WO2018048141A1 - Composition comprenant une protéine multivalent de transport de polysaccharide capsulaire et son utilisation - Google Patents
Composition comprenant une protéine multivalent de transport de polysaccharide capsulaire et son utilisation Download PDFInfo
- Publication number
- WO2018048141A1 WO2018048141A1 PCT/KR2017/009569 KR2017009569W WO2018048141A1 WO 2018048141 A1 WO2018048141 A1 WO 2018048141A1 KR 2017009569 W KR2017009569 W KR 2017009569W WO 2018048141 A1 WO2018048141 A1 WO 2018048141A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- capsular polysaccharide
- protein
- composition
- conjugate
- capsular
- Prior art date
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Classifications
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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
-
- 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
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/02—Bacterial antigens
- A61K39/09—Lactobacillales, e.g. aerococcus, enterococcus, lactobacillus, lactococcus, streptococcus
-
- 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
- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55516—Proteins; Peptides
Definitions
- the present invention relates to vaccine compositions for the prevention of pneumococcal disease comprising 13 or 14 capsular polysaccharide-carrying protein conjugates and immunogenic compositions against pneumococci.
- Streptococcus pneumonia is a leading cause of meningitis, pneumonia and severe invasive diseases in infants and children around the world. More than 1.6 million people die each year from pneumococcal disease (2008 International Health Organization), and the incidence of invasive infectious diseases caused by pneumococcal in children under 5 years old and elderly people 65 years or older with low immunity high.
- Pneumococci are classified into more than 90 serotypes according to the structural and immunological characteristics of the capsular polysaccharides, the main pathogenic factors surrounding them, of which 20 to 80% in humans It is known to be associated with pathogenicity.
- the only host of pneumococci is humans, and they usually exist in colonies in the nasopharynx of healthy normal people (20-40% in infants, 5-10% in adults).
- the US Centers for Disease Control and Prevention (CDC) estimated that approximately 2.1 million children under 5 years of age died from pneumonia, and 1.2 million of them died from developing countries alone annually.
- pneumococcal meningitis and sepsis are reported to be about 3,000 and 50,000 cases per year, respectively (Peters TR, et al . (2007) JAMA (297) 1825-6; Invasive pneumococcal disease). .
- pneumoACTION which is a database of pneumococcal disease, showed that 24,047 cases of pneumococcal infections occurred in Korean children in 2000 and 47 of them died (www.pneumoadip.org).
- pneumococci are the most common cause of invasive infections (43.7%) in infants aged 3 to 59 months. appear.
- multidrug resistant bacteria that are resistant to not only penicillin but also to three or more drugs are increasing, further increasing the difficulty of treating pneumococcal infectious diseases. Therefore, the need for pneumococcal vaccination for children and the elderly, which is a high risk group of pneumococcal infectious diseases, has been continuously raised.
- multivalent pneumococcal polysaccharide vaccines have been developed and approved since 1977, and these capsular polysaccharide vaccines have proven useful in preventing pneumococcal disease in elderly and high-risk patients.
- the immune system since the maturity of the immune system is lower than that of adults, when only the polysaccharide vaccine is received, the immune system does not recognize the polysaccharide antigen as an external invading factor, so it is difficult to expect a role as a vaccine.
- a 7-valent pneumococcal conjugate vaccine a capsular polysaccharide-protein conjugated vaccine conjugated with a carrier protein that increases immunogenicity to polysaccharide antigens ( 7vPnC, Prevenar ® (Prevenar ®)) has been used in the development, has been reported to be effective for the prevention of invasive disease and otitis media in infants and children in many materials.
- 7vPnC Prevenar ®
- Prevenar ® Prevenar ®
- the use of the 7-valent vaccine induced a decrease in invasive disease caused by vaccine serotypes used in the vaccine, but also showed a relative increase in pneumococcal disease caused by some non-vaccine serotypes.
- the capsular polysaccharide-protein conjugate vaccine in renal flow Rix ® (Synflorix ®) and the landscape in Prevenar the vena ® A 13 add serotypes 6 species in the primary serotype of Streptococcus pneumoniae conjugate vaccine 13 ® (Prevenar13 ® Have been developed and are now commercially available, but the possibility that the efficacy as a vaccine may not be sufficient for some of the serotypes included is mentioned [Andrews NJ et al , (2014) Lancet Infec Dis (14) 839; EMEA Assessment Report for Prevenar 13 (2009) EMA / 798877/2009], showing higher and more stable titers due to the risk of developing serotype replacement by non-vaccinating pneumococcal serotypes not included in the vaccine. There is also a continuing need for the development of new vaccine formulations that can cover more diverse serotypes.
- Pribena 13 ® the highest serotype coverage of Pfizer's 13-valent vaccine, does not contain serotype 2 capsular polysaccharides, and cross-reactivity of the other 13 capsular polysaccharide antigens It is known to be absent.
- the present inventors have made efforts to develop a vaccine for preventing pneumococcal disease having a higher and more stable titer and higher coverage than a conventionally developed vaccine formulation, and as a result, the same serotype as the conventionally released 13-valent vaccine.
- a novel trivalent pneumococcal conjugate vaccine that is more effective by applying a conjugation process different from the existing trivalent vaccine, and also contains serotype 2 capsular polysaccharide antigen in 13 species of the trivalent vaccine.
- the present invention has been completed by developing a 14-valent pneumococcal conjugate vaccine, which has expanded coverage and optimized immunogenicity through optimization of the conjugation process.
- the 13-valent pneumococcal conjugate vaccine of the present invention contains 13 kinds of capsular polysaccharide antigens, and has a higher titer than the known 13-valent pneumococcal conjugate vaccine, and the 14-valent pneumococcal conjugate vaccine contains 14 kinds of capsular polysaccharide antigens. Including, it can provide a higher coverage and improved coverage compared to the existing vaccine, it is excellent in preventing invasive pneumococcal disease.
- One object of the invention comprises 13 capsular polysaccharide-carrying protein conjugates, wherein said 13 conjugates are Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A , 13B capsular polysaccharides derived from 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F are covalently conjugated to a carrier protein, the carrier protein is CRM197 protein, and the conjugate Is to provide a vaccine composition for the prevention of pneumococcal disease, in which the capsular polysaccharide and the transport protein have a structure linked by -OC (NH) -NH- group using a cyanylation method.
- 13 conjugates are Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A , 13B capsular polysaccharides derived from 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F are covalently conjugated to a carrier protein, the carrier protein is CRM197 protein, and the conjugate Is to provide
- Another object of the present invention comprises 14 capsular polysaccharide-carrying protein conjugates, wherein the 14 conjugates are Streptococcus pneumoniae serotypes 1, 2, 3, 4, 5, 6A, 6B, 7F, 9V, Each of the 14 capsular polysaccharides from 14, 18C, 19A, 19F, and 23F is covalently conjugated to a carrier protein, the carrier protein is CRM197 protein, and the conjugate is capsular polysaccharide and transport using a cyanylation method. It is to provide a vaccine composition for the prevention of pneumococcal disease, in which the protein has a structure linked by -OC (NH) -NH- group.
