CN108245674A - A kind of prescription of multivalent pneumococcal conjugate combination-vaccine and preparation method thereof - Google Patents
A kind of prescription of multivalent pneumococcal conjugate combination-vaccine and preparation method thereof Download PDFInfo
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- A61K2039/6037—Bacterial toxins, e.g. diphteria toxoid [DT], tetanus toxoid [TT]
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Abstract
本发明涉及一种多价肺炎球菌结合物组合疫苗的处方及其制备方法，所述组合疫苗由选自肺炎球菌血清型2、8、9N、10A、11A、12F、15B、17F、20、22F和33F的肺炎球菌荚膜多糖与生理上可接受的载体蛋白质制备而成。本发明通过选择适合不同型别肺炎球菌多糖的结合方法制备多糖蛋白结合物原液，并将它们进行组合制备疫苗。该组合疫苗，用于预防非上市肺炎球菌多糖蛋白结合疫苗血清型肺炎球菌引起的感染性疾病。The invention relates to a prescription and a preparation method of a multivalent pneumococcal conjugate combination vaccine, wherein the combination vaccine is selected from pneumococcal serotypes 2, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20, 22F and 33F pneumococcal capsular polysaccharide and physiologically acceptable carrier protein. The invention prepares polysaccharide-protein conjugate stock solution by selecting suitable binding methods for polysaccharides of different types of pneumococcus, and combines them to prepare vaccines. The combined vaccine is used to prevent infectious diseases caused by serotype pneumococcus, which is not on the market.
Description
Technical field
The present invention relates to a kind of prescriptions of multivalent pneumococcal conjugate combination-vaccine and preparation method thereof.It is suitable by selecting
The combined method for closing different type polysaccharide prepares conjugate stoste, and they are combined and prepares vaccine.The combination-vaccine is used
The infectious diseases caused by non-listing pneumococcal Polysaccharide Conjugate Vaccine Pneumococcal serotype is prevented.The combination-vaccine by
Selected from serotype 2,8,9N, 10A, 11A, 12F, 15B, 17F, 20, the pneumococcal capsular polysaccharide of 22F and 33F and physiologically may be used
The carrier protein of receiving is prepared.
Background technology
Pneumococcus is the most important pathogenic bacteria of meningitis, bacteremia, pneumonia and tympanitis, while can cause whole body sense
Dye.Pneumococcus makes therapeutic scheme increasingly sophisticated, and thus lead the drug resistance of penicillin and other common antimicrobial agents
Cause treatment failure.Immunoprophylaxis preparation is considered as safely and effectively precautionary measures.
The immune formulation of prevention pneumococcal infection is divided into two kinds of polysaccharide vaccine and combined vaccine, and listing at present uses more
Saccharide vaccines are " 23 valency pneumococcal polysaccharide vaccine ", list the combined vaccine that uses for " 10 valent pneumococcal conjugate vaccine " and
" 13 valent pneumococcal conjugate vaccine ".Pneumococcal polysaccharide vaccine can be used for 2 years old or more crowd, be mainly used for over-65s old age
Immunoprophylaxis of the people to disease.Pneumococcal conjugated vaccine has numerous advantages better than polysaccharide vaccine, applies generally to each year
Age crowd is a main direction of studying of current Pnu-Imune 23.
" 10 valent pneumococcal conjugate vaccine " containing pneumonia serum type 1,4,5,6B, 7F, 9V, 14,18C, 19F and 23F,
" 13 valent pneumococcal conjugate vaccine " contains pneumonia serum type 1,3,4,5,6A, 6B, 7F, 9V, 14,18C, 19A, 19F and 23F.
Known pneumonia serum type has 90 kinds, as " 10 valent pneumococcal conjugate vaccine " and " 13 valent pneumococcal conjugate vaccine " is complete
The use of ball while immunity inoculation reduces vaccine serotype pneumococcus bacterial bearing rate, can lead to nonvaccine serotype pneumonia ball
The increase of bacterium bacterial bearing rate.
