WO2015144031A1 - Vaccin polysaccharidique conjugué à une protéine efficace contre le pneumocoque et sa méthode de préparation - Google Patents

Vaccin polysaccharidique conjugué à une protéine efficace contre le pneumocoque et sa méthode de préparation Download PDF

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WO2015144031A1
WO2015144031A1 PCT/CN2015/074925 CN2015074925W WO2015144031A1 WO 2015144031 A1 WO2015144031 A1 WO 2015144031A1 CN 2015074925 W CN2015074925 W CN 2015074925W WO 2015144031 A1 WO2015144031 A1 WO 2015144031A1
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protein
polysaccharide
pneumococcal
capsular polysaccharide
capsular
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PCT/CN2015/074925
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Chinese (zh)
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朱涛
宇学峰
邱东旭
毛慧华
邵忠琦
刘正
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天津康希诺生物技术有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/02—Bacterial antigens
    • A61K39/09—Lactobacillales, e.g. aerococcus, enterococcus, lactobacillus, lactococcus, streptococcus
    • A61K39/092—Streptococcus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/6415—Toxins or lectins, e.g. clostridial toxins or Pseudomonas exotoxins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/646—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent the entire peptide or protein drug conjugate elicits an immune response, e.g. conjugate vaccines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the invention relates to the field of immunology, in particular to a pneumococcal polysaccharide protein conjugation vaccine and a preparation method thereof.
  • Infections caused by pneumococci are a major cause of morbidity and mortality worldwide.
  • Pneumonia, febrile bacteremia, and meningitis are the most common manifestations of invasive pneumococcal disease, and bacterial spread in the respiratory tract can lead to middle ear infections, sinusitis, or recurrent bronchitis.
  • Non-invasive manifestations are usually less severe than invasive diseases, but are more common. Due to the spread of antibiotic-resistant infectious diseases, and pneumococcal pneumonia often appear after influenza infection, the possibility of pneumococcal disease attacking during the flu is further increased. Diseases caused by S. pneumoniae have become an important public health problem worldwide. Pneumococcal has become the number one killer of children worldwide.
  • the mortality rate of pneumonia in China is 16.4%, among which middle-aged and elderly people over 50 years old and infants under 1 year old are as high as 28.6% and 22.0% respectively.
  • the pneumococcal rate in China is high in healthy children. According to statistics, the carrying rate of healthy children in the northern region is 24.2%, and that in the southern region is 31.3%.
  • the disease is an important cause of death in children under five years of age. The main reason is that the development of the immune system in infants and young children is not perfect and the immunity is weak. And the younger the baby, the weaker the immunity.
  • the 23-valent pneumococcal vaccine produced by the Chengdu Bioindustry Research Institute of China Biotechnology Group selected 23 of the most common pathogens (1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, 33F), respectively, fermented and isolated and purified various types of polysaccharides on the pneumococcal capsule, and mixed in equal proportions to prepare a vaccine.
  • the bacterial polysaccharide is a thymus-independent antigen.
  • the main difference between this antigen and the thymus-dependent antigen is that the former does not require the help of T lymphocytes to produce antibodies. Therefore, the polysaccharide vaccine has the following problems: (1) it can only produce a weak immune response in young animals or infants, and even does not produce an immune response, the immune response increases with age; (2) produces low-affinity antibodies; 3) only produce short-lived immunity The reaction does not have the immunological memory and immune enhancement effect at the time of repeated vaccination; (4) It is easy to produce immune tolerance; (5) The common adjuvant does not easily exert an immune enhancement effect on the antigen.
  • the 23-valent polysaccharide vaccine has a protection rate of 50-70% for invasive lung chain infection. It can only be used for vaccination in people over 2 years of age, and the peak age of onset of pneumonia is 6-12 months old.
  • the polysaccharide protein conjugation vaccine (conjugate vaccine) is currently the most advanced vaccine technology, and the addition of a protein carrier to a specific antigen can increase its immunogenicity.
  • the protein carrier has T cell-dependent properties, and the polysaccharide protein conjugate vaccine can convert the non-T cell-dependent polysaccharide antigen into a T cell-dependent antigen, which stimulates the body's T helper cells to produce a series of immune enhancement effects.
  • the capsular polysaccharide conjugate vaccine adds a protein carrier to the polysaccharide and changes from a non-T cell-dependent antigen to a T cell-dependent antigen, increasing its immunogenicity.
  • the antibody produced after vaccination is 400-1000 times higher in quality and quantity than the first-generation vaccine, resulting in wider and stronger immune protection and longer protection time for efficient protection.
  • Pfizer Inc. developed a more targeted 7 (4, 6B, 9V, 14, 18C, 19F and 23F) pneumococcal protein vaccine for infants and young children. It is also effective for children under 5 years of age.
  • the capsular polysaccharide protein conjugate vaccine which adds a protein carrier to the polysaccharide and changes from a non-T cell-dependent antigen to a T cell-dependent antigen, can increase its immunogenicity and can be used for children over 6 weeks of age.
  • Pfizer is currently registering a 13-valent conjugate vaccine in China, adding six serotypes (1, 3, 5, 7F, 6A, 19A).
