is formed, wherein polysaccharide is the meningococcal polysacharide that derives from different sero-groups.Therefore, the present invention comprises the compositions of the meningococcal polysacharide that derives from A, C, W135, four groups of Y and derives from the multivalence combined vaccines that OMP formed of B group meningitis cocci, and described polysaccharide is present in the combined vaccine with form independently respectively.
The invention provides the combined vaccine that the outer membrane protein composite (OMP) that derives from the polysaccharide in A, the C group meningitis cocci and derive from the B group meningitis cocci is formed, wherein polysaccharide is the meningococcal polysacharide that derives from different sero-groups.Therefore, the present invention comprises the compositions of the meningococcal polysacharide that derives from A, two groups of C and derives from the multivalence combined vaccines that OMP formed of B group meningitis cocci, and described polysaccharide is present in the combined vaccine with form independently respectively.
The invention provides the combined vaccine that the outer membrane protein composite (OMP) that is selected from the polysaccharide in A, C, W135, the Y group meningitis cocci and derives from the B group meningitis cocci is formed.Wherein polysaccharide is the meningococcal polysacharide that derives from different sero-groups.Therefore, the present invention comprises the compositions of the meningococcal polysacharide that is selected from A, C, W135, four groups of Y and derives from the multivalence combined vaccines that OMP formed of B group meningitis cocci, and described polysaccharide is present in the combined vaccine with form independently respectively.
The invention provides derive from A, C, W135, the Y group meningitis cocci with the link coupled polysaccharide of protein carrier and derive from the combined vaccine that the outer membrane protein composite (OMP) of B group meningitis cocci is formed.Wherein, described and the link coupled protein carrier of polysaccharide be any in tetanus toxoid (TT), diphtheria toxoid (DT), sudden change nontoxic diphtheria toxin, diphtherotoxin albumen (CRM197), B group meningitis cocci outer membrane protein (OMP) preferably, most preferably is TT.With selected protein carrier with derive from different sero-group meningococcal polysacharides and distinguish coupling.
The invention provides derive from A, C, W135, the Y group meningitis cocci with protein carrier coupling or non-link coupled polysaccharide and derive from the combined vaccine that the outer membrane protein composite (OMP) of B group meningitis cocci is formed.Wherein, described OMP extracts, behind the purification, remerges and form from each protein type bacterial strain of B group meningitis cocci respectively.In the preferred embodiment of the invention, the B group meningitis cocci protein type bacterial strain of preparation OMP is preferred 1,2a, 2b, 3,4,5,8,9,12,14,15,16,17,19 type bacterial strains, more preferably 2a, 2b, 4,15 type bacterial strains most preferably are 4 types or 15 type bacterial strains.Further, the B group meningitis cocci bacterial strain of preparation OMP is according to the popular dominant strain in place and definite.In other words, OMP of the present invention prepares the back remix respectively by a plurality of different protein type bacterial strains, and preferably ten tetravalences are more preferably tetravalence, most preferably are two valencys or unit price.In the present invention, described OMP is a B group meningitis cocci outer membrane protein composite, and its component comprises compositions such as outer membrane protein, lipopolysaccharide, phospholipid, residual DNA and remaining capsular polysaccharide.
In mucosal meningococcal multivalence combined vaccines provided by the invention, B group meningitis cocci OMP component that is comprised and Chinese patent 03131108.3 described B group meningitis cocci OMP are diverse.Both effect differences of playing the part of at first, OMP of the present invention is present in the combined vaccine as the vaccine active component, and role is the character of one of effective antigen of vaccine.And 03131108.3 OMP is a protein carrier as combined vaccine carry out coupling with A group and C group meningitis cocci polysaccharide respectively after, be present in the vaccine with the conjugate form.Next immunogenicity difference, OMP of the present invention is present in the combined vaccine with a kind of independently form, and the whole sites of its antigen are not closed.And 03131108.3 OMP because and polysaccharide carry out coupling, its antigen site part is sealed by link coupled polysaccharide.Therefore, the immunne response that two kinds of OMP produced fully different people such as (, Chinese microbiology and Journal of Immunology, 20 (2): 152-155,2000) Sun Yinyan.
In the present invention, the method and the standard of making and examining and determine the meningococcal capsular polysaccharide are technology known in those skilled in the art, the technical staff can be with reference to manufacturing of meningococcal capsular polysaccharide and vertification regulation (WHOTechnical Report the Series formal promulgation of World Health Organization (WHO) and that carried out revision for several times, No.594,1975, WHO Technical ReportSeries, No.658,1980, WHO Technical Report Series, No.904,2002) the preparation meningococcal polysacharide.In the present invention, preferred four sero-groups of A, C, W135, Y in meningococcus of capsular polysaccharide preparation.In the preferred embodiment of the invention, capsular polysaccharide extracts respectively and purification from different sero-group meningococcuss.For example, preparation A group capsular polysaccharide from A group meningitis cocci bacterial strain, preparation C group capsular polysaccharide from C group meningitis cocci bacterial strain, preparation W135 group capsular polysaccharide from W135 group meningitis cocci bacterial strain, preparation Y group capsular polysaccharide from Y group meningitis cocci bacterial strain.
In the preferred embodiment of the invention, polysaccharide form independently of one another is present in the combined vaccine.Promptly uniting the component that comprises is: A group's polysaccharide, C group's polysaccharide, W135 group's polysaccharide, Y group's polysaccharide and B group OMP; Unite the component that comprises or: A group's polysaccharide, C group's polysaccharide and B group OMP; Uniting the component that comprises further is: the polysaccharide and the B group OMP that are selected from A group, C group, W135 group, Y group;
In the preferred embodiment of the invention, polysaccharide more can be present in the combined vaccine with the link coupled combining form of protein carrier, each polysaccharide respectively with a protein carrier coupling.For example when protein carrier was preferably TT, the component that combined vaccine comprises was: A group polysaccharide-TT, C group polysaccharide-TT, W135 group polysaccharide-TT, Y group polysaccharide-TT and B group OMP; Unite the component that comprises or: A group polysaccharide-TT, C group polysaccharide-TT and B group OMP; Uniting the component that comprises further is: the coupling conjugate and the B group OMP that are selected from A group polysaccharide-TT, C group polysaccharide-TT, W135 group polysaccharide-TT, Y group polysaccharide-TT;
In the present invention, the method of capsular polysaccharide and albumen coupling is a technology known in those skilled in the art, the technical staff can make and vertification regulation (WHO Technical Report Series according to C group meningitis cocci combined vaccine and b type hemophilus influenza combined vaccine (Hib) of the present invention and that formally issue with reference to World Health Organization (WHO) and carried out revision for several times, No.924,2004, WHO Technical Report Series, No.897,2000) preparation polysaccharide and protein conjugate.In the preferred embodiment of the invention, earlier polysaccharide is carried out activation processing with Bromine cyanide. (CNBr), being that difunctional nucleophilic is basic at interval with adipic dihydrazide (ADH) again adds in the activatory polysaccharide, form polysaccharide-ADH derivant, pass through the condensation and the protein carrier covalent bond of carbodiimide (EDAC) mediation again, obtain the polysaccharide-protein conjugate, purified again acquisition is used to prepare the conjugate component of combined vaccine.Polysaccharide and proteic coupling have multiple known method, and coupling method described herein is only used for illustrating the present invention.So, can adopt the various methods that are equal to realize coupling process of the present invention, therefore any capsular polysaccharide and link coupled method of protein carrier and technology or process of being used for all might be used to implement the present invention.