Before " 7 valent pneumococcal conjugate vaccine " listing during research, there are 9 as caused by nonvaccine serotype pneumococcus
Affecting conditions, wherein control group 6, test group 3 [Black S, et al, 2000].In one research of Israel, with reference to
Vaccine can effectively reduce vaccine serotype pneumococcus pharynx nasalis bacterial bearing rate, but nonvaccine serotype pneumococcus bacterial bearing rate from
15%-20% before inoculation increases to 32%-39%, total pneumococcus bacterial bearing rate do not change [Dagan R, et al,
1996].Show that serotype distribution is converted.The reduction simultaneous nonvaccine serotype of vaccine serotype disease causes
The increase of disease, such case are known as " substituting disease ".The earliest evidence of disease is substituted from a 7 valency pneumococcus knots of evaluation
Close the clinical test [Eskola J, et al, 2001] that vaccine prevention Finnish children (is less than 2 years old) tympanitis (AOM).Disease is pre-
Children caused by the ABCs project datas of anti-control centre (CDC) show nonvaccine serotype pneumococcus (are less than 5 years old) invasion
Property disease number of cases averagely increased 21% [Centers for Disease Control and between 1998/1999 and 2003 year
Prevention, 2005].Analysis shows pneumococcus may pass through to adapt to the use of vaccine and constantly obtain gene object
Matter and change capsular serotypes.In one tympanitis research of Finland, pneumococcal conjugated vaccine can reduce vaccine serotype band
Bacterium rate, so as to open an ecological niche for tympanitis, can be invaded by nonvaccine serotype pneumococcus [Kilpi T, et al,
2003] [Eskola J, et al, 2001] [Straetemans M, et al, 2003].
So far, disease increasing degree caused by nonvaccine serotype pneumococcus is led with vaccine serotype pneumococcus
Causing the reduction amplitude of disease, harm should not be underestimated compared to also very little, but its trend can not be ignored.Nonvaccine serotype pneumonia ball
Bacterium is propagated in crowd, it is meant that nonvaccine serotype pneumococcus will be as the main pathogen of aggressive pneumonia.To contain this
The sprawling of trend needs to consider to combine nonvaccine serotype pneumococcus conjugate, for preventing nonvaccine serotype pneumonia
Infectious diseases caused by coccus.
A kind of thinking of infectious diseases is by serotypes as more as possible caused by preventing nonvaccine serotype pneumococcus
Pneumococcal capsular polysaccharide be attached in a kind of combined vaccine, such as include the polysaccharide combination epidemic disease of 24 Pneumococcus serotypes
Seedling, so as to which once and for all solves the problems, such as prevention pneumococcal infection.Although in combined vaccine the type of contained polysaccharide it is more more more
It is good, but technically there is certain challenges.Which part is the reason is that production technology is more difficult.In addition, in vaccine formulation
Carrier protein total amount must limit, too many carrier protein can influence to polysaccharide antigen immune response [Herzenberg LA,
Et al, 1982] [Renjifo X, et al, 1998] [Dagan R, et al, 1998].Carrier protein is immunized in T cell
Property is to critically important in the immune response of polysaccharide, but B cell may be unfavorable for carrier antibody to the immunity of carrier protein
It induces [Barington T, et al, 1994] [Barington T, et al, 1993].When polysaccharide and protein specific B are thin
For born of the same parents in the case where conjugate is captured in competition, a large amount of anti-carrier protein antibody may inhibit the immune response [Dagan to polysaccharide
R, et al, 1998] [Fattom A, et al, 1999] [Insel RA, 1995] [Peeters CC, et al, 1991]
[Barington T, et al, 1993].If combined vaccine be must take into consideration into work for older children and adult
The latent effect of carrier protein for booster vaccine.In a research, combined vaccine can induce adult and child couple
Immune response that lockjaw and diphtheria carrier protein are significantly strengthened [0lander RM, et al, 2001].
The present invention, which selects, is not included in the pneumococcal conjugated vaccine of any listing at present but included in " 23 valency pneumonia
The pneumococal polysaccharide of Streptococcus polysaccharides vaccine " serotype prepares various conjugate, then conjugate is prepared using suitable method
For multivalent pneumococcal combined vaccine, component contained by the combined vaccine is few, and production technology is also relatively simple, covers simultaneously
Pathogenic and popular higher Pneumococcus serotypes in " 23 valency pneumococcal polysaccharide vaccine ", with having listed pneumococcus knot
It closes vaccine to be used cooperatively, can effectively prevent infectious diseases caused by non-listing combined vaccine Pneumococcal serotype, to control
The infection of pneumococcus has important value.
Invention content
The present invention relates to a kind of prescriptions of multivalent pneumococcal conjugate combination-vaccine and preparation method thereof.It is suitable by selecting
The combined method for closing different type polysaccharide prepares conjugate stoste, and they are combined and prepares vaccine.The combination-vaccine is used
The infectious diseases caused by non-listing pneumococcal conjugated vaccine Pneumococcal serotype is prevented simultaneously has synergistic function.