  • Pfizer 7-valent pneumococcal conjugate vaccine is only about 50%.
  • the coverage of the 13-valent conjugate vaccine is only 70%.
  • Wyeth's 7-valent pneumococcal conjugate vaccine requires 4 doses of injection, 860 yuan per needle, which is expensive and not conducive to promotion.
  • the 13-valent vaccine is estimated to be more expensive. Therefore, Pfizer's 7- and 13-valent conjugate vaccines are not suitable for the prevention of large-scale pneumonia in children in China.
  • the technical problem to be solved by the present invention is to provide a pneumococcal polysaccharide protein conjugation vaccine.
  • Another technical problem to be solved by the present invention is to provide a method for preparing the above pneumococcal polysaccharide protein conjugation vaccine.
  • the technical solution of the present invention is:
  • a pneumococcal polysaccharide protein conjugation vaccine comprising one or more pneumococcal capsular polysaccharides
  • the protein is coupled to the bound immunoconjugate, wherein at least one immunoconjugate of the immunoconjugate is formed by coupling a single S. pneumoniae capsular polysaccharide to two or more proteins.
  • the above pneumococcal polysaccharide protein conjugation vaccine comprising an immunological composition of a multivalent pneumococcal conjugate, is a method for isolating and purifying a capsular polysaccharide on a plurality of serotypes of pneumococcal capsules and coupling the protein (carrier protein) After mixing.
  • the protein for binding to the capsular polysaccharide is a protein that can be used for direct coupling with a capsular polysaccharide or by a chemical linker.
  • the pneumococcal polysaccharide protein conjugating vaccine is diphtheria toxoid, tetanus toxoid, carrier protein CRM197, Haemophilus influenzae surface protein HiD, pertussis Prn Surface protein, pertussis Fha antigen and/or S. pneumoniae surface protein PspA.
  • one or two or more proteins for binding to the capsular polysaccharide are one of the protective antigens and the other protein is There is no limit and you can choose any one.
  • the pneumococcal polysaccharide protein conjugating vaccine the two or more proteins for coupling with the capsular polysaccharide, one of which is a Haemophilus influenzae surface protein HiD or a PspA protein .
  • the pneumococcal polysaccharide protein conjugate vaccine wherein the S. pneumoniae capsular polysaccharide is a capsular polysaccharide isolated and purified on a serotype pneumococcal capsule, the serotype of the serotype pneumococcal includes 1, 2, 3 , 4, 5, 6A, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and/or 33F.
  • the method for preparing the pneumococcal protein vaccine, the coupling method of the capsular polysaccharide and the carrier protein in the step (3) comprises:
  • the capsular polysaccharide is coupled to the carrier protein by CDAP (1-amino-4-dimethyl-pyridine-boron tetrafluoride) and triethylamine activation.
  • CDAP 1-amino-4-dimethyl-pyridine-boron tetrafluoride
  • This reaction is an isourea linkage reaction.
  • CDAP reacts with the hydroxyl groups on the polysaccharide residue to convert to cyanate esters, and the amino groups on the carrier protein react rapidly to form the isourea linkage.
  • the method is simple to operate and easy to repeat; or
  • the capsular polysaccharide is coupled to the carrier protein and can also be linked to the amino or carboxyl group on the carrier protein by fragmenting the polysaccharide, derivatizing the linker.
  • the preparation method of the pneumococcal polysaccharide protein conjugation vaccine described above the five methods of coupling the capsular polysaccharide and the carrier protein in the step (3) can be used to link the surface protein of the lung chain polysaccharide, the present invention
  • the above type (2) is preferred.
  • connection manner of a capsular polysaccharide coupled with two or more proteins in the step (3) comprises:
  • the preparation method of the above pneumococcal polysaccharide protein conjugation vaccine comprises the following steps:
  • the 24 serotypes are 1, 2, 3, 4, 5, 6A, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B , 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F;
  • the above pneumococcal protein vaccine is used in the preparation of a medicament for inducing an immune response against a Streptococcus pneumoniae capsular polysaccharide conjugate and a carrier protein.
  • the above pneumococcal polysaccharide protein conjugation vaccine is an immunoconjugate containing two or more different carrier proteins, which is more immunogenic than the existing pneumococcal conjugate vaccine and can be used in a wider population.
  • the protective protein epitopes also induce a higher immune response than the mixed injection of the two proteins, synergistically, further enhancing
  • the immunogenicity of the carrier protein increases the body's immune response to polysaccharides; its preparation method is simple and suitable for large-scale industrial production.
  • capsular polysaccharide and carrier protein Obtain capsular polysaccharide and carrier protein:
  • the molecular size of the activated polysaccharide was determined using a gel filtration chromatography column and multi-angle laser light scattering using a dextran molecular size standard to calibrate.
  • the content of the polysaccharide was determined by the anthrone method, and the amount of the introduced aldehyde group was determined by the method described in Park, JT and Johnson, MJ (1949) Journal of Biological Chemistry, 18l, pages 49-151.
  • the structural integrity of the activated polysaccharide was determined by proton 1H and 13C NMR.
  • the purity of the activated polysaccharide is determined by measuring the LAL (endotoxin) content.
  • Each activated 7F polysaccharide was separately placed in a triangular flask, and the polysaccharide was diluted to 11 g/L with purified water, and then 1/9 volume of sterile phosphate buffer (500 mM) was added, and 5 g/L of CRM197 was added according to Table 2.