In the present invention, be used for the protein carrier of coupling polysaccharide preferably from TT, DT, CRM197 or B group OMP.Selecting for use these albumen to prepare combined vaccine as modal carrier and the coupling of antibacterial class capsular polysaccharide is to well known to a person skilled in the art preferred version, for example select for use these protein carriers to prepare b type hemophilus influenza combined vaccine, preparation pneumococcal conjugated vaccine, preparation meningococcus combined vaccine (Lee, people Infect Med 19 (3): 127-133 such as Chi-Jen, 2002).In the preferred embodiment of the invention, the protein carrier of coupling polysaccharide most preferably is TT.If satisfy the demand, also can adopt other protein carrier, the protein carrier that herein provides only is for illustrative the present invention.
In the present invention, the preparation method of the OMP of B group meningitis cocci is a technology known in those skilled in the art.At present, the preparation method of B group meningitis cocci OMP has several, and the technical staff can find these methods (Frasch from of the present invention and general document, people such as CE, Infect Immun 37 (1): 271-80,1982, Arigita, people such as C, Vaccine21:950-960,2003, Zhang Yanling, vaccinology, Science Press, 947-948 page or leaf in 2004) preparation B group meningitis cocci OMP.In the preferred embodiment of the invention, will derive from the different protein type strains of B group meningitis cocci through number generation go down to posterity cultivate after, transferred species to fermentation tank carries out liquid culture, with the sodium deoxycholate sterilization, through centrifugal results culture.Thalline is through sodium acetate-lithium chloride cracking and extracting, and reuse ethanol enucleation acid treatment is after column chromatography purification is made B group OMP.The OMP that will prepare according to the B group meningitis cocci bacterial strain of different protein types mixes again, is mixed with multivalence or the monovalent OMP component as combined vaccine.Preparation B group meningitis cocci OMP has multiple known method, and said preparation method is only used for illustrating the present invention.So, can adopt the various methods that are equal to realize OMP of the present invention, therefore any method that is used to prepare B group meningitis cocci OMP and technology or process all might be used to implement the present invention.
In meningococcus combined vaccine provided by the invention, vaccine dose is determined according to the known technical standard of pharmaceutical field those skilled in the art.For example, when determining dosage, should be taken into account antigenic property (polysaccharide antigen is that absolute version exists, still so that link coupled combining form exists with protein carrier), inoculator's factors such as age, vaccine injection approach.In the preferred embodiment of the invention, capsular polysaccharide antigen is as being present in the combined vaccine with absolute version; Preferred each polysaccharide dosage is 5～100 μ g, and preferred each polysaccharide dosage is 20～80 μ g, and most preferred each polysaccharide dosage is 30～50 μ g.Capsular polysaccharide antigen is as so that link coupled combining form is present in the combined vaccine with protein carrier; Preferred each polysaccharide dosage is 0.1～50 μ g, and preferred each polysaccharide dosage is 1～25 μ g, and most preferred each polysaccharide dosage is 3～15 μ g.No matter capsular polysaccharide with which kind of form is present in the combined vaccine, preferred each protein type B group meningitis cocci OMP dosage is 1～100 μ g (protein content), preferred each protein type B group meningitis cocci OMP dosage is 5～80 μ g (protein content), and most preferred each protein type B group meningitis cocci OMP dosage is 15～50 μ g (protein content).
In the preferred embodiment of the invention, combined vaccine also can comprise this area adjuvant commonly used.Preferred adjuvants has aluminium adjuvant, calcium phosphate adjuvant, choleratoxin B subunit (CTB), Soap chitin Q21, lipoid, monophosphoryl lipid A (MPL), MF59, escherichia coli heat-labile toxin (LT), preferred adjuvant is an aluminium adjuvant, as aluminium hydroxide, aluminum phosphate or aluminum sulfate.
In meningococcus combined vaccine provided by the invention, the dosage form of vaccine and compatibility are determined according to the known technical standard of pharmaceutical field those skilled in the art.In the preferred embodiment of the invention, the vaccine dosage form is liquid dosage form, freeze-dried formulation, pill, tablet, capsule formulation preferably, is more preferably liquid dosage form or freeze-dried formulation.In preferred another embodiment of the present invention, described combined vaccine is a freeze-dried formulation, and the freeze dried vaccine diluent preferably contains PBS, water for injection, physiological sodium chloride solution adjuvant or that do not contain adjuvant except that kind known in those skilled in the art.In the present invention preferably further in the embodiment, combined vaccine of the present invention can also carry out lyophilizing in the container and seals packing into protein carrier coupling or non-link coupled polysaccharide branch, absorption B group meningitis cocci OMP liquid subpackage adjuvant or non-absorption adjuvant is gone into another container, as the diluent of lyophilizing polysaccharide antigen.
In the preferred embodiment of the invention, combined vaccine can be the preservative free vaccine.In preferred another embodiment of the present invention, combined vaccine comprises antiseptic, and preferred antiseptic is thimerosal, 2-phenoxyethanol, benzyl alcohol.
Mucosal meningococcal multivalence combined vaccines provided by the invention, route of inoculation comprise intradermal injection, subcutaneous injection, intramuscular injection, lumbar injection, also comprise via intranasal application, oral cavity, anus, vagina, mucosa administration.
The present invention passes through following embodiment, but unrestricted, further describes core content of the present invention for example, and described embodiment sets forth notion of the present invention and several embodiment preferred.Other embodiments of the invention are predicted by those skilled in the art under the prerequisite that does not deviate from core of the present invention.