The combination-vaccine is by being selected from serotype 2,8,9N, 10A, 11A, 12F, 15B, 17F, 20, the pneumococcal capsule of 22F and 33F
Polysaccharide is prepared with physiologically acceptable carrier protein.
The preparation method of multivalent pneumococcal conjugate combination-vaccine of the present invention, be by be selected from serotype 2,8,
9N, 10A, 11A, 12F, 15B, 17F, 20, the pneumococal polysaccharide conjugate combination of 22F and 33F are prepared.
Wherein, the pneumococcus conjugate is corresponding Pneumococcus serotypes capsular polysaccharide and physiologically acceptable load
Polysaccharide protein conjugate prepared by body protein matter.
Wherein, the pneumococcal capsular polysaccharide is：2nd, 8,9N, 10A, 11A, 12F, 15B, 17F, 20,22F and 33F blood
Clear type.
Wherein, the pneumococcus conjugate combination-vaccine is：2nd, 8,9N, 10A, 11A, 12F, 15B, 17F, 20,22F and
The combination of two or more arbitrary conjugates in 33F serotypes.
For this purpose, the present invention provides a kind of multivalent pneumococcal conjugate combination-vaccine, the combination-vaccine is by being selected from pneumonia
Pneumoniae serotype type 2,8,9N, 10A, 11A, 12F, 15B, 17F, 20, the pneumococcus conjugate combination of 22F and 33F are prepared,
Between polysaccharide protein quality ratio in the pneumococcus conjugate is 1: 1-1: 2.
Preferably, combination-vaccine of the present invention contains Pneumococcus serotypes 2,8,9N, 10A, 11A, 12F.
Or
Contain Pneumococcus serotypes 11A, 15B, 17F, 20,22F, 33F.
Or
Contain Pneumococcus serotypes 8,9N, 10A, 20,22F, 33F.
Wherein, the polysaccharide protein quality ratio in the pneumococcus conjugate is all pneumonia in 1: 1 or each combination
Coccus conjugate polysaccharide concentration is 4 μ g/ml.
Wherein, the physiologically acceptable carrier protein is selected from：Diphtheria toxoid (DT) and its cross reacting material
(CRM), CRM be it is a kind of form the substance reacted with diphtheria antitoxin (DAT), containing such as CRM197, CRM9, CRM173, CRM228 and
CRM45；Tetanus toxoid (TT), pertussis toxoid (PT), choleratoxin B subunit, thermo-labile escherichia coli enterotoxin
(LT), thermotolerant coliform enterotoxin (sT), Pseudomonas aeruginosa Exotoxin A (EPA)；Outer membrane protein composite (OMPC), pneumonia ball
Bacterium hemolysin (PLY), Pneumococal surface protein A (PspA), pneumococcal adhesin protein A (PsaA), haemophilus influenzae egg
White D.Carrier protein preferred DT, TT and CRM197, most preferably DT.
The preparation method of multivalent pneumococcal conjugate combination-vaccine of the present invention, may be used below in conjunction with side
Method：
1. directly in conjunction with method：
It is coupled using reactive group intrinsic on polysaccharide structures directly or by interval dose and carrier protein.Such as using more
Carboxyl in sugared structure by carbodiimide-mediated, is combined with adipyl dihydrazide, then is reacted with the carboxyl on carrier protein,
Form polysaccharide protein conjugate.
2. cyano activation method：
It is connected by the adjacent hydroxyl in cyanogen root activated polysaccharide structure, then with interval dose adipyl dihydrazide, it is more prepares derivative
Sugar.Polysaccharide derivative and carrier protein form O- under carbodiimide-mediated, by the carboxyl on carbodiimide and carrier protein
Acyl isourea intermediate, then react to form polysaccharide protein conjugate with the amido on polysaccharide derivative.
The cyanide reagent that this cyano activation method uses is usually cyanogen bromide, 1 cyano, 4 dimethyl aminopyridine tetrafluoro
Change boron etc..The interval dose of use includes two hydrazine class compounds such as succinic acid hydrazide ii, adipyl dihydrazide, further includes diamino second
The diamino alkyl compound such as alkane, diaminopropanes, diaminobutane, diamino hexane, also including two succinyl of adipic acid Asia
The ester type compounds such as amine ester are further included containing the inconsistent interval dose of reactive functionality, such as amineothiot.Also have and do not use interval
Agent after CDAP activated polysaccharides, directly reacts with the amino of carrier protein and prepares polysaccharide protein conjugate.
