CN102068690A - Polyvalent pneumococcal capsular polysaccharide conjugate vaccine and preparation method thereof - Google Patents
Polyvalent pneumococcal capsular polysaccharide conjugate vaccine and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a polyvalent pneumococcal capsular polysaccharide conjugate vaccine which comprises conjugates of capsular polysaccharides of 23 serotype pneumococci and a carrier protein, and the serotypes of the 23 serotype pneumococci are 1, 2, 3, 4, 5, 6B, 7F, 8, 9V, 9N, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F and 33F. The conjugate vaccine provided by the invention can stimulate a receptor to generate immune response and further generate protection for like pneumococcal pathogens generating the capsular polysaccharide ingredient. The 23-valent pneumococcal capsular polysaccharide conjugate vaccine provided by the invention has more extensive coverage and better immune effect in comparison with the prior art.
Description
Technical field
The present invention relates to a kind of multivalent pneumococcal capsular polysaccharide combined vaccine and preparation method thereof.
Background technology
Twoth century does not in the past have several infectious agents can be equal to mutually with streptococcus pneumoniae at the M ﹠ M in the whole world, causes whole world death of child below 100 ten thousand 5 years old every year.Streptococcus pneumoniae remains the main cause of community acquired pneumonia, mainly causes lobar pneumonia in the adult, the normal diseases such as bacterial pneumonia, meningitis, otitis media, pleuritis that cause in the child.Before not having antibiotic, the patient death of being in hospital because of the pulmonitis strain mass formed by blood stasis more than 70% is arranged.The acute otitis media of the 20%-48% of infant and 50% suppurative otitis media are microbial by pneumonia streptococcus, and the bacteremia infection can cause higher mortality rate.Streptococcus pneumoniae property pneumonia is 0.1-0.47% in sickness rate every year of adult according to estimates, and case fatality rate is 11%.China's pneumonia sickness rate is very high always, and over nearly more than 40 years, its bacteremia mortality rate farce is always wandered between 25%-29%, outside the institute in the acquired pneumonia streptococcus pneumoniae property pneumonia can reach 46%-76%.At the infection of streptococcus pneumoniae, adopt antibiotic therapy for many years always.But Resistant strain reaches more than 96% now, and presents the multidrug resistant character.Therefore developing vaccine is crucial with this microbial disease of prevention.
The streptococcus pneumoniae of having found has more than 90 serotype, is that pettiness difference and the rabbit immune organ that is based upon k antigen discerned the fine difference between the pod membrane chemical analysis, and produces every kind of antigenic specific antibody basis typing that comes up.The k antigen of streptococcus pneumoniae be up to now in the bacterial vaccine antigenic structure the most complicated, the macromole polymer that its type specificity polysaccharide is made up of many constitutional repeating units, a thymus independent antigen (thymus-independent, characteristic TI) have been constituted.(Capsular polysaccharide promptly is that the virulence factor of antibacterial is again a kind of important protective antigen CPS) to capsular polysaccharide.
Preparing component vaccine with the capsular polysaccharide of chemical method purification of bacterial is one of serious achievement of 20th century vaccine development, also is one of sign of vaccine revolution for the second time.4 valency polysaccharide vaccines such as worldwide widely used polysaccharide vaccine such as epidemic cerebrospinal meningitis coccus A, C, Y, W135, pneumonia 23 valency polysaccharide vaccines, Typhoid Vi Polysaccharide Vaccine etc.A large amount of clinical test results show that the side reaction that the inoculation polysaccharide vaccine causes is very rare, and these vaccines are remarkable for prevention adult and big-age-child's corresponding infection aspect effect.The antibody affinity that produces in young child of polysaccharide vaccine is low regrettably, and is limited or invalid to the effect of infant.The bacterial capsule polysaccharide combined by chemical mode with protein carrier can solve this shortcoming, can with polysaccharide thymus not the dependency antigenic shift be thymus dependent antigen, produce a series of immune-enhancing effect thereby start the auxiliary lymphocyte of T, and the generation immunological memory is replied; Another the upright journey upright stone tablet on the combined vaccine development history has been started in the successful development of Type B hemophilus influenza (Hib) combined vaccine in 1987, and combined vaccine becomes a focus in child's vaccine research.C group meningitis combined vaccine and 7 valencys, 10 valency streptococcus pneumoniae combined vaccines have appearred on the international market afterwards successively.Other all kinds of pod membrane types or the combined vaccine that contains the lipopolysaccharide antibacterial also enter II, III phase clinical research successively.