Embodiment
Embodiment 1
The preparation of A, C, W135, Y group meningitis cocci capsular polysaccharide
With A, C, W135, the Y group meningitis cocci freeze-drying lactobacillus difference breakdown of cryopreservation, and, be seeded to 10% Sanguis caprae seu ovis plain agar culture medium, put 8%CO with after the common meat water recovery
2In the environment, cultivated 16～24 hours in 35～37 ℃.Transferred species to epidemic encephalitis improvement doup closes solid medium, puts 8%CO
2In the environment, cultivated 8～12 hours in 35～37 ℃.The continuation transferred species is closed solid medium to epidemic encephalitis improvement doup and is increased the bacterium cultivation, puts 8%CO
2In the environment, cultivated 8～12 hours in 35～37 ℃.The culture transferred species is closed in the fermentation tank of fluid medium to adding the epidemic encephalitis doup, under pressure 0.01～1.0mpa, ventilation 1～10L/m, stirring 50～200rpm, pH6.0～7.2 conditions, cultivated 6～12 hours in 35～37 ℃.Fermentation finishes, and adds the formaldehyde sterilization treatment of final concentration 0.50～1.50%.With 20～150L/h, 12,000～18, the centrifugal collection culture supernatants of 000rpm adds the cetyl trimethyl ammonium bromide of final concentration 0.08～0.20%, behind the stirring and evenly mixing, leaves standstill 12～24 hours in 8～20 ℃ to the fermentor cultivation thing.Centrifugal 12,000～18,000rpm collects polysaccharide-cetyl trimethyl ammonium bromide complex precipitation, adds final concentration 0.3～1.5mol/L CaCl
2Solution in 2～8 ℃ of vibrations 2～4 hours, makes polysaccharide and cetyl trimethyl ammonium bromide depolymerization.Add ethanol to final concentration 20～25%, 2～8 ℃ left standstill 1～3 hour, centrifugal 2,500～3, and supernatant is collected in 500rpm, enucleation acid in 60 minutes.Add ethanol again to final concentration 75～80%, 2～8 ℃ left standstill 10～14 hours, centrifugal 3,500～5,000rpm, collected the crude polysaccharides precipitate in 30 minutes.Crude polysaccharides is with dehydrated alcohol and acetone washing by soaking each 2～4 times, in 2～8 ℃ of dryings 12～24 hours, stores-20 ℃ with down to being further purified.
With 10～15% saturated neutral sodium acetates dissolving crude polysaccharides, make the crude polysaccharides final concentration reach 10～20mg/ml, centrifugal 3,500～4 by 1: 2 cold phenol extraction of capacity, 500rpm, 60 minutes, the collection supernatant repeats cold phenol extraction 3～5 times.The supernatant of collecting carries out dialysis treatment, and dialysis solution is 0.1～0.5mol/L CaCl
2Solution or 0.5～1.5mol/L sodium chloride solution.Adding ethanol to final concentration is 75～80%, and left standstill 10～14 hours in 2～8 ℃ the vibration back, centrifugal 3,500～4,500rpm, 60 minutes, collecting precipitation polysaccharide.Polysaccharide is used dehydrated alcohol and acetone washing by soaking respectively 2～4 times, in 2～8 ℃ of dryings 24～48 hours, dissolve dried polysaccharide with sterilized water for injection, obtain A, C, W135, Y group meningitis cocci purified polysaccharide respectively after the reuse 0.22 μ m filter aseptic filtration, be stored in below-20 ℃ with liquid or lyophilized form respectively.Press the Pharmacopoeia of the People's Republic of China (version in 2005) prescriptive procedure and measure solid amount, protein content, nucleic acid content, phosphorus or projects such as sialic acid content, O-acetyl content, KD value and KD≤0.5 polysaccharide recovery, discrimination test, endotoxin content and sterility test.
Embodiment 2
The preparation of B group meningitis cocci outer membrane protein composite (OMP)
With the freeze-drying lactobacillus B4 strain of the different protein types of the B group meningitis cocci of cryopreservation, B15 strain, B2a strain breakdown respectively, and after recovering with common meat water, be seeded to 10% Sanguis caprae seu ovis plain agar culture medium, put 8%CO
2In the environment, cultivated 16～24 hours in 35～37 ℃.Transferred species to epidemic encephalitis improvement doup closes solid medium, puts 8%CO
2In the environment, cultivated 8～12 hours in 35～37 ℃.The continuation transferred species is closed solid medium to epidemic encephalitis improvement doup and is increased the bacterium cultivation, puts 8%CO
2In the environment, cultivated 8～12 hours in 35～37 ℃.The culture transferred species is closed in the fermentation tank of fluid medium to adding the epidemic encephalitis doup, under pressure 0.01～1.0mpa, ventilation 1～10L/m, stirring 50～200rpm, pH6.0～7.2 conditions, cultivated 6～12 hours in 35～37 ℃.Fermentation finishes, and the sodium deoxycholate solution sterilization that adds final concentration 0.05～0.20% is handled.To the fermentor cultivation thing with 20～150L/h, 12,000～18, the centrifugal collection bacterial sediment of 000rpm thing, and put-20 ℃ frozen.Frozen thalline is thawed, add sodium acetate and the 0.3～0.6mol/L lithium chloride solution cracking thalline of 0.2～0.8mol/L, centrifugal 3,500～5 in 50～60 ℃ of vibrations 2～4 hours, 000rpm, 60 minutes collects supernatant.Add ethanol to final concentration 25～35% enucleation acid, 2～8 ℃ were stirred 2～4 hours, centrifugal 3,500～5, and 000rpm, 60 minutes collects supernatant.Continue to add ethanol to final concentration 65～80%, centrifugal 3,500～5,000rpm, 60 minutes, collecting precipitation.Precipitation is dissolved with sterilized water for injection, through 0.22 μ m filter aseptic filtration, uses 300～500KD, the ultrafiltration of 30KD ultrafilter membrane more respectively.Through Sephacryl S-300 chromatographic column purification, refined solution obtains the B group meningitis cocci OMP of B4 strain, B15 strain, B2a strain respectively through 0.22 μ m filter aseptic filtration again.After the projects such as the Pharmacopoeia of the People's Republic of China (version in 2005) prescriptive procedure calibrating protein content and purity, KD value, discrimination test, sterility test of pressing were qualified, it was standby to put 2～8 ℃ of preservations.