- Another object of the invention comprises 13 capsular polysaccharide-carrying protein conjugates, wherein said 13 conjugates are Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14,
- 13 conjugates are Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14,
- Each of 13 capsular polysaccharides derived from 18C, 19A, 19F and 23F is covalently conjugated to a carrier protein, the carrier protein is CRM197 protein, and the conjugate is used to obtain the capsular polysaccharide and carrier protein using a cyanation method. It is to provide an immunogenic composition for pneumococcal, which has a structure linked by -OC (NH) -NH- group.
- Another object of the present invention comprises 14 capsular polysaccharide-carrying protein conjugates, wherein the 14 conjugates are Streptococcus pneumoniae serotypes 1, 2, 3, 4, 5, 6A, 6B, 7F, 9V, Each of the 14 capsular polysaccharides from 14, 18C, 19A, 19F, and 23F is covalently conjugated to a carrier protein, the carrier protein is CRM197 protein, and the conjugate is capsular polysaccharide and transport using a cyanylation method. It is to provide an immunogenic composition for pneumococcal, in which the protein has a structure linked by -OC (NH) -NH- group.
- Still another object of the present invention is to provide a method for preventing pneumococcal disease by administering the vaccine composition or immunogenic composition to a subject in need thereof.
- Another object of the present invention comprises 13 capsular polysaccharide-carrier protein conjugates, wherein the 13 conjugates are Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F.
- Each of 13 capsular polysaccharides from 9V, 14, 18C, 19A, 19F and 23F is covalently conjugated to a carrier protein, the carrier protein is CRM197 protein, and the conjugate is cyanylated ( It is to provide a use for the use of the composition for the preparation of a vaccine composition for the prevention of pneumococcal disease, wherein the capsular polysaccharide and the carrier protein has a structure linked by -OC (NH) -NH- group using a cyanylation) method .
- Another object of the invention comprises 14 capsular polysaccharide-carrier protein conjugates, wherein the 14 conjugates are Streptococcus pneumoniae serotypes 1, 2, 3, 4, 5, 6A, 6B 14 capsular polysaccharides derived from 7F, 9V, 14, 18C, 19A, 19F and 23F are covalently conjugated to a carrier protein, the carrier protein is CRM197 protein, and the conjugate is Provided for use of the composition in the preparation of a vaccine composition for the prevention of pneumococcal disease, wherein the capsular polysaccharide and the carrier protein have a structure linked by -OC (NH) -NH- groups using a cyanylation method. It is.
- the 14 conjugates are Streptococcus pneumoniae serotypes 1, 2, 3, 4, 5, 6A, 6B 14 capsular polysaccharides derived from 7F, 9V, 14, 18C, 19A, 19F and 23F are covalently conjugated to a carrier protein, the carrier protein is CRM197 protein, and the
- the present invention in order to develop a novel vaccine formulation that can prevent pneumococcal disease with a more excellent effect, it differs from the conventionally released 13-valent vaccine and includes 13 capsular polysaccharide-carrying protein conjugates.
- a composition was prepared. Specifically, the composition is each of 13 capsular polysaccharides derived from Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F It includes 13 kinds of capsular polysaccharide-carrying protein conjugates prepared by covalently conjugation to CRM197, which is a carrier protein.
- the composition of the present invention can be expected to have a very good effect for the prevention of pneumococcal disease.
- Serotype 2 is a more frequent serotype than some serotypes (4, 7F, 3) included in Prevena 13 ® .
- the present inventors may indicate titer and / or functional antibody titer when the capsular polysaccharide derived from Streptococcus pneumoniae serotype 2 is further included in the trivalent vaccine formulation. It was confirmed.
- immunogenicity may be lowered due to interference between the serotypes of capsular polysaccharides or carrier proteins.
- One aspect of the present invention for achieving the above object is a vaccine composition for the prevention of pneumococcal disease comprising 13 capsular polysaccharide-carrying protein conjugates.
- the 13 conjugates are 13 capsular polysaccharides derived from Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F.
- Each of the capsular polysaccharides may be covalently conjugated to the carrier protein CRM197.
- the present invention relates to a vaccine composition
- a vaccine composition comprising 13 different polysaccharide-protein conjugates, each conjugate comprising a different serotype of the capsular polysaccharide from Streptococcus pneumoniae conjugated to a carrier protein, wherein the capsular polysaccharide is Serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F.
- Another aspect of the invention is a vaccine composition for the prevention of pneumococcal disease comprising 14 species of capsular polysaccharide-carrying protein conjugates.
- the 14 conjugates are each of 14 capsular polysaccharides derived from Streptococcus pneumoniae serotypes 1, 2, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F. It may be covalently conjugated to the carrier protein CRM197.
- the present invention provides a vaccine composition
- a vaccine composition comprising 14 different polysaccharide-protein conjugates, each conjugate comprising a different serotype of a capsular polysaccharide derived from Streptococcus pneumoniae conjugated to a carrier protein, wherein the capsular polysaccharide is Serotypes 1, 2, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F.
- the present inventors compared two representative methods of conjugation, reductive amination and cyanylation, to find a method for enhancing the immunogenicity of pneumococcal vaccines. It was confirmed that the cyanation method is much superior to the reductive amination reaction in terms of the bonding yield and the time required. Based on this, 13 serotypes were optimized for serotype-optimized conjugation using different cyanation reactions from prevena 13 ® using the same 13 serotypes as prevena 13 ® with the highest coverage. Has confirmed that the titers of all serotypes are very good compared to the prevenna13 ® standard.
- the conjugate is characterized by having a structure in which the capsular polysaccharide and the transport protein are connected by -O-C (NH) -NH- group using a cyanylation method.
- the 13- or 14-valent vaccine compositions of the present invention can be conjugated by known reductive amination. It is possible to show significantly better titers in all serotypes compared to the 13- or 14-valent vaccine composition.
- pneumococcal pneumonia is a kind of acute inflammatory disease of the lung parenchyma, and the infectious agents are mainly Streptococcus pneumoniae and Klebsiella pneumoniae .
- pneumococcal pneumonia accounts for about 50% of all pneumonia, severe chills, fever, cough and chest pain, sputum is often bloody, complications that can cause pleurisy, meningitis, endocarditis, peritonitis Stein GE et al . (2001 Mar) Diagn. Microbiol.Infect, Dis 39: 181-185; Comparative serum bactericidal activity of clarithromycin and azithromycin against macrolide-sensitive and resistant strains of Streptococcus pneumoniae).
- pneumococcus in the present invention refers to Streptococcus pneumoniae and is generally a commensal organism that colonizes the mucosal surface of human nasopharynx. If the host's factor allows access to the lower respiratory tract of the organism, then a vigorous inflammatory response follows, which causes dense consolidation when the alveolar space fills the exudate, resulting in pneumonia May cause.
- the pneumococci can synthesize more than 90 structurally unique capsular polysaccharides, and the serotypes of pneumococci are classified according to the structural and immunological characteristics of these capsular polysaccharides.
- the immune response may be different depending on the type of capsular polysaccharide, that is, the serotype of pneumococcal from which capsular polysaccharide is derived.
- the vaccine composition of the present invention specifically contains 13 capsular polysaccharides derived from Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F. It can be prepared using.