CTB is the nontoxic subunit of cholera toxin, can with nerve node glycosides fat (GM1) receptors bind on most of mammalian cell membranes.CTB is about 12kDa; The long 375bp of encoding gene (ctxB), 124 aminoacid of encoding, wherein preceding 21 aminoacid are signal peptide sequence (Yamamoto et al., 1995).
CTB can be used as immune carrier, because it has the function in conjunction with GM1, can make the easier and digestive tract mucosa effect with the albumen of its fusion, and then cause a series of biochemical reactions, produces stronger immune effect.CTB can also be as the stable carrier of some allogenic polypeptide; after the antigen of it and chemical coupling or gene fusion enters in the body simultaneously; can evoke the immunogenicity that merges epitope antigen; make body produce intensive immunoreation; might reach immanoprotection action (Gonzales et al., 1993).
CTB can be used as the good albumen hapten and the carrier of poor antigen, can also give the hapten immunogenicity simultaneously, strengthens immunogenicity (Tochikubo et al., 1998 of poor antigen; Wu et al., 1998).
Although new antibiotic constantly comes out, the Modern Nursing level improves constantly, and is still high by the M ﹠ M that streptococcus pneumoniae infection causes.The enhanced immunne response of developing streptococcus pneumoniae combined vaccine energy inducing function, and induction of immunity memory and persistent immunoprotection are for the infection of protection aggressive streptococcus pneumoniae in the high-risk group provides new chance.
Summary of the invention
The purpose of this invention is to provide a kind of multivalent pneumococcal capsular polysaccharide combined vaccine and its production and application.
Combined vaccine provided by the invention, comprise the 23 kinds of pneumococcal capsular polysaccharides of serotype of separation and purification and the conjugate of carrier protein, described 23 kinds of pneumococcal serotypes of serotype are 1,2,3,4,5,6B, 7F, 8,9V, 9N, 10A, 11A, 12F, 14,15B, 17F, 18C, 19F, 19A, 20,22F, 23F and 33F.
Polyvalent vaccine provided by the invention also can comprise adjuvant, and wherein, described adjuvant is preferably aluminium hydroxide, aluminum sulfate or aluminum phosphate for containing aluminum salt adjuvant, and the content of wherein said aluminum salt adjuvant (in aluminum content) is preferably the 0.2mg/ml vaccine.
Wherein, the mass ratio of described capsular polysaccharide and carrier protein is 0.2～3: 1.
Wherein, described carrier protein is diphtheria toxoid or choleratoxin B subunit, is preferably choleratoxin B subunit.
The present invention also provides the method for purification pneumococcal capsular polysaccharide, comprising:
1) in the streptococcus pneumoniae culture, adds NaTDC, sterilize;
2) the centrifugal thalline that goes is collected supernatant;
3) add ethanol and make its final concentration reach 30～50%, centrifugal removal nucleic acid;
4) add ethanol and make its final concentration reach 60～80%, centrifugal, collecting precipitation;
5) dissolution precipitation again, the cold phenol extracting that adds 1-2 times of volume is removed albumen for several times;
6) add ethanol and make its final concentration reach 60%～80%, centrifugal, collecting precipitation thing, the streptococcus pneumoniae polysaccharides of acquisition purification.
Multivalent pneumococcal capsular polysaccharide combined vaccine provided by the invention, it is any in spray-type, liquid dosage form, freeze-dried formulation, capsule formulation, tablet and the pill.
The present invention also provides preparation described multivalent pneumococcal capsular polysaccharide combined vaccine, comprise the steps: to separate and purification 1,2,3,4,5,6B, 7F, 8,9V, 9N, 10A, 11A, 12F, 14,15B, 17F, 18C, 19F, 19A, 20,22F, 23F and the pneumococcal capsular polysaccharide of 33F serotype, described capsular polysaccharide is carried out covalent coupling with carrier protein respectively obtain the unit price conjugate, described unit price conjugate is mixed obtaining the multivalence combined vaccine.