Embodiment 3
The preparation of the protein carrier-tetanus toxoid of coupling polysaccharide (TT)
With the clostridium tetanus freeze-drying lactobacillus breakdown of cryopreservation, with the physiological sodium chloride solution recovery, be seeded to two peptone solid mediums, cultivated 24～72 hours in 33～36 ℃.Transferred species was cultivated 24～72 hours in 33～36 ℃ to two peptone solid mediums again.Continue transferred species and to the seed bottle that contains two peptone fluid mediums, increase the bacterium cultivation, cultivated 24～72 hours in 33～36 ℃.Culture transferred species in the seed bottle to the fermentation tank that contains two peptone fluid mediums, under ventilation 20～80L/m, stirring 50～200rpm, pH6.0～7.2 conditions, was cultivated 72～96 hours in 33～36 ℃.Fermentation finishes, and adds the formaldehyde sterilization treatment of final concentration 0.25～0.85%.Through centrifugal 12,000～18,000rpm, 30 minutes collects supernatant.Supernatant concentrates through 100～300KD membrane ultrafiltration through 0.22 μ m filter aseptic filtration again.Add NaHCO respectively
3To final concentration 0.55～0.85%, (NH
4)
2SO
4To final concentration 12.0～16.0%, stirred 30 minutes, put room temperature and left standstill 18～24 hours.Centrifugal 12,000～18,000rpm, 30 minutes collects supernatant.In the supernatant of collecting, add (NH
4)
2SO
4To final concentration 6.0～10.0%, stirred 30 minutes, put room temperature and left standstill 18～24 hours.Centrifugal 12,000～18,000rpm, 90 minutes, collecting precipitation also is dissolved in 0.1%NaHCO
3In the solution.In 2～8 ℃, the dialysis 60～72 hours after, again through 0.22 μ m filter aseptic filtration.Liquid after the aseptic filtration adds sodium chloride to final concentration 0.75～0.85%, adds formaldehyde again to final concentration 0.12～0.16%, and pH transfers to 6.5～7.0, puts 35～37 ℃ of detoxifications 14～18 days.TT stock solution after the detoxification is pressed the Pharmacopoeia of the People's Republic of China (version in 2005) gainer and method calibrating, and it is standby that stock solution is put 2～8 ℃ of preservations behind the assay approval.
Embodiment 4
A, C, W135, Y group meningitis cocci capsular polysaccharide respectively with the preparation of the link coupled unit price conjugate of tetanus toxoid (TT)
Respectively A, C, W135, Y group meningitis cocci capsular polysaccharide are diluted to 2.5～5.5mg/ml with water for injection, add Bromine cyanide. to final concentration 1.0～4.0mg/mg polysaccharide with activated polysaccharide, regulate pH and keep pH9.5～11.5 with NaOH, stirred 30～60 minutes in 20～26 ℃.Add adipic dihydrazide again to final concentration 12.0～18.0mg/ml, regulate and keep pH8.0～10.0, kept 15～30 minutes.In 20～26 ℃ of stirrings 30～60 minutes, put again at 2～8 ℃ and stirred 18～24 hours, form polysaccharide-adipic dihydrazide derivant.With polysaccharide-adipic dihydrazide derivant in 2～8 ℃ the dialysis 72～96 hours, again through 0.45 μ m filter aseptic filtration.TT is diluted to 1.0～4.0mg/ml, is that 1: 0.5～2 ratios (v/v) add TT in polysaccharide-adipic dihydrazide derivant in polysaccharide-adipic dihydrazide derivant: TT, regulates and keep pH5.0～6.0.Add carbodiimide to final concentration 20～30mg/ml, regulate and keep pH5.0～6.0, keep 60～90 minutes after, regulate and keep pH6.5～7.5.Put 2～8 ℃ of dialysis 72～96 hours, through 300KD ultrafilter membrane ultrafiltration and concentration.With Sephacryl S-400 gel chromatography, purified polysaccharide-TT conjugate, collect V
0The peak through 0.22 μ m filter aseptic filtration, obtains A group's polysaccharide-TT conjugate, C group's polysaccharide-TT conjugate, W135 group's polysaccharide-TT conjugate, Y group's polysaccharide-TT conjugate respectively again.Press the Pharmacopoeia of the People's Republic of China (version in 2005) prescriptive procedure calibrating protein content, phosphorus or projects such as sialic acid content, polyoses content, polysaccharide/albumen ratio, macromolecular compound, KD=0.2 polysaccharide recovery, free polysaccharide, floating preteins, discrimination test, endotoxin content and sterility test qualified after, store 2～8 ℃ standby.
Embodiment 5
The preparation of mucosal meningococcal multivalence combined vaccines
The raw material of preparation mucosal meningococcal multivalence combined vaccines comprises: A group's polysaccharide, C group's polysaccharide, W135 group's polysaccharide, Y group's polysaccharide, A group's polysaccharide-TT conjugate, C group's polysaccharide-TT conjugate, W135 group's polysaccharide-TT conjugate, Y group's polysaccharide-TT conjugate, B group OMP, 100～200mM phosphate physiological sodium chloride solution, lactose, water for injection, 1% thimerosal.
(1) preparation of combined vaccine (4 valency coupling polysaccharide+unit price BOMP) high dose
With water for injection dilution A group polysaccharide-TT conjugate, C group's polysaccharide-TT conjugate, W135 group's polysaccharide-TT conjugate, Y group's polysaccharide-TT conjugate, B group OMP, the phosphate physiological sodium chloride solution, make finished product component and content be: A group's polysaccharide-TT conjugate final concentration is calculated as 40 μ g/ml by polyoses content, C group's polysaccharide-TT conjugate final concentration is calculated as 40 μ g/ml by polyoses content, W135 group's polysaccharide-TT conjugate final concentration is calculated as 40 μ g/ml by polyoses content, Y group's polysaccharide-TT conjugate final concentration is calculated as 40 μ g/ml by polyoses content, B group OMP (B4 strain) final concentration is calculated as 120 μ g/ml by albumen, the phosphate physiological sodium chloride solution is 10mM, lactose final concentration 8～20mg/ml, pH transfers to 6.80～7.20.By sucking-off amount 〉=0.5ml packing cillin bottle, vacuum freeze-drying seals, and is the freeze dried vaccine diluent with aseptic apyrogeneity PBS.Press the Pharmacopoeia of the People's Republic of China (version in 2005) prescriptive procedure calibrating outward appearance, moisture, polyoses content, dissociation amylase content, protein content, discrimination test, sterility test, abnormal toxicity test, pyrogen test, potency test, qualified back is a mucosal meningococcal multivalence combined vaccines.
(2) preparation of dosage in the combined vaccine (4 valency coupling polysaccharide+unit price BOMP)
Same present embodiment (1) method preparation, finished product component and content are adjusted to: A group's polysaccharide-TT conjugate final concentration by polyoses content be calculated as 20 μ g/ml, C group's polysaccharide-TT conjugate final concentration by polyoses content be calculated as 20 μ g/ml, W135 group's polysaccharide-TT conjugate final concentration by polyoses content be calculated as 20 μ g/ml, Y group's polysaccharide-TT conjugate final concentration is calculated as 20 μ g/ml, B group OMP (B4 strain) final concentration by polyoses content and is calculated as 60 μ g/ml, lactose final concentration 8～20mg/ml by albumen.