  • sterile phosphate buffer 500 mM
  • 5 g/L of CRM197 was added according to Table 2.
  • Protein powder and 5 g/L pneumonia surface protein PspA powder, and stirred with magnetic stirring with magnetic seeds 2 g/L sodium cyanoborohydride was added, stirred and dissolved, and after 1.1 hours, 1.1 g/L sodium borohydride was added.
  • the molecular weight distribution of the polysaccharide protein conjugate was detected by CL-4B, SEC-MALLS method; the protein and polysaccharide species in the polysaccharide protein conjugate were determined by immunodouble amplification method; the polysaccharide was detected by anthrone method
  • the polysaccharide content of the protein conjugate; the total protein content of the polysaccharide protein conjugate detected by the Lowry method protein content, and the polysaccharide protein binding ratio (Ratio) of the conjugate was calculated by calculation; the CRM197 and PspA protein concentrations were detected by enzyme-linked immunosorbent assay .
  • Table 1 is the 7F type capsule described in Example 1.
  • the concentration of polysaccharide protein with sugar and two different carrier protein conjugates The concentration of polysaccharide protein with sugar and two different carrier protein conjugates.
  • the molecular size of the activated polysaccharide was determined using a gel filtration chromatography column and multi-angle laser light scattering using a dextran molecular size standard to calibrate.
  • the content of the polysaccharide was determined by the anthrone method, and the amount of the introduced aldehyde group was determined by the method described in Park, JT and Johnson, MJ (1949) Journal of Biological Chemistry, 18l, pages 49-151.
  • the structural integrity of the activated polysaccharide was determined by proton 1H and 13C NMR.
  • the purity of the activated polysaccharide is determined by measuring the LAL (endotoxin) content.
  • Each activated type 3 polysaccharide was placed in a triangular flask, and the polysaccharide was diluted to 11 g/L with purified water, and then 1/9 volume of sterile phosphate buffer (500 mM, pH 7.2) was added, followed by 5 g/L.
  • CRM197 protein powder and stirred with magnetic stirring with magnetic seeds, adding 2g / L sodium cyanoborohydride, stirring and dissolving, after 18 hours of reaction, adding ammonium sulfate to 1.5mol / L, with 1.5M ammonium sulfate solution + 50mM
  • the phosphate buffer pH 7.5
  • polysaccharide-protein single carrier conjugate After loading, it was washed with the above buffer for 5 column volumes, and finally eluted with 50 mM phosphate buffer and collected.
  • Polysaccharide-protein single carrier conjugate The polysaccharide-protein conjugate solution was subjected to 5 equal volumes of ultrafiltration with physiological saline in an ultrafiltration system equipped with a 100 KDa filter, and then concentrated to a polysaccharide concentration of 5 g/L, and 5 g/L of HiD protein was added, 1 g/ L sodium cyanoborohydride, stirred and dissolved, after reacting for 48 hours, 0.7 g/L sodium borohydride was added, and after mixing for 4 hours, ammonium sulfate was added to 1.5 mol/L, and 1.5 M ammonium sulfate solution + 50 mM phosphate buffer (pH 7.5) was used.
  • the column buffer was washed again with 5 buffer volumes, and finally eluted with 50 mM phosphate buffer and the polysaccharide-protein double carrier conjugate was collected.
  • the polysaccharide-protein conjugate solution was subjected to 15 equal volumes of ultrafiltration with physiological saline in an ultrafiltration system equipped with a 100 KDa filter, collected by reflux, and sterilized by filtration using a capsule filter, and stored at 4 °C.
  • the molecular weight distribution of the polysaccharide protein conjugate was detected by CL-4B, SEC-MALLS method; the protein and polysaccharide species in the polysaccharide protein conjugate were determined by immunodouble amplification method; the polysaccharide was detected by anthrone method
  • Table 2 is the type 3 capsular polysaccharide described in Example 2.
  • Single carrier conjugates such as 4,6B, 9V, 14, 18C, 19F, 23F are prepared according to methods well known in the art, wherein the carrier protein is CRM197.
  • a double carrier conjugate of a polysaccharide of type 1,3,5,6A,7F,19A was prepared according to the method described in Example 1 or 2, wherein the polysaccharide of type 1,5,7F was PspA as a second carrier, 3,6A,19A HiD is used as the second carrier.
  • Various binding products were prepared as described in Table 3 below. After these monovalent components were mixed, an aluminum phosphate adjuvant having a final concentration of 0.5 mg/L was added.
  • the procedure was performed 3 times at weeks 0, 2, and 4, and 0.5 ml per young rat (0.5 ug conjugate). Blood was collected from each experimental group 7 days after the third injection, and the serum was separated and stored at -20 ° C until use.
  • indirect ELISA was used to dissolve each type of pneumonia polysaccharide and carrier protein in 0.05 mol/L pH 9.6 carbonate buffer solution, and the enzyme label was coated at a concentration of 20 ug/ml. Plate, 2% BSA liquid blocked.
  • the serum to be tested was diluted with 100, 200, 400, 800, 1600, 3200, 6400, 12800, 25600, 51200, 102400, 204800, 409600 times, added to the enzyme standard plate, and reacted at 37 ° C for 40 min. Root peroxidase-labeled goat anti-mouse secondary antibody. A serum-free buffer was also added as a negative control.
  • the color was developed with tetraaminobenzidine, and the A value was read at a wavelength of 450 nm. Calculate the ratio of the A value to the negative hole A in each well, but the ratio is greater than the maximum dilution factor in the 2.1 era.
  • the antibody titer in the serum, the geometric mean of the titer of 10 mice, and the logarithm of the base 10 The results are shown in Table 4.