Multivalent pneumococcal capsular polysaccharide combined vaccine provided by the invention, can be applicable to prevent or treat the medicine of the disease that streptococcus pneumoniae brings out, it can carry out immunity by the method for skin, injection, oral, collunarium or mucosa spraying, preferably, can adopt the mode of collunarium to carry out immunity, thus the misery when reducing patient's immunity.
Multivalent pneumococcal capsular polysaccharide combined vaccine provided by the invention, 23 streptococcus pneumoniae hypotypes of employing, existing 7 valency pneumonia combined vaccines cover more extensive.In addition, the chemical coupling method cyanogen bromide-activated method that the present invention adopts, the method combination rate height, immunogenicity is good.The 23 valency pneumonia combined vaccine finished products that do not add adjuvant provided by the invention also can reach good immune effect.23 valency combined vaccines provided by the invention use the CTB protein carrier, use the immunization route of collunarium, the misery when reducing patient's immunity.
Description of drawings
Fig. 1 is a CTB ion-exchange chromatography spectrogram.
The specific embodiment
Following examples are used to illustrate the present invention, but are not used for limiting the scope of the invention.
The preparation of embodiment 1 capsular polysaccharide
Select 1,2,3,4,5 respectively for use, the streptococcus pneumoniae of 6B, 7F, 8,9V, 9N, 10A, 11A, 12F, 14,15B, 17F, 18C, 19F, 19A, 20,22F, 23F and 33F hypotype, line picking strain from seeding is criticized, be inoculated in the 5ml culture fluid, expand the 500ml culture fluid to, expand the 5L culture fluid again to.Condition of culture is a streptococcus pneumoniae condition of culture well known in the art.
As pneumococcal culture fluid OD
600〉=1.5 o'clock, the adding w/v was 1 ‰ NaTDC in the streptococcus pneumoniae culture, sterilizes.
The centrifugal thalline that goes is collected supernatant;
Add ethanol and make its final concentration reach 40%, centrifugal removal nucleic acid;
Add ethanol and make its final concentration reach 70%, centrifugal, collecting precipitation;
Again dissolution precipitation, the cold phenol extracting that adds 2 times of volumes is removed albumen for several times;
Adding ethanol makes its final concentration reach 80%, centrifugal, the collecting precipitation thing, obtain purification 1,2,3,4,5, the pneumococcal capsular polysaccharide of 6B, 7F, 8,9V, 9N, 10A, 11A, 12F, 14,15B, 17F, 18C, 19F, 19A, 20,22F, 23F and 33F hypotype.
The structure of embodiment 2 vibrio cholera B subunit engineering bacterias
1, the vibrio cholera B subunit encoding gene of announcing according to NCBI (GenBank accession number: EU854477.1) design primer, forward primer CTB-F:GATAT
ATGATTAAATTAAAATTTG (SEQ ID No.1), downstream primer CTB-R:CCG
TTAATTTGCCATACTAATTGC (SEQ ID No.2);
2, be template with vibrio cholerae O 1 bacterial strain V.cholerae 569B (available from Chinese medicine antibacterial preservation administrative center) genomic DNA, obtain the encoding gene fragment of the vibrio cholera B subunit of 375bp through pcr amplification;
3, this target gene fragment is carried out double digestion with Bgl II and Xho I, be connected with expression vector pET-22b with the identical nucleic acid endonuclease digestion, import host cell E.coli BL21 (DE3), obtain the engineered strain of efficient secretory expression choleratoxin B subunit, called after: E.coli MHCTB03 through screening;
4, according to the requirement of " biological product production is examined and determine with bacterium kind rule of management ", carry out the foundation in cholera toxin B unit expression strain three-class strain storehouse.
The preparation of embodiment 3 cholera B subunits
The preparation of cholera B subunit is divided into several stages: seed liquor preparation, big jar cultivate, centrifugal, concentrated and purified, filtration sterilization and cryopreservation.