(3) preparation of combined vaccine (4 valency coupling polysaccharide+unit price BOMP) low dosage
Same present embodiment (1) method preparation, finished product component and content are adjusted to: A group's polysaccharide-TT conjugate final concentration by polyoses content be calculated as 10 μ g/ml, C group's polysaccharide-TT conjugate final concentration by polyoses content be calculated as 10 μ g/ml, W135 group's polysaccharide-TT conjugate final concentration by polyoses content be calculated as 10 μ g/ml, Y group's polysaccharide-TT conjugate final concentration is calculated as 10 μ g/ml, B group OMP (B4 strain) final concentration by polyoses content and is calculated as 30 μ g/ml, lactose final concentration 8～20mg/ml by albumen.
(4) preparation of combined vaccine (4 valencys polysaccharide+unit price BOMP) high dose
Same present embodiment (1) method preparation, finished product component and content are adjusted to: A group's polysaccharide final concentration by polyoses content be calculated as 160 μ g/ml, C group's polysaccharide final concentration by polyoses content be calculated as 160 μ g/ml, W135 group's polysaccharide final concentration by polyoses content be calculated as 160 μ g/ml, Y group's polysaccharide final concentration is calculated as 160 μ g/ml, B group OMP (B4 strain) final concentration by polyoses content and is calculated as 120 μ g/ml, lactose final concentration 8～20mg/ml by albumen.
(5) preparation of dosage in the combined vaccine (4 valencys polysaccharide+unit price BOMP)
Same present embodiment (1) method preparation, finished product component and content are adjusted to: A group's polysaccharide final concentration by polyoses content be calculated as 100 μ g/ml, C group's polysaccharide final concentration by polyoses content be calculated as 100 μ g/ml, W135 group's polysaccharide final concentration by polyoses content be calculated as 100 μ g/ml, Y group's polysaccharide final concentration is calculated as 100 μ g/ml, B group OMP (B4 strain) final concentration by polyoses content and is calculated as 60 μ g/ml, lactose final concentration 8～20mg/ml by albumen.
(6) preparation of combined vaccine (4 valencys polysaccharide+unit price BOMP) low dosage
Same present embodiment (1) method preparation, finished product component and content are adjusted to: A group's polysaccharide final concentration by polyoses content be calculated as 60 μ g/ml, C group's polysaccharide final concentration by polyoses content be calculated as 60 μ g/ml, W135 group's polysaccharide final concentration by polyoses content be calculated as 60 μ g/ml, Y group's polysaccharide final concentration is calculated as 60 μ g/ml, B group OMP (B4 strain) final concentration by polyoses content and is calculated as 30 μ g/ml, lactose final concentration 8～20mg/ml by albumen.
(7) preparation of combined vaccine (divalent coupling polysaccharide+unit price BOMP)
Same present embodiment (1) method preparation, finished product component and content are adjusted to: A group's polysaccharide-TT conjugate final concentration by polyoses content be calculated as 20 μ g/ml, C group's polysaccharide-TT conjugate final concentration is calculated as 20 μ g/ml, B group OMP (B15 strain) final concentration by polyoses content and is calculated as 60 μ g/ml, lactose final concentration 8～20mg/ml by albumen.
(8) preparation of combined vaccine (divalent polysaccharide+unit price BOMP)
Same present embodiment (1) method preparation, finished product component and content are adjusted to: A group's polysaccharide final concentration by polyoses content be calculated as 100 μ g/ml, C group's polysaccharide final concentration is calculated as 100 μ g/ml, B group OMP (B15 strain) final concentration by polyoses content and is calculated as 60 μ g/ml, lactose final concentration 8～20mg/ml by albumen.
(9) preparation of combined vaccine (4 valency coupling polysaccharide+divalent BOMP)
Same present embodiment (1) method preparation, finished product component and content are adjusted to: A group's polysaccharide-TT conjugate final concentration is calculated as 20 μ g/ml, C group's polysaccharide-TT conjugate final concentration by polyoses content and is calculated as 20 μ g/ml, W135 group's polysaccharide-TT conjugate final concentration by polyoses content and is calculated as 20 μ g/ml, Y group's polysaccharide-TT conjugate final concentration by polyoses content and is calculated as 20 μ g/ml, B group OMP (B4 strain) final concentration by polyoses content and is calculated as 60 μ g/ml, B group OMP (B15 strain) final concentration by albumen and is calculated as 60 μ g/ml, lactose final concentration 8～20mg/ml by albumen.
(10) preparation of combined vaccine (divalent coupling polysaccharide+divalent BOMP)
Same present embodiment (1) method preparation, finished product component and content are adjusted to: A group's polysaccharide-TT conjugate final concentration is calculated as 20 μ g/ml, C group's polysaccharide-TT conjugate final concentration by polyoses content and is calculated as 20 μ g/ml, B group OMP (B4 strain) final concentration by polyoses content and is calculated as 60 μ g/ml, B group OMP (B1 5 strains) final concentration by albumen and is calculated as 60 μ g/ml, lactose final concentration 8～20mg/ml by albumen.
(11) preparation of combined vaccine (4 valencys polysaccharide+divalent BOMP)
Same present embodiment (1) method preparation, finished product component and content are adjusted to: A group's polysaccharide final concentration is calculated as 100 μ g/ml, C group's polysaccharide final concentration by polyoses content and is calculated as 100 μ g/ml, W135 group's polysaccharide final concentration by polyoses content and is calculated as 100 μ g/ml, Y group's polysaccharide final concentration by polyoses content and is calculated as 100 μ g/ml, B group OMP (B4 strain) final concentration by polyoses content and is calculated as 60 μ g/ml, B group OMP (B15 strain) final concentration by albumen and is calculated as 60 μ g/ml, lactose final concentration 8～20mg/ml by albumen.
(12) preparation of combined vaccine (divalent polysaccharide+divalent BOMP)
Same present embodiment (1) method preparation, finished product component and content are adjusted to: A group's polysaccharide final concentration is calculated as 100 μ g/ml, C group's polysaccharide final concentration by polyoses content and is calculated as 100 μ g/ml, B group OMP (B4 strain) final concentration by polyoses content and is calculated as 60 μ g/ml, B group OMP (B15 strain) final concentration by albumen and is calculated as 60 μ g/ml, lactose final concentration 8～20mg/ml by albumen.