- the vaccine composition of the present invention contains 14 kinds of capsular polysaccharides derived from Streptococcus pneumoniae serotypes 1, 2, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F. It can be prepared using.
- the capsular polysaccharide is recognized as an antigen when administered in the body, so that it can produce an antibody against it, thereby preparing a vaccine composition for preventing pneumococci.
- the term “antigen” refers to a substance that can specifically induce an immune response when the substance invades the body.
- 13 kinds of capsular polysaccharides derived from Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F are antigens. Can work.
- 14 types of capsular polysaccharides derived from Streptococcus pneumoniae serotypes 1, 2, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F may act as antigens. Can be.
- the capsular polysaccharide can be prepared by standard techniques known to those skilled in the art, and are not particularly limited in its method.
- the capsular polysaccharide can be reduced in size through hydrolysis to reduce viscosity and induce effective immunogenicity.
- Streptococcus pneumoniae having 14 different serotypes (1, 2, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F). Each was lysed using sodium deoxycholate and the polysaccharide bound to the cells was liberated. Then, 12 serotypes 1, 2, 3, 4, 5, 6A, 6B, 9V, 18C, 19A, 19F and 23F were purified by performing CTAB process because they can be ion-bonded with CTAB (cetyltrimethylammonium bromide). Two serotypes 7F and 14, which do not react with CTAB, were purified using an aluminum phosphate gel (Algel) solution.
- Algel aluminum phosphate gel
- the conjugate protein and the capsular polysaccharide are conjugated. It was prepared and used.
- carrier protein refers to a protein that can be covalently conjugated with the capsular polysaccharide to increase the immunogenicity of the polysaccharide antigen.
- CRM197 was used.
- the carrier protein may be conjugated with the capsular polysaccharide through a standard conjugation method, and the capsular polysaccharide-carrying protein conjugate formed therefrom may be one or a plurality of capsular polysaccharides conjugated to one carrier protein.
- CRM197 in the present invention is a non-toxic variant of diphtheria toxin (ie, toxoid) isolated from the culture of Corynebacterium diphtheriae strain C7 ( ⁇ 197).
- CRM197 can be purified via ultrafiltration, ammonium sulphate precipitation and ion exchange chromatography.
- the CRM197 may be recombinantly prepared according to US Pat. No. 5,614,382.
- All known methods for preparing conjugates of capsular polysaccharides and carrier proteins can be included within the scope of the present invention, wherein the conjugates are linked to the -OC (NH) -NH- group by using the cyanylation method.
- the cyanation method may be appropriately performed by those skilled in the art through a known method, for example, may be performed using CDAP (1-cyano-4-dimethylaminopyridinium tetrafluoroborate) or CNBr, but is not limited thereto.
- purified capsular polysaccharides can be chemically activated and each chemically activated capsular polysaccharide can be conjugated to the carrier protein one by one to form a glycoconjugate.
- Cyanation activity by treatment with CDAP (1-cyano-4-dimethylaminopyridinium tetrafluoroborate) converts the hydroxyl group of the capsular polysaccharide to a cyanate group, thereby covalently binding to the amino group of the carrier protein CRM197.
- CDAP 1-cyano-4-dimethylaminopyridinium tetrafluoroborate
- the cyanation reaction by the CDAP may be specifically terminated by adding 3 molar equivalents of glycine (glycine) solution to 1 molar equivalent of CDAP and adjusting the pH to 9.0, but is not limited thereto.
- the reaction solution and reaction conditions can be adjusted accordingly.
- the capsular polysaccharide-carrying protein conjugates obtained can be purified by various methods. Examples of these methods include concentration / dialysis filtration processes, column chromatography and multilayer filtration. Purified polysaccharide-protein conjugates can be mixed and formulated into vaccine compositions of the invention and used respectively. Formulations of vaccine compositions of the invention can be carried out using methods known in the art. For example, 13 individual capsular polysaccharide-carrying protein conjugates can be formulated with a physiologically acceptable vehicle to make a composition. Examples of such vehicles may include, but are not limited to, water, buffered saline, polyols (eg, glycerol, propylene glycol, liquid polyethylene glycols) or dextrose solutions.
- a physiologically acceptable vehicle may include, but are not limited to, water, buffered saline, polyols (eg, glycerol, propylene glycol, liquid polyethylene glycols) or dextrose solutions.
- 1) dissolution of 14 capsular polysaccharides and 14 hydrolysis, 2) conjugation reaction of each capsular polysaccharide with CRM197 using CDAP (1-cyano-4-dimethylaminopyridinium tetrafluoroborate) 14 kinds of capsular polysaccharide-carrying protein conjugates were prepared through a process, 3) termination of conjugation reaction, 4) ultrafiltration, 5) bactericidal filtration, and 6) adsorption.
- the term “vaccine” refers to a biological agent containing an antigen that immunizes a living body, and refers to an immunogen or antigenic substance that immunizes the living body by administering it to a human or an animal to prevent infection.
- the vaccine composition may further include one or more selected from the group consisting of an adjuvant, a preservative, a buffer, a cryoprotectant, a salt, a divalent cation, a nonionic detergent, and a free radical oxidation inhibitor.
- adjuvant in the present invention refers to a substance used to increase the immunogenicity of the immunogenic composition of the present invention.
- the adjuvant is often provided to enhance the immune response, which is well known to those skilled in the art.
- adjuvants suitable for increasing the effectiveness of the vaccine composition of the present invention include, but are not limited to:
- aluminum salts eg, aluminum hydroxide, aluminum phosphate, aluminum sulfate, etc.
- Oil-in-water emulsion formulations (with or without muramyl peptide (defined below) or other specific immune stimulants such as bacterial cell wall components), for example (a) MF59 (WO 90/14837): Contains 5% Squalene, 0.5% Tween 80 and 0.5% Span 85 (optionally contains varying amounts of MTP-PE (although not required, see below)), Model 110Y Micro Formulated into submicron particles using a microfluidizer such as a microfluidizer (Microfluidics, Newton, Mass.), (B) SAF: 10% squalene, 0.4% Tween 80, 5% Pluronic -Block polymer L121 and thr-MDP (see below), microfluidized with a submicron emulsion, or vortexed to form a large particle size emulsion, and (c) Ribi TM adjuvant System (RAS) (Corixa, Hamilton, MT): 2% squalene, 0.
- Tween 80 and from the group consisting of 3-O-deacylated monophosphoryl lipid A (MPL TM) (Corixa), trehalose dimicholate (TDM) and cell wall backbone (CWS) described in US Pat. No. 4,912,094. Contains at least one bacterial cell wall component, preferably MPL + CWS (Detox TM);
- Saponin adjuvant such as Quill A or STIMULON TM QS-21 (Antigenics, Framingham, MA, US Pat. No. 5,057,540), may be used or produced from particles such as ISCOM ( Immunostimulatory complexes));
- cytokines such as interleukins (eg, IL-1, IL-2, IL-4, IL-5, IL-6, IL-7, IL 12, IL-15, IL-18, etc.) Interferon (eg gamma interferon), granulocyte macrophage colony stimulating factor (GM-CSF), macrophage colony stimulating factor (MCSF), tumor necrosis factor (TNF), costimulatory molecules B7-1 and B7-2, and the like;
- interleukins eg, interleukins (eg, IL-1, IL-2, IL-4, IL-5, IL-6, IL-7, IL 12, IL-15, IL-18, etc.)