The work seed lot bacterial classification inoculation that embodiment 2 is prepared is in containing the fresh LB fluid medium that final concentration is 50 μ g/mL ampicillin earlier, 32 ℃ of overnight incubation prepare seed liquor, for fermentation tank inoculation usefulness, fermentation culture can be selected the culture medium of suitable escherichia coli growth.In fermentation tank, when bacterial growth arrives OD
600=20 o'clock, the adding final concentration was that the IPTG of 0.2mmol/L induces, after continuing to cultivate 6～8h, stop to cultivate, regulate fermentation liquid pH to 6.5,8000rpm, 4 ℃ of continuous centrifugals, collect supernatant, the ultrafilter membrane that is not more than 10kD concentrates CTB solution, ion-exchange chromatography purification, and the Tris buffer solution elution target protein with containing 2mol/L NaCl detects chromatographic peak under the 280nm wavelength, collect the target peak (Fig. 1) about 26min, obtain CTB solution.CTB solution behind the purification carries out aseptic filtration, is sub-packed in the big bottle, in 2～8 ℃ of preservations.
With embodiment 1 preparation 1,2,3,4,5, the capsular polysaccharide of 6B, 7F, 8,9V, 9N, 10A, 11A, 12F, 14,15B, 17F, 18C, 19F, 19A, 20,22F, 23F or 33F hypotype is with mass ratio 1: 1, activation is 1 hour between pH10～11, transfer between pH8～9, add the 0.1M adipic dihydrazide and react 4 ℃ of standing over night after 10 minutes.Changed liquid with the film bag ultrafiltration of 100KD on the 2nd day, the polysaccharide after deriving mixes by mass ratio with carrier protein CTB at 1: 1, transfers pH5～6 to add carbodiimides reaction 5 hours, through 4FF agarose gel column purification sample, receives near the peak of outer water.
Embodiment 5 polysaccharide coupling proteins (sodium iodate activation, boron hydrocyanation sodium)
Add sodium periodate oxidation in the capsular polysaccharide with 12F, 14,15B, 17F, 18C, 19F, 19A, 20,22F, 23F or the 33F hypotype of embodiment 1 preparation, (polysaccharide is 1M with the ratio of sodium metaperiodate: 1.6M), detect aldehyde radical, molecular weight size and sugared content, add again diphtheria toxoid and boron hydrocyanation sodium (the ratio 1M of polysaccharide and boron hydrocyanation sodium: 1.6M), react the polysaccharide-protein conjugate.
Adopt the ultrafilter purification of 100KD, residual to remove, boron hydrocyanation sodium obtains the conjugate of preliminary purification.
The preparation of embodiment 6 multivalence capsular polysaccharide combined vaccines
With embodiment 4 preparation 1,2,3,4,5,7F, 8,9V, 9N, 10A, 11A, 12F, 14,15B, 17F, 18C, 19F, 19A, 20,22F, the various unit price conjugate of 23F, 33F be by 4 μ g/ml, 6B unit price conjugate 8 μ g/ml mix the back and form 23 valency pneumonia polysaccharide conjugate vaccines.
The preparation of embodiment 7 multivalence capsular polysaccharide combined vaccines
With embodiment 4 preparation 1,2,3,4,5,7F, 8,9V, 9N, 10A, 11A, 12F, 14,15B, 17F, 18C, 19F, 19A, 20,22F, the various unit price conjugate of 23F, 33F be by 4 μ g/ml, 6B unit price conjugate 8 μ g/ml mix adding aluminum phosphate adjuvant and form 23 valency pneumonia polysaccharide conjugate vaccines, and wherein aluminum content is the 0.2mg/ml vaccine.
The preparation of embodiment 8 multivalence capsular polysaccharide combined vaccines
With embodiment 4 preparation 1,2,3,4,5,7F, 8,9V, 9N, 10A, 11A, 12F, 14,15B, 17F, 18C, 19F, 19A, 20,22F, the various unit price conjugate of 23F, 33F be by 4 μ g/ml, 6B unit price conjugate 8 μ g/ml mix the back low-temperature vacuum drying and form 23 valency lyophilizing pneumonia polysaccharide conjugate vaccines.
Experimental example 1
According to embodiment 6 preparation combined vaccines, the mice of immune 12-14g, immunity 3 was measured pneumoniae antibody through the blood sampling of eye socket posterior vein with the ELISA method in 40 days inferior to collunarium immunity in the 1st, 14,28 day.