Embodiment 6
With aluminium hydroxide is the preparation of the liquid combined vaccine of adjuvant
With sterile physiological sodium chloride solution dilution A group polysaccharide-TT conjugate, C group's polysaccharide-TT conjugate, W135 group's polysaccharide-TT conjugate, Y group's polysaccharide-TT conjugate, B group's (B4 strain) OMP, B group (B15 strain) OMP be dissolved in the aluminium hydroxide sterile solution of physiological sodium chloride, slowly add aluminium hydroxide solution, abundant mixing, make antigen component evenly be adsorbed in aluminum hydroxide particles, become suspension.Finished product component and content are: A group's polysaccharide-TT conjugate final concentration is calculated as 20 μ g/ml by polyoses content, C group's polysaccharide-TT conjugate final concentration is calculated as 20 μ g/ml by polyoses content, W135 group's polysaccharide-TT conjugate final concentration is calculated as 20 μ g/ml by polyoses content, Y group's polysaccharide-TT conjugate final concentration is calculated as 20 μ g/ml by polyoses content, B group OMP (B4 strain) final concentration is calculated as 60 μ g/ml by albumen, B group OMP (B15 strain) final concentration is calculated as 60 μ g/ml by albumen, aluminum content 0.2mg/ml.PH transfers to 6.0～7.2, by sucking-off amount 〉=0.5ml packing cillin bottle, is the multivalence combined vaccines of liquid.Press that the Pharmacopoeia of the People's Republic of China (version in 2005) prescriptive procedure calibrating outward appearance, loading amount, pH, polyoses content, dissociation amylase content, protein content, discrimination test, sterility test, abnormal toxicity test, pyrogen test, potency test are qualified to be mucosal meningococcal multivalence combined vaccines.
Embodiment 7
With aluminum phosphate is the preparation of the liquid combined vaccine of adjuvant
With sterile physiological sodium chloride solution dilution A group polysaccharide-TT conjugate, C group's polysaccharide-TT conjugate, W135 group's polysaccharide-TT conjugate, Y group's polysaccharide-TT conjugate, B group's (B4 strain) OMP, B group (B15 strain) OMP be dissolved in the aluminum phosphate sterile solution of physiological sodium chloride, slowly add aluminum phosphate solution, abundant mixing, make antigen component evenly be adsorbed in the aluminum phosphate granule, become suspension.Finished product component and content are: A group's polysaccharide-TT conjugate final concentration is calculated as 20 μ g/ml by polyoses content, C group's polysaccharide-TT conjugate final concentration is calculated as 20 μ g/ml by polyoses content, W135 group's polysaccharide-TT conjugate final concentration is calculated as 20 μ g/ml by polyoses content, Y group's polysaccharide-TT conjugate final concentration is calculated as 20 μ g/ml by polyoses content, B group OMP (B4 strain) final concentration is calculated as 60 μ g/ml by albumen, B group OMP (B1 5 strains) final concentration is calculated as 60 μ g/ml by albumen, aluminum content 0.2mg/ml.PH transfers to 6.0～7.2, by sucking-off amount 〉=0.5ml packing cillin bottle, is the multivalence combined vaccines of liquid.Press that the Pharmacopoeia of the People's Republic of China (version in 2005) prescriptive procedure calibrating outward appearance, loading amount, pH, polyoses content, dissociation amylase content, protein content, discrimination test, sterility test, abnormal toxicity test, pyrogen test, potency test are qualified to be mucosal meningococcal multivalence combined vaccines.
Embodiment 8
With aluminum salt is the preparation of the lyophilizing combined vaccine of adjuvant
The diluent PBS of the lyophilizing combined vaccine (4 valency coupling polysaccharide+divalent BOMP) of embodiment 5 (9) preparation is replaced with the physiological sodium chloride solution of aluminium hydroxide or aluminum phosphate, and the dilution liquid aluminium content is 0.2mg/ml.Redissolve with aseptic pyrogen-free physiological sodium chloride aluminum salt diluent before vaccine uses, fully use immediately behind the mixing.
Embodiment 9
The freeze dried vaccine of coupling polysaccharide and contain aluminium adjuvant and OMP preparation as the combined vaccine of diluent
With sterile physiological sodium chloride solution dilution A group polysaccharide-TT conjugate, C group's polysaccharide-TT conjugate, W135 group's polysaccharide-TT conjugate, Y group's polysaccharide-TT conjugate, make A group's polysaccharide-TT conjugate final concentration by polyoses content be calculated as 20 μ g/ml, C group's polysaccharide-TT conjugate final concentration by polyoses content be calculated as 20 μ g/ml, W135 group's polysaccharide-TT conjugate final concentration by polyoses content be calculated as 20 μ g/ml, Y group's polysaccharide-TT conjugate final concentration is calculated as 20 μ g/ml by polyoses content.PH transfers to 6.0～7.2, and by sucking-off amount 〉=0.5ml packing cillin bottle, it is 4 valency coupling polysaccharide lyophilizing combined vaccines that lyophilizing is sealed.
Reuse sterile physiological sodium chloride solution dilutes B group's (B4 strain) OMP, B group (B15 strain) OMP and has been dissolved in the aluminium hydroxide sterile solution of physiological sodium chloride, slowly add aluminium hydroxide solution, fully mixing makes the OMP component evenly be adsorbed in aluminum hydroxide particles, becomes suspension.B group OMP (B4 strain) final concentration is calculated as 60 μ g/ml, B group OMP (B15 strain) final concentration by albumen and is calculated as 60 μ g/ml, aluminum content 0.2mg/ml by albumen.PH transfers to 6.0～7.0, by sucking-off amount 〉=0.5ml packing cillin bottle, is the diluent that contains adjuvant and B group OMP of liquid.
Press that the Pharmacopoeia of the People's Republic of China (version in 2005) prescriptive procedure calibrating outward appearance, loading amount, pH, polyoses content, dissociation amylase content, protein content, discrimination test, sterility test, abnormal toxicity test, pyrogen test, potency test are qualified to be mucosal meningococcal multivalence combined vaccines.With the diluent that contains aluminum and the B group OMP freeze dried 4 valency coupling polysaccharide conjugate vaccines of recovering, inject behind the mixing before using.
Embodiment 10
The test of multivalence combined vaccines immunogenicity
Multivalence combined vaccines is diluted 4 times respectively as animal dosage, select cleaning level BALB/C or NIH mice for use, 12～14g, 10 every group, each experimental vaccine is used two groups, subcutaneous injection combined vaccine, negative control group injection 0.5ml sterile physiological sodium chloride.By 0,14 day program immunity two pin, respectively at blood sampling in 14,28 days, separation of serum was measured the serum antibody titer of respectively organizing 4 times of dilutions of every mice with the ELISA method, and, calculate immunogenicity sun rate of rotation with 2.1 times of positive criterions of the average OD value of control group mice serum.In micro-96 hole ELISA Plate, ambient temperature overnight is washed bag and is dried by plate with antigen coated.Add test serum, 37 ℃ hatch after, the detersive enzyme target dries.Add anti-Mus ELIAS secondary antibody, 37 ℃ hatch after, the detersive enzyme target adds the substrate solution of new preparation, 37 ℃ hatch after, add stop buffer, cessation reaction is measured the OD value with microplate reader.