- Interferon eg gamma interferon
- GM-CSF granulocyte macrophage colony stimulating factor
- MCSF macrophage colony stimulating factor
- TNF tumor necrosis factor
- costimulatory molecules B7-1 and B7-2 costimulatory molecules
- -2002/098368 and WO-2002 / 098369 pertussis toxin (PT), or E. coli heat-labile toxin (LT), in particular LT-K63, LT-R72, CT-S109, PTK9 / G129
- WO Detoxified mutants of bacterial ADP-ribosylated toxins such as -93/13302 and WO-92 / 19265;
- the muramyl peptides include N-acetyl-muramil-L-threonyl-D-isoglutamine (thr-MDP), N-acetyl-normuramyl-L-alanine-2- (1'-2 'dipalmityl) -sn-glycero-3-hydroxyphosphoryloxy) -ethylamine (MTP-PE) and the like, but is not limited thereto.
- the aluminum salt adjuvant may be an aluminum-precipitated vaccine or an aluminum-adsorbed vaccine.
- Aluminum salts include hydrated alumina, alumina hydrate, alumina trihydrate (ATH), aluminum hydrate, aluminum trihydrate, alhydrogel, Superfos, amphogel, aluminum hydroxide, aluminum hydroxyphosphate adjuvant (APA), Amorphous alumina, and the like, but is not limited thereto.
- APA refers to a suspension of aluminum hydroxyphosphate.
- Aluminum chloride and sodium phosphate are mixed at a ratio of 1: 1, aluminum hydroxyphosphate sulfate is precipitated, and the precipitate is made to have a size of 2 to 8 ⁇ m using a high shear mixer, followed by dialysis and sterilization with physiological saline.
- commercially available Al (OH) 3 eg alhydrogel or Superfos
- OH alhydrogel
- 50 to 200 g of protein can be adsorbed per mg of aluminum hydroxide, and this ratio is dependent on the pH of the protein and the pH of the solvent.
- Low pI proteins bind more strongly than proteins with high pi.
- Aluminum salts can form antigen reservoirs that slowly release antigens for two to three weeks to nonspecifically activate macrophages, complement, and innate immune mechanisms.
- preservative means an anti-viral and / or antimicrobial agent that inhibits the growth of microorganisms in the vaccine composition, for example, chimerosal, phenoxyethanol, 2-phenoxyethanol. It may be, but is not limited to, formaldehyde, or mixtures thereof, all conventional preservatives used in the art may be used.
- the vaccine composition may comprise one or more physiologically acceptable buffers.
- the buffer may have buffering capacity at pH 4.0 to 10.0, specifically, pH 5.0 to 9.0, more specifically pH 6.0 to 8.0.
- the buffer may be selected from the group consisting of TRIS, acetate, glutamate, lactate, maleate, tartrate, phosphate, citrate, carbonate, glycinate, histidine, glycine, succinate, triethanolamine buffer.
- the buffer may be selected from buffers suitable for USP.
- buffers include monobasic acids such as acetic acid, benzoic acid, gluconic acid, glyceric acid, lactic acid; Dibasic acids such as aconitic acid, adipic acid, ascorbic acid, carbonic acid, glutamic acid, malic acid, succinic acid, tartaric acid; Polybasic acids such as citric acid and phosphoric acid; It may be selected from the group consisting of ammonia, diethanolamine, glycine, triethanolamine, TRIS and the like.
- the vaccine composition of the present invention may include a nonionic detergent.
- a nonionic detergent for example, polysorbate 20 and polysorbate 80 in polyoxyethylene sorbitan esters (commonly called Tweens); Copolymers of ethylene oxide (EO), propylene oxide (PO), butylene oxide (BO) (eg DOWFAX TM); Oxoxynols having a different repeating number of oxy-1,2-ethanediyl groups, especially ostoxynol-9 (Triton-100); Ethylphenoxypolyethoxyethanol (IGEPAL CA-630 / NP-40); Phospholipids such as lecithin; Nonylphenol ethoxylates such as NP series; Polyoxyethylene fatty acid ethers (Brij surfactants) derived from lauryl, cetyl, stearyl, oleyl alcohols, in particular triethyleneglycol monolauryl ether (Brij 30); Sorbitan ethers, also known
- Tween 80 may be included in the emulsion and a mixture of nonionic detergents such as Tween 80 / Span 85 may be used.
- Combinations of polyoxyethylene sorbitan esters such as Tween 80 with octocinols such as Triton X-100 are also suitable, and combinations of Laureth 9 with Tween and or octosinol are also useful.
- polyoxyethylene sorbitan esters such as Tween 80 may be used in an amount of 0.01% to 1% (w / v), in particular 0.1%; Octylphenoxy polyoxyethanol or nonylphenoxy polyoxyethanol (such as Triton X-100) may range from 0.001% to 0.1%, in particular from 0.005% to 0.02%;
- the polyoxyethylene ether eg laureth 9 may comprise 0.1% to 20%, preferably 0.1% to 10%, in particular 0.1% to 1% or about 0.5%.
- composition of the present invention may be formulated in a single dose dose vial, multiple dose dose vial or prefilled syringe form, and may further comprise a physiologically acceptable carrier.
- Physiologically acceptable carriers used in liquid formulations include aqueous or non-aqueous solvents, suspensions, emulsions, oils. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, ethyl oleate.
- Aqueous carriers include water, alcohol / aqueous solvents, emulsions or suspensions, physiological saline, buffer solutions.
- oils include vegetable or animal oils, peanut oils, soybean oils, olive oils, sunflower oils, synthetic oils such as liver oils, marine oils, and lipids derived from milk or eggs.
- Vaccine compositions of the present invention may be isotonic, hypertonic or hypotonic, and pharmaceutical compositions administered by infusion or injection are preferably but is not limited to isotonicity. On the other hand, isotonicity or hypertension may be advantageous for storage of the composition. If the vaccine composition is hypertonic, it can be diluted to isotonic prior to administration. Isotonic agents for dilution can be ionic tonicity agents such as salts or nonionic tonicity agents such as carbohydrates. Ionic isotonic agents include, but are not limited to, sodium chloride, calcium chloride, potassium chloride, magnesium chloride, and the like. Nonionic isotonic agents include, but are not limited to, sorbitol, glycerol, and the like.
- the amount of the conjugate at each vaccine dose may be chosen to be an amount that induces an immunoprotective response without significant side effects, which amount may vary depending on the serotype of pneumococcal.
- the vaccine composition is a serotype 1-derived capsular polysaccharide, serotypes 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F and 23F derived capsular polysaccharides are 0.9 to 1.1
- the capsular polysaccharide derived from serotype 6B may be 1.8 to 2.2 in content ratio, but is not limited thereto.
- the capsular polysaccharide derived from serotype 2 in the vaccine composition may have a content ratio of 0.9 to 1.1 compared to the capsular polysaccharide derived from serotype 1, but is not particularly limited thereto.