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Abstract

La présente invention concerne un vaccin polysaccharidique conjugué à une protéine efficace contre Streptococcus pneumonia, et sa méthode de préparation. Le vaccin polysaccharidique conjugué à une protéine efficace contre Streptococcus pneumonia selon l'invention comprend un ou plusieurs conjugués immunitaires couplant le polysaccharide capsulaire de Streptococcus pneumonia à la protéine. Au moins l'un des conjugués immunitaires est formé par couplage d'un seul polysaccharide capsulaire de Streptococcus pneumonia à au moins deux protéines.
PCT/CN2015/074925 2014-03-26 2015-03-24 Vaccin polysaccharidique conjugué à une protéine efficace contre le pneumocoque et sa méthode de préparation WO2015144031A1 (fr)

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CN109091668A (zh) * 2017-06-20 2018-12-28 浙江博和瑞达生物科技有限公司 16价肺炎链球菌结合疫苗组合物
WO2021228167A1 (fr) * 2020-05-15 2021-11-18 神州细胞工程有限公司 Procédé permettant d'améliorer l'immunogénicité d'un antigène par formation d'un glycoconjugué de protéine de fusion de fragment fc

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CN115721711B (zh) * 2022-10-28 2024-01-23 普大生物科技(泰州)有限公司 一种肺炎球菌荚膜多糖-带状疱疹病毒重组蛋白结合疫苗及其制备方法

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