Combined vaccine dosiology result of study (table 1) shows that all kinds combined vaccine all can cause the immune response of mice to polysaccharide and B group OMP.Dosage height no matter, the polysaccharide antigen of coupling TT causes that the IgG GMT to polysaccharide is higher than non-link coupled polysaccharide (P＜0.01) significantly.And link coupled polysaccharide can produce tangible immune anamnesis reaction behind injection second pin, but not the reaction of the booster response of coupling polysaccharide is then not obvious.The equal energy of B group OMP in the combined vaccine of coupling polysaccharide and in the combined vaccine of non-coupling polysaccharide produces good immune response, and can also produce tangible immune anamnesis reaction.
The immunogenicity result of study (table 2) of multivalence B group OMP shows in the combined vaccine, and the OMP of different protein types can produce certain cross-immune reaction in the mice body, and polyvalent OMP can provide more broad-spectrum immunne response.
Adjuvant research (table 3, table 4) result proves that aluminium adjuvant significance ground has improved the immunne response to polysaccharide and OMP, and especially when 32 weeks, IgG GMT is significantly higher than no Adjuvanted vaccines.For freeze dried vaccine, aluminium adjuvant can be added in the diluent, before using, redissolve, can play the effect of adjuvant equally.Other method, as liquid diluting liquid, the freeze dried coupling polysaccharide conjugate vaccine of redissolution before using can have been given play to the function of adjuvant equally with aluminium adjuvant and OMP.
The immunogenicity of table 1 combined vaccine various dose is (IgG GMT) relatively
| The combined vaccine kind | Immunizing dose polysaccharide/albumen μ g | Anti-A group's polysaccharide | Anti-C group's polysaccharide | Anti-W135 group's polysaccharide | Anti-Y group's polysaccharide | Anti-B (4) group OMP | |||||
| 14 days | 28 days | 14 days | 28 days | 14 days | 28 days | 14 days | 28 days | 14 days | 28 days | ||
| 4 valency coupling polysaccharide+unit price BOMP | 1.25/3.75 | 18.9 | 39.6 | 19.0 | 56.7 | 17.2 | 73.8 | 23.3 | 103.9 | 134.3 | 658.6 |
| 4 valency coupling polysaccharide+unit price BOMP | 2.5/7.5 | 32.6 | 132.1 | 21.5 | 173.0 | 31.6 | 156.3 | 30.4 | 156.4 | 267.2 | 1632.3 |
| 4 valency coupling polysaccharide+unit price BOMP | 5.0/15.0 | 43.8 | 253.3 | 37.5 | 198.1 | 42.3 | 244.3 | 41.2 | 233.2 | 532.1 | 3210.6 |
| 4 valencys polysaccharide+unit price BOMP | 7.5/3.75 | 3.9 | 13.3 | 4.8 | 9.5 | 9.6 | 13.6 | 7.7 | 18.4 | 472.8 | 2533.7 |
| 4 valencys polysaccharide+unit price BOMP | 12.5/7.5 | 5.0 | 21.4 | 6.3 | 18.0 | 11.2 | 21.1 | 9.2 | 20.1 | 631.3 | 2715.4 |
| 4 valencys polysaccharide+unit price BOMP | 20.0/15.0 | 10.2 | 22.5 | 7.5 | 20.3 | 12.1 | 17.6 | 11.2 | 22.5 | 665.6 | 2635.3 |
The immunogenicity of the different protein type B group of table 2 combined vaccine OMP is (IgG GMT) relatively
| The combined vaccine kind | The OMP source | Anti-A group's polysaccharide | Anti-C group's polysaccharide | Anti-W135 group's polysaccharide | Anti-Y group's polysaccharide | Anti-B (4) group OMP | Anti-B (15) group OMP | ||||||
| 14 days | 28 days | 14 days | 28 days | 14 days | 28 days | 14 days | 28 days | 14 days | 28 days | 14 days | 28 days | ||
| 4 valency coupling polysaccharide+divalent BOMP | B4/15 | 32.6 | 132.1 | 21.5 | 173.0 | 31.6 | 156.3 | 30.4 | 156.4 | 831.7 | 3278.2 | 975.5 | 4132.5 |
| Divalent coupling polysaccharide+divalent BOMP | B4/15 | 43.2 | 175.3 | 23.3 | 153.9 | 659.5 | 2513.5 | 1130.0 | 3675.3 | ||||
| Divalent coupling polysaccharide+unit price BOMP | B15 | 34.5 | 153.1 | 37.6 | 213.5 | 321.7 | 613.3 | 1035.2 | 3984.2 | ||||
| 4 valency coupling polysaccharide+unit price BOMP | B4 | 41.6 | 232.5 | 30.2 | 198.5 | 25.0 | 178.4 | 32.3 | 205.8 | 931.3 | 3521.2 | 423.3 | 635.0 |
| 4 valencys polysaccharide+divalent BOMP | B4/15 | 3.3 | 12.1 | 7.2 | 13.1 | 6.4 | 21.3 | 7.5 | 19.1 | 732.4 | 2138.4 | 763.3 | 3133.3 |
| Divalent polysaccharide+divalent BOMP | B4/15 | 6.4 | 18.3 | 8.6 | 15.3 | 811.1 | 2556.3 | 803.1 | 3452.1 | ||||
| Divalent polysaccharide+unit price BOMP | B15 | 4.6 | 13.5 | 7.1 | 19.5 | 235.5 | 563.6 | 821.0 | 3422.4 | ||||
| 4 valencys polysaccharide+unit price BOMP | B4 | 10.1 | 21.0 | 7.4 | 22.5 | 9.8 | 18.9 | 8.9 | 18.0 | 635.5 | 3812.5 | 222.4 | 513.3 |
Table 3 adjuvant is to the comparison (IgG GMT) of associating vaccine immunogenicity
| The combined vaccine kind | The adjuvant kind | Anti-A group's polysaccharide | Anti-C group's polysaccharide | Anti-W135 group's polysaccharide | Anti-Y group's polysaccharide | Anti-B (4) group OMP | Anti-B (15) group OMP | ||||||
| 14 days | 28 days | 14 days | 28 days | 14 days | 28 days | 14 days | 28 days | 14 days | 28 days | 14 days | 28 days | ||
| 4 valency coupling polysaccharide ++ divalent BOMP | No adjuvant | 32.6 | 132.1 | 21.5 | 173.0 | 31.6 | 156.3 | 30.4 | 156.4 | 656.3 | 2436.0 | 738.6 | 3215.7 |
| 4 valency coupling polysaccharide ++ divalent BOMP | Aluminium hydroxide | 21.4 | 98.7 | 23.1 | 182.4 | 22.1 | 145.3 | 32.4 | 203.8 | 715.8 | 2135.4 | 739.0 | 3011.2 |
| 4 valency coupling polysaccharide ++ divalent BOMP | Aluminum phosphate | 27.3 | 132.5 | 25.2 | 136.5 | 19.4 | 163.3 | 31.5 | 194.0 | 686.1 | 1895.5 | 639.2 | 2856.4 |
| 4 valency coupling polysaccharide §+ divalent BOMP | No adjuvant diluent | 40.5 | 193.8 | 32.2 | 189.5 | 37.2 | 203.5 | 42.4 | 203.6 | 1350.3 | 3055.6 | 933.1 | 3451.9 |