- each conjugate may comprise 0.1 to 100 ⁇ g, specifically 0.1 to 10 ⁇ g, more specifically 1 to 5 ⁇ g polysaccharide.
- the remaining polysaccharides that is, the capsular polysaccharides derived from serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F, and 23F, respectively, 2.2 ⁇ g
- the capsular polysaccharide derived from serotype 6B may be 4.4 ⁇ g, but is not limited thereto.
- CRM197 protein in the composition may be 0.1 to 100 ⁇ g, specifically 1 to 50 ⁇ g, more specifically 28 to 31 ⁇ g, most specifically 29.3 ⁇ g, but is not limited thereto.
- Optimal amounts of ingredients for a particular vaccine can be identified by standard studies involving the observation of an appropriate immune response in a subject. For example, the results of animal experiments can be extrapolated to determine the vaccination dose for humans. Those skilled in the art can also empirically determine the dose as needed.
- the vaccine composition may further include aluminum element and sodium chloride, but is not limited thereto.
- the vaccine composition may or may not contain a preservative depending on the purpose and use thereof.
- the vaccine composition according to the present invention can be used to protect a subject susceptible to pneumococcal and to prevent pneumococcal disease by administering a pharmaceutically effective amount in a systemic or mucosal route.
- prevention of the present invention refers to any action that inhibits or delays the infection caused by pneumococcal by administration of the vaccine composition of the present invention.
- a “pharmaceutically effective amount” refers to a dosage required to elicit an antibody that is capable of significantly reducing the probability of infection or the severity of infection.
- administration of the present invention refers to the introduction of certain substances into an individual in any suitable way.
- the vaccine composition of the present invention may be administered by inhalation route through oral, nasal, rectal, transdermal or aerosol, but may be administered by bolus or infused slowly, but is not limited thereto.
- the administration may be by injection via an intramuscular, intraperitoneal, intradermal or subcutaneous route; Or mucosal administration to the oral / digestive tract, airway or urogenital tract.
- intranasal administration can be used for the treatment of pneumonia or otitis media, in which case more effective prevention of nasopharyngeal carriers of pneumococci can attenuate the infection at an early stage.
- the term “individual” of the present invention means a living organism to which a pathogen can be infected, and in particular, may be a higher vertebrate, and more specifically, a mammal, but is not particularly limited thereto.
- composition of the present invention may be administered in a single inoculation, or two, three, four or more times at appropriate intervals, but is not limited thereto.
- routine inoculation plans for infants and newborns for invasive diseases caused by Streptococcus pneumoniae can be 2, 4, 6 and 12 to 15 months of age.
- composition may further comprise one or more proteins from Streptococcus pneumoniae.
- Streptococcus pneumoniae proteins suitable for inclusion may include all of the proteins identified in WO-2002 / 053855, as well as the proteins described in WO-2002 / 053761, within the scope of the present invention.
- each polysaccharide in a total of 0.5 mL except that 6B is 4.4 ⁇ g; About 29.3 ⁇ g CRM197 transport protein; 0.5 mg of elemental aluminum (2 mg aluminum phosphate) adjuvant; About 4.25 mg sodium chloride (without preservatives) or about 3.5 mg (with preservatives); About 295 ⁇ g succinate buffer; About 3 mg of 2-phenoxyethanol and about 60 ⁇ g of formaldehyde were mixed (including preservatives) to prepare a vaccine composition (named 'LBVE013') for the prevention of 13-valent pneumococcal disease.
- each polysaccharide in a total of 0.5 mL except that 6B is 4.4 ⁇ g; About 31 ⁇ g CRM197 transport protein; 0.5 mg of elemental aluminum (2 mg aluminum phosphate) adjuvant; About 4.25 mg sodium chloride (without preservatives) or about 3.5 mg (with preservatives); About 295 ⁇ g succinate buffer; About 3 mg of 2-phenoxyethanol and about 60 ⁇ g of formaldehyde were mixed (with preservatives) to prepare a vaccine composition for the prevention of 14-valent pneumococcal disease.
- serum levels of rabbits inoculated with the vaccine composition confirmed higher serotype-specific IgG concentrations than Prevena 13 ® (Table 1 and Table 2).
- the functional immunogenicity test (Opsonophagocytic assay) shows a superior effect than the prebena 13 ® (Table 3 and Table 4).
- the vaccine composition of the present invention was found to have a very good effect for the prevention of pneumococcal disease.
- Another aspect of the invention is an immunogenic composition against pneumococci comprising 13 or 14 species of the capsular polysaccharide-carrying protein conjugate.
- the 13 or 14 conjugates and pneumococci are as described above.
- composition comprising 13 capsular polysaccharide-carrying protein conjugates of the present invention comprises Streptococcus pneumoniae- derived capsular polysaccharides having 13 different serotypes, which are recognized as antigens when administered to the body. By causing an immune response to produce an antibody against it, it can be used as an immunogenic composition against pneumococcal.
- Another aspect of the invention is a method of preventing pneumococcal disease by administering the vaccine composition or immunogenic composition to a subject in need thereof.
- Another aspect of the invention comprises 13 capsular polysaccharide-carrier protein conjugates, wherein the 13 conjugates are Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, Each of 13 capsular polysaccharides derived from 18C, 19A, 19F and 23F is covalently conjugated to a carrier protein, the carrier protein is CRM197 protein, and the conjugate is used to obtain the capsular polysaccharide and carrier protein using a cyanation method.
- a composition having a structure linked by -OC (NH) -NH- groups is provided for use in the preparation of a vaccine composition for the prevention of pneumococcal disease.
- Another embodiment of the present invention comprises 14 capsular polysaccharide-carrier protein conjugates, wherein the 14 conjugates are Streptococcus pneumoniae serotypes 1, 2, 3, 4, 5, 6A, 6B, 7F, 9V, Each of the 14 capsular polysaccharides from 14, 18C, 19A, 19F, and 23F is covalently conjugated to a carrier protein, the carrier protein is CRM197 protein, and the conjugate is capsular polysaccharide and transport using a cyanylation method. It is to provide a use for the use of the composition in the manufacture of a vaccine composition for the prevention of pneumococcal disease, wherein the protein has a structure linked by -OC (NH) -NH- group.
- Vaccine compositions immunogenic compositions, and prevention of pneumococcal disease are as described above.
- Another embodiment of the present invention provides a method for screening each of 13 isolated capsular polysaccharides derived from Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F.
- a method of preparing the immunogenic composition comprising the step of conjugating the capsular polysaccharide and the transport protein to the carrier protein CRM197 to have a structure linked by -OC (NH) -NH- group using a nilation method.
- inventions each comprise 14 isolated capsular polysaccharides derived from Streptococcus pneumoniae serotypes 1, 2, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F. It is a method for producing the immunogenic composition comprising the step of conjugating the capsular polysaccharide and the transport protein to the carrier protein CRM197 to have a structure linked by -OC (NH) -NH- group using a cyanylation method.
- the composition according to the present invention comprises a capsular polysaccharide derived from pneumococcal having 13 different serotypes, or includes a capsular polysaccharide derived from serotype 2 pneumococcal in addition to 13 capsular polysaccharides, which is a CRM197 protein carrier.