The result shows that after three immunity of 23 type pneumonia capsular polysaccharides, the concentration of mice serum IgG (OD value) does not have significant difference (P＞0.05) with the normal saline group; Various GL-PP conjugate and 23 valent pneumococcal conjugate vaccine mice immunized, the concentration (OD value) of the second time and the serum IgG of taking a blood sample for the third time significantly improves (P＜0.01) than the concentration (OD value) of the serum IgG of taking a blood sample for the first time.Illustrate that each group unit price GL-PP conjugate and 23 valent pneumococcal conjugate vaccines have good immunogenicity, and tangible immunological memory is arranged.
Experimental example 2
The preparation combined vaccine, the mice of immune 12-14g, immunity 3 was measured pneumoniae antibody through the blood sampling of eye socket posterior vein with the ELISA method in 40 days inferior to collunarium immunity in the 1st, 14,28 day.Immune group is the 23 valency pneumonia combined vaccines that do not contain adjuvant that contain adjuvant 23 valency pneumonia combined vaccines and embodiment 6 preparations of embodiment 7 preparations.Each immunizing dose is with the immunity amount of the multivalence combined vaccine in the experimental example 1.Each test group is respectively tested 15 above-mentioned mices.
The result shows, after containing adjuvant 23 valency pneumonia combined vaccines and not containing three immunity of adjuvant 23 valency pneumonia combined vaccines, and the no significant difference of the concentration of both mice serum IgG (OD value) (P＞0.05).Illustrate that containing adjuvant 23 valency pneumonia combined vaccines also has good immunogenicity, and tangible immunological memory is arranged.
The above only is a preferred implementation of the present invention; should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the technology of the present invention principle; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (10)
1. multivalent pneumococcal capsular polysaccharide combined vaccine, it is characterized in that, comprise the 23 kinds of pneumococcal capsular polysaccharides of serotype of separation and purification and the conjugate of carrier protein, described 23 kinds of pneumococcal serotypes of serotype are 1,2,3,4,5,6B, 7F, 8,9V, 9N, 10A, 11A, 12F, 14,15B, 17F, 18C, 19F, 19A, 20,22F, 23F and 33F.
2. combined vaccine according to claim 1 is characterized in that, also comprises adjuvant, and described adjuvant is for containing aluminum salt adjuvant.
3. combined vaccine according to claim 2 is characterized in that, the mass ratio of described capsular polysaccharide and carrier protein is 0.2～3: 1.
4. combined vaccine according to claim 3 is characterized in that, described carrier protein is diphtheria toxoid or choleratoxin B subunit.
5. combined vaccine according to claim 4 is characterized in that, described carrier protein is a choleratoxin B subunit.
6. combined vaccine according to claim 1 is characterized in that, described pneumococcal capsular polysaccharide carries out purification as follows:
1) in the streptococcus pneumoniae culture, adds NaTDC, sterilize;
2) the centrifugal thalline that goes is collected supernatant;
3) add ethanol and make its final concentration reach 30～50%, centrifugal removal nucleic acid;
4) add ethanol and make its final concentration reach 60～80%, centrifugal, collecting precipitation;
5) dissolution precipitation again, the cold phenol extracting that adds 1-2 times of volume is removed albumen for several times;
6) add ethanol and make its final concentration reach 60%～80%, centrifugal, collecting precipitation thing, the streptococcus pneumoniae polysaccharides of acquisition purification.
7. combined vaccine according to claim 1 is characterized in that, this vaccine is any in spray-type, liquid dosage form, freeze-dried formulation, capsule formulation, tablet and the pill.
8. the method for preparing each described combined vaccine of claim 1～7, it is characterized in that, comprise the steps: to separate and purification 1,2,3,4,5,6B, 7F, 8,9V, 9N, 10A, 11A, 12F, 14,15B, 17F, 18C, 19F, 19A, 20,22F, 23F and the pneumococcal capsular polysaccharide of 33F serotype, described capsular polysaccharide is carried out covalent coupling with carrier protein respectively obtain the unit price conjugate, described unit price conjugate is mixed obtaining the multivalence combined vaccine.
9. the application of each described combined vaccine of claim 1～7 in the medicine of the disease of preventing or treating streptococcus pneumoniae to bring out.
10. application according to claim 9 is characterized in that, carries out immunity by following manner: skin, injection, oral, collunarium or mucosa spraying.
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