| 4 valency coupling polysaccharide §+ divalent BOMP | The aluminium hydroxide dilution | 37.5 | 121.3 | 31.4 | 203.5 | 35.6 | 198.4 | 33.7 | 235.2 | 1213.4 | 3146.8 | 1315.0 | 2735.1 |
| 4 valency coupling polysaccharide § | Contain aluminum OMP diluent | 32.9 | 189.6 | 37.5 | 176.5 | 36.5 | 210.1 | 30.3 | 187.5 | 891.7 | 2733.1 | 1013.5 | 2913.3 |
T combined vaccine dosage form is a liquid dosage form, and the § combined vaccine is a freeze-dried formulation
Table 4 different diluent is to lyophilizing combined vaccine (4 valency coupling polysaccharide+unit price BOMP) lasting immunity Journal of Sex Research (IgG GMT)
| The diluent kind | Anti-A group's polysaccharide | Anti-C group's polysaccharide | Anti-W135 group's polysaccharide | Anti-Y group's polysaccharide | Anti-B (4) group OMP | ||||||||||||||||||||
| 2 weeks | 8 weeks | 16 weeks | 32 weeks | 48 weeks | 2 weeks | 8 weeks | 16 weeks | 32 weeks | 48 weeks | 2 weeks | 8 weeks | 16 weeks | 32 weeks | 48 weeks | 2 weeks | 8 weeks | 16 weeks | 32 weeks | 48 weeks | 2 weeks | 8 weeks | 16 weeks | 32 weeks | 48 weeks | |
| PBS | 16.3 | 102.5 | 203.4 | 175.6 | 82.3 | 19.2 | 205.4 | 236.2 | 163.5 | 54.3 | 21.4 | 136.8 | 2059 | 142.3 | 71.2 | 31.3 | 198.5 | 233.4 | 215.6 | 101.3 | 75.9 | 1231.3 | 2221.5 | 1835.6 | 1355.4 |
| Aluminium hydroxide | 7.9 | 31.5 | 356.2 | 1384.5 | 2133.3 | 10.3 | 52.3 | 431.2 | 2311.5 | 2356.1 | 11.2 | 38.5 | 457.2 | 1668.0 | 2031.3 | 7.3 | 45.2 | 325.4 | 2138.3 | 1983.5 | 21.3 | 493.5 | 321.5 | 3232.5 | 2893.8 |
| Aluminum phosphate | 8.3 | 54.3 | 415.5 | 1616.6 | 1938.4 | 9.5 | 63.1 | 325.3 | 2551.3 | 2711.5 | 9.3 | 41.6 | 572.3 | 2875.2 | 2213.4 | 9.5 | 50.5 | 431.4 | 2232.4 | 2512.3 | 18.5 | 325.8 | 532.3 | 2935.4 | 3245.3 |
| Aluminum sulfate | 10.6 | 44.3 | 431.6 | 1523.1 | 2432.5 | 11.2 | 50.5 | 315.4 | 1935.8 | 2346.6 | 9.0 | 55.2 | 505.4 | 1893.2 | 2011.3 | 10.8 | 60.3 | 450.2 | 2012.2 | 2123.5 | 15.3 | 415.3 | 1275.4 | 3102.6 | 3315.2 |
Claims (14)
1, a kind of mucosal meningococcal multivalence combined vaccines that derives from B group meningitis cocci outer membrane protein composite (OMP) that contains is characterized in that the antigenic component of described combined vaccine also comprises except that containing above-mentioned OMP:
Derive from one or more capsular polysaccharides in A, C, W135, the Y group meningitis cocci, described capsular polysaccharide is to be present in the combined vaccine with protein carrier coupling or non-coupling form.
2, combined vaccine according to claim 1 is characterized in that, capsular polysaccharide is 1 valency, divalent, 3 valencys or the 4 valency capsular polysaccharides that derive from A, C, W135, Y group meningitis cocci.
According to each described combined vaccine of claim 1 or 2, it is characterized in that 3, capsular polysaccharide is the 4 valency capsular polysaccharides that derive from A, C, W135, Y group meningitis cocci.
According to claim 1 or 2 each described combined vaccines, it is characterized in that 4, capsular polysaccharide is the divalent capsular polysaccharide that derives from A, C group meningitis cocci.
5,, wherein be selected from tetanus toxoid (TT), diphtheria toxoid (DT), sudden change nontoxic diphtheria toxin, diphtherotoxin albumen (CRM197) or the B group meningitis cocci outer membrane protein (OMP) any with the link coupled protein carrier of capsular polysaccharide according to each described combined vaccines of claim 1 or 2.
6, according to claim 1 or 2 each described combined vaccines, wherein said B group meningitis cocci outer membrane protein composite is to prepare remix from a plurality of protein type bacterial strains of B group meningitis cocci respectively to form.
7, require 6 described combined vaccines according to profit, wherein said B group meningitis cocci outer membrane protein composite is to prepare remix from B group meningitis cocci B4 and B15 strain respectively to form.
8, combined vaccine according to claim 6, wherein said B group meningitis cocci outer membrane protein composite are to be prepared from from B group meningitis cocci B4 strain.
9, according to claim 1 or 2 each described combined vaccines, it further comprises aluminum salt adjuvant.
10, combined vaccine according to claim 9, wherein said aluminum salt adjuvant is selected from aluminium hydroxide, aluminum phosphate or aluminum sulfate.
11, according to claim 1 or 2 each described combined vaccines, it further comprises pharmaceutically acceptable excipient.
12, be used for preventing or improving the application of the medicine of patient's meningococcal infection in preparation according to the combined vaccine of claim 1 or 2.
13, according to the application of claim 12, wherein the combined vaccine with preparation is included in two containers, a container comprises and protein carrier coupling or non-link coupled freeze dried capsular polysaccharide, a container comprises the liquid B group OMP that adsorbs adjuvant, the latter dilutes freeze dried combined vaccine antigenic component as diluent before using.
14, the application of meningococcus combined vaccine according to claim 1 and 2, wherein the combined vaccine with preparation is included in two containers, a container comprises and protein carrier coupling or non-link coupled freeze dried polysaccharide antigen and B group OMP antigen, container includes the diluent of adjuvant or does not have the diluent of adjuvant, the latter dilutes freeze dried combined vaccine antigenic component as diluent before using.
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