- a capsular polysaccharide derived from pneumococcal having 13 different serotypes or includes a capsular polysaccharide derived from serotype 2 pneumococcal in addition to 13 capsular polysaccharides, which is a CRM197 protein carrier.
- Streptococcus pneumoniae strains were smeared on blood agar medium to identify pneumococci and the existing media components were removed. Among the 10 or more single colonies, a single good growing colony was selected, inoculated and cultured in a liquid medium containing no animal-derived components, and a research cell bank (RCB) containing synthetic glycerol was prepared.
- RBC research cell bank
- Master cell bank was prepared by taking out one vial from the cell bank for which the expression of polysaccharides with unique serotypes was confirmed, proliferating the cells in a liquid medium containing no animal-derived components, and adding synthetic glycerol. One vial was taken out of the bank to proliferate cells in a liquid medium containing no animal-derived components, and then synthetic glycerol was added to prepare a cell bank for production. The prepared cell banks were stored under ultra-freezing conditions of -70 deg.
- the main culture was performed while maintaining the pH of the medium by using sterilized potassium hydroxide solution with minimal stirring at 37 ⁇ 2 ° C. Sampling was carried out after 2 hours after incubation to determine the cell concentration in the culture medium and the glucose concentration in the medium. The culture was terminated when glucose in the medium was depleted.
- Phosphoric acid was added to the sample treated with sodium deoxycholate for a long time, and the supernatant was recovered by centrifugation. The recovered supernatant was passed through a depth filter and then buffer exchanged with concentrated and phosphate buffer. After the buffer exchange, the sample was passed through an active carbon filter, and then impurities were removed by the following two methods.
- CTAB cetyltrimethylammonium bromide
- the sample was subjected to a depth filter and ultrafiltration (UF / DF), and then stored in a raw form while controlling the amount of ethanol and sodium chloride.
- UF / DF depth filter and ultrafiltration
- the equilibrated complex was dissolved by incubation (37 ⁇ 2 ° C.) in sodium phosphate (Na 3 PO 4 ) buffer solution at a rate of 0.1 M per 20 g of saccharides, followed by addition of cyanoborohydride (100 mg / mL).
- the conjugation reaction was started. After incubation at 37 ⁇ 2 ° C. for about 44-52 hours, the temperature was lowered to 23 ⁇ 2 ° C. and 1 mL of 0.9% NaCl solution was added to the reactor.
- Sodium borohydride solution (100 mg / mL) is added to 1.8 to 2.2 molar equivalents of sodium borohydride per mole of saccharide and the mixture is stirred at 23 ⁇ 2 ° C.
- the mixture was diluted with 5 mL of 0.9% aqueous sodium chloride solution and the diluted conjugate mixture was diafiltered using a 100 kDa MWCO membrane.
- a 2M NaCl polysaccharide solution was prepared by adding sodium chloride powder to a 9V polysaccharide stock solution prepared without hydrolysis.
- CDAP (1-cyano-4-dimethylaminopyridinium tetrafluoroborate) was dissolved at a ratio of 0.5 w / w% to polysaccharide, added to a 9V polysaccharide solution, and stirred for 15 minutes to induce a polysaccharide activation reaction.
- the sodium hydroxide solution was then raised until the pH was 9.5 ⁇ 0.1 ° C. and then stirred for 3 minutes so that the hydroxyl groups of the polysaccharides could be sufficiently activated by CDAP.
- CRM197 was added at a ratio of CRM197 1.0 w / w% to polysaccharide in the polysaccharide solution that had undergone polysaccharide activation, and the conjugation reaction was performed at room temperature for 1 hour.
- the conjugation reaction was terminated by adding 2 M glycine solution in 3 molar equivalents to 1 molar equivalent of CDAP and incubating overnight at room temperature with pH adjusted to 9.0.
- the terminated conjugate was concentrated and diafiltered into an ultrafiltration filter through a buffer containing 0.9% sodium chloride.
- Step 1-1 Dissolution and Hydrolysis of 13 Capsular Polysaccharides
- the original capsular polysaccharide originated from each serotype was dissolved in water for injection so that the final concentration range was within the range described below and filtered through a 0.45 ⁇ m filter.
- Hydrolysis was performed by incubating the solution at the pH and temperature ranges described below for each serotype. Specifically, phosphoric acid at 70-80 ° C. overnight for serotypes 1, 3, 5, 6B, 7F, 14 and 23F, 70-80 ° C. for 1-4 hours for serotypes 6A and 19F, for serotypes 9V and 18C. The solution was incubated at pH 2.0, 65-80 ° C. for 1-3 hours. The hydrolysis was then stopped by cooling to 21-24 ° C. and adding sodium hydroxide to a target pH of 6.0 ⁇ 1.0. Serotypes 4 and 19A did not undergo hydrolysis.
- Step 1-2 Dissolution and Hydrolysis of 14 Capsular Polysaccharides
- the original capsular polysaccharide originated from each serotype was dissolved in water for injection so that the final concentration range was within the range described below and filtered through a 0.45 ⁇ m filter.
- serotypes 6A and 19A were dissolved in the range of 8-12 mg / ml, 2-4 mg / ml for 14 and 23F, and in the range of 6-10 mg / ml for serotype 7F, followed by filtration.
- the immunogenicity of conjugate vaccines is known to be subject to immune interference induced by interactions between polysaccharide or carrier proteins involved (Dagan R et al . (2010) Vaccines, 28). (5513) Glycoconjugate vaccines and immune interference: A review.
- the present inventors applied the 13-valent conjugate vaccine and other polysaccharide hydrolysis methods in serotypes 3, 4, 6A, and 7F as follows. The joining process was optimized.
- Hydrolysis of the polysaccharide was carried out by incubation of the solution in the pH and temperature ranges described below for each serotype. Specifically, overnight at 70-80 ° C for serotypes 1, 2, 4, 5, 6A, 6B, 14 and 23F, 70-80 ° C for 1-4 hours for serotype 19F, serotypes 3, 7F, 9V and 18C In the case of using a phosphoric acid solution, the incubation process was performed at pH 2.0, 65-80 °C for 1-3 hours. The hydrolysis was then stopped by cooling to 21-24 ° C. and adding sodium hydroxide to a target pH of 6.0 ⁇ 1.0. 19A did not proceed with hydrolysis.
- % Was dissolved at 4 w / w% ratio for serotypes 5, 9V, 18C, 19F, 23F and added to each polysaccharide solution. After 1 to 3 minutes, sodium hydroxide solution was added to raise the pH to 9.4 to 9.7, followed by stirring for 3 to 7 minutes so that the hydroxyl groups of the polysaccharides could be sufficiently activated by CDAP. Conjugation reaction was performed for 1 hour to 4 hours by adding CRM197 0.5-1.0 w / w% to polysaccharide to each serotype polysaccharide solution. The reaction conversion was measured using HPLC-SEC, and CDAP was added as needed.
- the reaction was terminated by adding 3-6 molar equivalents of glycine solution relative to 1 molar equivalent of CDAP added for all serotypes and adjusting the pH to 9.0.
- the conjugation solution was stirred at 21-24 ° C. for one hour and then stored overnight at 2-8 ° C. low temperature.