3. Amine reduction：
Polysaccharide is oxidized or hydrolysis after, aldehyde radical can be generated in end, aldehyde radical can react to form schiff bases structure with amino, then
It is restored through reducing agent, forms stable C-N structures, form polysaccharide protein conjugate.
Mostly using sodium periodate method, periodic acid is a kind of oxidant for polysaccharide oxidation.Polysaccharide contains abundant glycol-based
(CHOH-CHOH), two terminal aldehyde groups after periodate oxidation, are broken to form.The characteristics of periodic acid is not aoxidize further
Generated aldehyde radical.
4. other combined methods：
Including oxime chemical reaction, diazo-reaction, disulfide bond coupled reaction etc..N- succinimide -3- dithiopyridines
Propionic acid (SPDP) is common disulfide bond coupled reaction reagent, and first SPDP is connected on amino-containing component, and containing sulfydryl
Sulfydryl exchange reaction occurs for component, forms the polysaccharide protein conjugate connected with disulfide bond.
The preparation method of multivalent pneumococcal conjugate combination-vaccine of the present invention, polysaccharide in pneumococcus conjugate
Between mass ratio with protein is 1: 1-1: 2, wherein the quality is with the Mass Calculation of capsular polysaccharide.For example, in this hair
In bright multivalent pneumococcal conjugate combination-vaccine, in unit dose, the content of various capsular polysaccharide can be 0.1-10 μ g；
Preferred content is 0.5-5 μ g；Most preferred content is 1-4 μ g.In the conjugate combination-vaccine of the present invention, the content of various polysaccharide can
With identical, can also be different.
The preparation method of multivalent pneumococcal conjugate combination-vaccine of the present invention, may also include needed for vaccine preparation
The necessary auxiliary material wanted, such as may include adjuvant and/or buffer solution.The adjuvant be selected from aluminium adjuvant, as aluminium hydroxide, aluminum phosphate,
Aluminum sulfate etc.；Or oil-in-water or bacteria cell wall composition, such as MF59, SAE, RAS；Or saponin adjuvant, as Quil A,
QS-21；Or bacteria lipopolysaccharide or synthesis lipoid A adjuvants；Or cell factor, such as interleukins, interferon, colony-stimulating
The factor, tumor necrosis factor, costimulation molecules B7-1, B7-2 etc.；Or toxin subunit class adjuvant, such as cholera toxin and sub- list
Position, pertussis toxin, E.coli LT etc..The buffer solution is selected from phosphate buffer or Tris buffer solutions,
It can also be physiological sodium chloride solution.Buffer concentration can be 0.01-0.05mol/L, preferably 0.01-0.02mol/L, optimal
Select 0.01mol/L.
The preparation method of multivalent pneumococcal conjugate combination-vaccine of the present invention, also may include stabilizer and/or
Dispersant.Stabilizer is selected from amino acid, and amino acid can be histidine, preferably L-Histidine, excellent using concentration 1-00mmol/L
Select 2-50mmol/L, most preferably more preferable 3-10mmol/L, 5mmol/L.Histidine can occur in the form of histidine buffering liquid.
Dispersant be selected from poly sorbitol ester, preferably Tween 80, using concentration 0.01-1%, more preferable 0.01-0.1%, most preferably
0.02-0.05%.
The preparation method of multivalent pneumococcal conjugate combination-vaccine of the present invention can be made for each of clinic
Kind dosage form, the dosage form are selected from liquid dosage form, freeze-dried formulation, preferred liquid dosage form.
Multivalent pneumococcal conjugate combination-vaccine of the present invention, route of inoculation include intramuscular injection, subcutaneous note
It penetrates, intracutaneous injection approach.
Multivalent pneumococcal conjugate combination-vaccine of the present invention after immune mouse and rat, can be generated and be directed to
The specific IgG antibodies of each Pneumococcal serotype polysaccharide, each serotype specificity antibody titer of generation is higher, Conversion rate base
Originally 100% is attained by, does not occur immune interference situation.