- the diluted conjugate mixture was concentrated and diafiltered into an ultrafiltration filter using at least 20 volumes of buffer.
- the buffer was maintained in the range of pH 5.5 to 6.5, and a buffer containing 0.9% sodium chloride was used.
- Fractional molecular weight of the ultrafiltration filter was carried out using 300 kDa in all serotypes, and the permeate was discarded.
- the residue after diafiltration was diluted to less than 0.4 g / L based on polysaccharide concentration using a buffer and filtered through a 0.22 ⁇ m filter.
- the filtered product was subjected to in-process control (sugar content, residual DMAP). In-process controls were performed on the filtered residue to determine if further concentration, diafiltration and / or dilution were needed.
- Aluminum salts (mainly aluminum phosphate) were added to the sterile filtrate so that the final concentration was 1 mg / mL based on aluminum ions, and extra salts were added to maintain a pH range of 5.5 to 6.5. After the adsorption, the stock solution was subjected to quality inspection to confirm quality suitability, and refrigerated at 2 to 8 ° C. until use.
- the required amount of final bulk concentrate was calculated based on batch volume and bulk polysaccharide concentration.
- the required amount of 0.85% sodium chloride, succinate buffer, 2-phenoxyethanol and formaldehyde were added to a previously labeled formulation vessel, followed by the bulk concentrate. Then it was thoroughly mixed and filtered through a 0.22 ⁇ m filter.
- the formulated bulk liquid was slowly mixed, then bulk aluminum phosphate was added and mixed well. pH was checked and adjusted if necessary.
- the formulated bulk product was stored at 2-8 ° C.
- the resulting vaccine composition (hereinafter referred to as 'LBVE013') contains 2.2 ⁇ g of each polysaccharide in 0.5 mL total, except that 6B is 4.4 ⁇ g; About 29.3 ⁇ g CRM197 transport protein; 0.5 mg of elemental aluminum (2 mg aluminum phosphate) adjuvant; About 4.25 mg sodium chloride; About 295 ⁇ g succinate buffer; It contains about 3 mg of 2-phenoxyethanol and about 60 ⁇ g of formaldehyde (applicable when preservatives are added).
- the required amount of the final bulk concentrate was calculated based on the batch volume and bulk polysaccharide concentration.
- the required amount of 0.85% sodium chloride, succinate buffer, 2-phenoxyethanol and formaldehyde were added to a previously labeled formulation vessel, followed by the bulk concentrate. Then it was thoroughly mixed and filtered through a 0.22 ⁇ m filter.
- the formulated bulk liquid was slowly mixed, then bulk aluminum phosphate was added and mixed well. pH was checked and adjusted if necessary.
- the formulated bulk product was stored at 2-8 ° C.
- the resulting vaccine composition (hereinafter referred to as 'LBVE014') contains 2.2 ⁇ g of each polysaccharide in 0.5 mL total, except that 6B is 4.4 ⁇ g; About 31 ⁇ g CRM197 transport protein; 0.5 mg of elemental aluminum (2 mg aluminum phosphate) adjuvant; About 4.25 mg sodium chloride; About 295 ⁇ g succinate buffer; It contains about 3 mg of 2-phenoxyethanol and about 60 ⁇ g of formaldehyde (applicable when preservatives are added).
- Example 3 a study was conducted to evaluate whether the multivalent pneumococcal vaccine composition (LBVE013, LBVE014) prepared in Example 3 has an ability to induce an immune response in a laboratory rabbit. This immunogenicity was confirmed by antigen-specific ELISA for serum IgG concentration and by Opsonophagocytic assay (OPA) for the production of functional antibodies.
- OPA Opsonophagocytic assay
- Formulated LBVE013, LBVE014 or Controlbena13 ® as a control human dose (2.2 ⁇ g of polysaccharide, exception: 6B 4.4 ⁇ g) into the muscles of New Zealand White rabbits at Parking 0, Parking 2 and Parking 4 Immunizations were made and serum was taken at two week intervals after inoculation.
- the results of IgG measurement using ELISA for the collected serum are shown in Table 1 and Table 2. This will be described in detail as follows.
- Capsular polysaccharides for each of the 13 or 14 serotypes were treated in 96-well plates at 5 ⁇ g / well and coated for 16 hours at room temperature.
- serum of each individual was reacted with C-PS 333.3 ⁇ g / mL and serotype 22F capsular polysaccharide (PnPs 22F) at 333.3 ⁇ g / mL for 30 minutes at room temperature, followed by Tween 20. Diluted with appropriate dilution buffer.
- the coated plate was washed four times with washing buffer, 50 ⁇ l of previously adsorbed and diluted serum was added to the coated well-plate and allowed to react at room temperature for 1 hour.
- Serum obtained from rabbits was subjected to OPA analysis to evaluate the functionality of antibodies induced by the serotypes of LBVE013 and LBVE014.
- THY medium Todd-Hewitt Broth w / 2% Yeast Extract
- Phagocytosis was stopped by lowering the temperature, and 10 ⁇ l of the reaction solution was plated in dried agar medium for 30 to 60 minutes in advance. Then, the cells were incubated for 12 to 18 hours in a CO 2 incubator (37 ° C.) and the number of colonies was counted. OPA titers were expressed as dilution folds where 50% killing was observed (Table 3; OPA titers labeled 2187 indicate that the titers were very high, even in the most diluted sections, where the 50% level was not reached compared to the negative control). .
- the immunogenic composition according to the present invention can be very useful for preventing diseases caused by pneumococci.
- the immunogenic composition according to the present invention can also be very useful for preventing diseases caused by pneumococcal.
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Abstract
Priority Applications (9)
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MYPI2019001207A MY192792A (en) | 2016-09-06 | 2017-08-31 | A composition of multivalent pneumococcal capsular polysaccharide-carrier protein conjugates and use thereof |
MA45283A MA45283B1 (fr) | 2016-09-06 | 2017-08-31 | Une composition de multivalent pneumococcal la protéine de polysaccaride-transporteur capsulaire se conjugue et utilisez de cela |
BR112019004303A BR112019004303A2 (pt) | 2016-09-06 | 2017-08-31 | composição de conjugados multivalentes de polissacarídeo capsular pneumocócico-proteína portadora e uso da mesma |
MX2019002552A MX2019002552A (es) | 2016-09-06 | 2017-08-31 | Composicion que comprende polisacarido capsular neumococico multivalente-proteina transportadora y uso de la misma. |
TNP/2019/000064A TN2019000064A1 (en) | 2016-09-06 | 2017-08-31 | Composition comprising multivalent capsular polysaccharide-transport protein and use thereof |
JOP/2019/0038A JOP20190038B1 (ar) | 2016-09-06 | 2017-08-31 | تركيب اقتراني من السكر المتعدد لكبسولة بكتيريا المكورات الرئوية وبروتين حامل واستخداماته |
EA201990451A EA201990451A1 (ru) | 2016-09-06 | 2017-08-31 | Композиция многовалентных пневмококковых конъюгатов капсульного полисахарида с белком-носителем и ее применение |
PH12019500377A PH12019500377A1 (en) | 2016-09-06 | 2019-02-21 | Composition comprising multivalent capsular polysaccharide-transport protein and use thereof |
ZA2019/01969A ZA201901969B (en) | 2016-09-06 | 2019-03-29 | A composition of multivalent pneumococcal capsular polysaccharide-carrier protein conjugates and use thereof |
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BR (1) | BR112019004303A2 (fr) |
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JO (1) | JOP20190038B1 (fr) |
MA (1) | MA45283B1 (fr) |
MX (1) | MX2019002552A (fr) |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11116828B2 (en) | 2017-12-06 | 2021-09-14 | Merck Sharp & Dohme Corp. | Compositions comprising Streptococcus pneumoniae polysaccharide-protein conjugates and methods of use thereof |
US11642406B2 (en) | 2018-12-19 | 2023-05-09 | Merck Sharp & Dohme Llc | Compositions comprising Streptococcus pneumoniae polysaccharide-protein conjugates and methods of use thereof |
WO2023218322A1 (fr) * | 2022-05-11 | 2023-11-16 | Pfizer Inc. | Procédé de production de formulations de vaccin avec des conservateurs |
US12016914B2 (en) | 2023-03-23 | 2024-06-25 | Merck Sharp & Dohme Llc | Compositions comprising Streptococcus pneumoniae polysaccharide-protein conjugates and methods of use thereof |
Families Citing this family (2)
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US11123417B2 (en) | 2018-02-05 | 2021-09-21 | Sanofi Pasteur Inc. | Multivalent pneumococcal polysaccharide-protein conjugate composition |
AU2019256218A1 (en) * | 2018-04-18 | 2020-12-03 | Sk Bioscience Co., Ltd. | Streptococcus pneumoniae capsular polysaccharides and immunogenic conjugate thereof |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995008348A1 (fr) * | 1993-09-22 | 1995-03-30 | Henry M. Jackson Foundation For The Advancement Of Military Medicine | Procede permettant d'activer un glucide soluble a l'aide de nouveaux reactifs cyanylants pour produire des structures immunogenes |
KR20130048262A (ko) * | 2005-04-08 | 2013-05-09 | 와이어쓰 엘엘씨 | 다가 폐렴구균 다당류-단백질 접합체 조성물 |
KR20130142574A (ko) * | 2012-06-20 | 2013-12-30 | 에스케이케미칼주식회사 | 다가 폐렴구균 다당류-단백질 접합체 조성물 |
WO2015175355A1 (fr) * | 2014-05-11 | 2015-11-19 | Kanvax Biopharmaceuticals Ltd | Compositions et procédés d'augmentation de l'immunogénicité de conjugués polysaccharide-protéine |
KR101609032B1 (ko) * | 2010-06-04 | 2016-04-04 | 와이어쓰 엘엘씨 | 스트렙토코커스 뉴모니아 백신 제제 |
CN103893751B (zh) * | 2014-03-26 | 2016-04-20 | 天津康希诺生物技术有限公司 | 一种肺炎球菌多糖蛋白缀合疫苗及其制备方法 |
-
2017
- 2017-08-31 BR BR112019004303A patent/BR112019004303A2/pt unknown
- 2017-08-31 JO JOP/2019/0038A patent/JOP20190038B1/ar active
- 2017-08-31 EA EA201990451A patent/EA201990451A1/ru unknown
- 2017-08-31 TN TNP/2019/000064A patent/TN2019000064A1/en unknown
- 2017-08-31 MY MYPI2019001207A patent/MY192792A/en unknown
- 2017-08-31 MX MX2019002552A patent/MX2019002552A/es unknown
- 2017-08-31 MA MA45283A patent/MA45283B1/fr unknown
- 2017-08-31 KR KR1020170111180A patent/KR101991457B1/ko active IP Right Grant
- 2017-08-31 WO PCT/KR2017/009569 patent/WO2018048141A1/fr active Application Filing
-
2019
- 2019-02-21 PH PH12019500377A patent/PH12019500377A1/en unknown
- 2019-03-04 SA SA519401232A patent/SA519401232B1/ar unknown
- 2019-03-29 ZA ZA2019/01969A patent/ZA201901969B/en unknown
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995008348A1 (fr) * | 1993-09-22 | 1995-03-30 | Henry M. Jackson Foundation For The Advancement Of Military Medicine | Procede permettant d'activer un glucide soluble a l'aide de nouveaux reactifs cyanylants pour produire des structures immunogenes |
KR20130048262A (ko) * | 2005-04-08 | 2013-05-09 | 와이어쓰 엘엘씨 | 다가 폐렴구균 다당류-단백질 접합체 조성물 |
KR101609032B1 (ko) * | 2010-06-04 | 2016-04-04 | 와이어쓰 엘엘씨 | 스트렙토코커스 뉴모니아 백신 제제 |
KR20130142574A (ko) * | 2012-06-20 | 2013-12-30 | 에스케이케미칼주식회사 | 다가 폐렴구균 다당류-단백질 접합체 조성물 |
CN103893751B (zh) * | 2014-03-26 | 2016-04-20 | 天津康希诺生物技术有限公司 | 一种肺炎球菌多糖蛋白缀合疫苗及其制备方法 |
WO2015175355A1 (fr) * | 2014-05-11 | 2015-11-19 | Kanvax Biopharmaceuticals Ltd | Compositions et procédés d'augmentation de l'immunogénicité de conjugués polysaccharide-protéine |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11116828B2 (en) | 2017-12-06 | 2021-09-14 | Merck Sharp & Dohme Corp. | Compositions comprising Streptococcus pneumoniae polysaccharide-protein conjugates and methods of use thereof |
US11850278B2 (en) | 2017-12-06 | 2023-12-26 | Merck Sharp & Dohme Llc | Compositions comprising Streptococcus pneumoniae polysaccharide-protein conjugates and methods of use thereof |
US11642406B2 (en) | 2018-12-19 | 2023-05-09 | Merck Sharp & Dohme Llc | Compositions comprising Streptococcus pneumoniae polysaccharide-protein conjugates and methods of use thereof |
WO2023218322A1 (fr) * | 2022-05-11 | 2023-11-16 | Pfizer Inc. | Procédé de production de formulations de vaccin avec des conservateurs |
US12016914B2 (en) | 2023-03-23 | 2024-06-25 | Merck Sharp & Dohme Llc | Compositions comprising Streptococcus pneumoniae polysaccharide-protein conjugates and methods of use thereof |
Also Published As
Publication number | Publication date |
---|---|
KR101991457B1 (ko) | 2019-09-30 |
JOP20190038B1 (ar) | 2023-09-17 |
EA201990451A1 (ru) | 2019-08-30 |
MA45283A1 (fr) | 2019-06-28 |
KR20180027353A (ko) | 2018-03-14 |
ZA201901969B (en) | 2019-12-18 |
BR112019004303A2 (pt) | 2019-05-28 |
JOP20190038A1 (ar) | 2019-03-06 |
MX2019002552A (es) | 2019-07-01 |
TN2019000064A1 (en) | 2020-07-15 |
PH12019500377A1 (en) | 2019-10-21 |
SA519401232B1 (ar) | 2022-10-23 |
MY192792A (en) | 2022-09-09 |
MA45283B1 (fr) | 2021-05-31 |
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