Illustrate beneficial effects of the present invention below by way of experimental data：The present invention prepares the combination of multivalent pneumococcal conjugate
Mouse immunity is tested：
The present invention is combined than right 3 pneumococcus conjugates, is combined for 6 valency conjugates, carrier protein is DT, institute
There is conjugate all to be prepared using Amine reduction.Wherein combination 1 contains Pneumococcus serotypes 2,8,9N, 10A, 11A, 12F, combination
2 containing Pneumococcus serotypes 11A, 15B, 17F, 20,22F, 33F, combination 3 containing Pneumococcus serotypes 8,9N, 10A, 20,
22F、33F.All pneumococcus conjugate polysaccharide concentrations are 4 μ g/ml in each combination.The Aluminium phosphate adjuvant group of each group setting simultaneously
Control.3 conjugate combinations are distinguished into subcutaneous inoculation NIH mouse with 3 control groups, every mouse immune 0.1ml is immunized 3 altogether
Needle, every needle interval 2 weeks, 4 weeks after final immunization, takes each Pneumococcus serotypes specific IgG antibodies titre of hematometry, with feminine gender
Comparison mean value add 2 times of SD as cutoff values judge serum antibody titer, antibody titer take the logarithm post analysis processing；With antibody
4 times or more increase evaluation Conversion rate, the results are shown in Table 1.It was found that each Pneumococcus serotypes specific antibody drop that 3 combinations generate
Degree is higher, and Conversion rate all reaches 100%；Situation containing adjuvant and without adjuvant group induction of antibodies titre, does not find notable difference.
1. multivalent pneumococcal conjugate of table combines Mouse immunogenicity
Specific embodiment：
With reference to embodiment, the present invention will be further described, and protection scope of the present invention is not limited to following institute
It states：
Embodiment 1：Multivalent pneumococcal conjugate combines prescription
Per 0.5ml dosage containing various pneumococal polysaccharide totally 22 μ g (polysaccharide total amount), wherein 2,8,9N, 10A, 11A, 12F,
15B, 17F, 20,22F and each 2 μ g of 33F.Various polysaccharide is adsorbed in Aluminium phosphate adjuvant (aluminium content after being combined with diphtheria toxoid
0.125mg), solvent is physiological sodium chloride solution.
Embodiment 2：Purify pneumococal polysaccharide verification result
11 kinds of pneumococcal capsular polysaccharides are purified respectively, per 3 batches, type, the quality arbitration result such as table 2 of each batch：
Embodiment 3：Pneumococcus conjugate verification result
With the pneumococcus conjugate of 11 kinds of types prepared by Amine reduction, various pneumococal polysaccharide and diphtheria toxoid
With reference to each type 3 batches, the verification result of each batch conjugate is shown in Table 3：
Embodiment 4：11 valency pneumonia conjugates combine Mouse immunogenicity
Various pneumococcus conjugate polysaccharide concentration is 4 μ g/ml in combination, after various polysaccharide is combined with diphtheria toxoid
It is adsorbed in Aluminium phosphate adjuvant (aluminium content 0.25mg/ml).Subcutaneous inoculation NIH mouse, every mouse immune 0.1ml are immunized 3 altogether
Needle, every needle interval 2 weeks, 4 weeks after final immunization, separation serum measures each Pneumococcus serotypes specific IgG antibodies titre, with
Negative control average value add 2 times of SD as cutoff values judge serum antibody titer, antibody titer take the logarithm post analysis processing；With
4 times of antibody or more increases evaluation Conversion rate, the results are shown in Table 4.
4.11 valency pneumococcus conjugate of table combines Mouse immunogenicity
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113194987A (en) * | 2018-10-12 | 2021-07-30 | 生物E有限公司 | Multivalent pneumococcal polysaccharide-protein conjugated vaccines |
| CN113274489A (en) * | 2021-04-30 | 2021-08-20 | 山东省药学科学院 | Chitin oligosaccharide vaccine for preventing fungal infection and preparation method thereof |
| US11116828B2 (en) | 2017-12-06 | 2021-09-14 | Merck Sharp & Dohme Corp. | Compositions comprising Streptococcus pneumoniae polysaccharide-protein conjugates and methods of use thereof |
| CN115006522A (en) * | 2022-06-16 | 2022-09-06 | 北京智飞绿竹生物制药有限公司 | A kind of preparation method of bivalent dysentery conjugate combination vaccine |
| US11642406B2 (en) | 2018-12-19 | 2023-05-09 | Merck Sharp & Dohme Llc | Compositions comprising Streptococcus pneumoniae polysaccharide-protein conjugates and methods of use thereof |
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| US11116828B2 (en) | 2017-12-06 | 2021-09-14 | Merck Sharp & Dohme Corp. | Compositions comprising Streptococcus pneumoniae polysaccharide-protein conjugates and methods of use thereof |
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| CN113274489B (en) * | 2021-04-30 | 2023-08-29 | 山东省药学科学院 | Chitin oligosaccharide vaccine for preventing fungal infection and preparation method thereof |
| CN115006522A (en) * | 2022-06-16 | 2022-09-06 | 北京智飞绿竹生物制药有限公司 | A kind of preparation method of bivalent dysentery conjugate combination vaccine |
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