WO2019220304A1 - Vaccin conjugué de polysaccharide pneumococcique 15-valent - Google Patents

Vaccin conjugué de polysaccharide pneumococcique 15-valent Download PDF

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WO2019220304A1
WO2019220304A1 PCT/IB2019/053921 IB2019053921W WO2019220304A1 WO 2019220304 A1 WO2019220304 A1 WO 2019220304A1 IB 2019053921 W IB2019053921 W IB 2019053921W WO 2019220304 A1 WO2019220304 A1 WO 2019220304A1
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composition
adjuvant
serotypes
group
polysaccharide
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PCT/IB2019/053921
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English (en)
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Kuppusamy Mosuvan
Sathyan KUPPUSAMY
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Tergene Biotech Pvt. Ltd.
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Publication of WO2019220304A1 publication Critical patent/WO2019220304A1/fr

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    • 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
    • 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
    • A61K47/646—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
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • 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
    • 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
    • A61K2039/55505—Inorganic adjuvants
    • 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
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
    • A61K2039/575—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 humoral response
    • 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
    • A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
    • A61K2039/6031—Proteins
    • A61K2039/6037—Bacterial toxins, e.g. diphteria toxoid [DT], tetanus toxoid [TT]
    • 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
    • A61K2039/62—Medicinal preparations containing antigens or antibodies characterised by the link between antigen and carrier
    • 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
    • A61K2039/62—Medicinal preparations containing antigens or antibodies characterised by the link between antigen and carrier
    • A61K2039/627—Medicinal preparations containing antigens or antibodies characterised by the link between antigen and carrier characterised by the linker
    • 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
    • A61K2039/70—Multivalent vaccine
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • the present invention relates to a novel multivalent immunogenic composition having distinct polysaccharide-protein conjugates and the process for manufacturing thereof.
  • the present invention also relates to method of using novel multivalent immunogenic composition having distinct polysaccharide-protein conjugates, which method comprises administration of the composition to a subject in need thereof.
  • the present invention also relates to novel 15 valent pneumococcal polysaccharide conjugate vaccine composition
  • novel 15 valent pneumococcal polysaccharide conjugate vaccine composition comprising 15 distinct polysaccharide-protein conjugates, linker, carrier protein, aluminum based adjuvant and additives, and the process for manufacturing thereof and a method of using the same, which method comprises administration of the composition to a subject in need thereof.
  • the present invention also relate to a method of inducing an immune response to a Streptococcus pneumoniae capsular polysaccharide conjugate, comprising administering to a human a novel multivalent immunogenic composition having distinct polysaccharide-protein conjugates.
  • the present invention also relates to compositions comprising novel multivalent immunogenic composition including 15 valent pneumococcal polysaccharide conjugate vaccine composition for use in immunization or protection against pneumococcal disease and preventing pneumococcal disease in animals and human beings, including infants and young children.
  • Streptococcus pneumoniae is the most common cause of community-acquired pneumonia, meningitis, and bacteremia in children and adults, including the elderly, and is responsible for high rates of morbidity and mortality worldwide.
  • Pneumococcal disease is a major public health problem worldwide. The disease most frequently affects individuals at extremes of age and those with immunological impairment (children or adults). Most cases of pneumococcal disease are caused by a limited number of serotypes that vary in nasopharyngeal carriage, infectivity and virulence. Recent epidemiological study estimates about 1.6 million people, including up to 1 million children aged ⁇ 5 years, die of IPD every year mainly in developing countries.
  • Streptococcus pneumoniae causes invasive and noninvasive infections of which invasive pneumococcal disease (IPD) is the leading cause of morbidity and mortality in children and adults.
  • IPD invasive pneumococcal disease
  • Pneumococcal diseases are responsible for significant morbidity and mortality in children in the Asia-Pacific region; incidences are highest in indigenous and younger children, with rates around 100-200 cases/lOO, 000 children aged ⁇ 2 years. However, a particularly high incidence of IPD of 1500 cases/lOO, 000 children aged ⁇ 5 years has been reported in India based on hospital admissions for IPD associated diagnoses.
  • Pneumococcal serotypes differ in their invasiveness and are chosen for vaccines based on their order of disease incidence. Pneumococcal serotypes are more prevalent in carriage, but they do not always exhibit invasiveness. About 20 serotypes of S. pneumoniae are responsible for more than 80% of IPD, and the 13 most common serotypes cause at least 70-75% of IPD in children worldwide. The dominant serotypes associated with IPD worldwide include 14, 4, 1, 6A, 6B, 3, 8, 7F, 23F, 18C, 19F, and 9V. In young children, seven serotypes (1, 5, 6A, 6B, 14, 19F, and 23F) accounted for more than half of IPD in every region. Serotypes causing IPD vary greatly across geographic regions (e.g., serotypes 1 and 5 are an important cause of IPD in Africa, Asia, but are uncommon in Europe and United States.
  • the 23-valent polysaccharide pneumococcal vaccine (PPV) approved in 1983 contains purified capsular polysaccharides from 23 pneumococcal serotypes (1, 2, 3, 4, 5, 6b, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F, and 33F).
  • This vaccine was approved for adults aged 65 years or older, as well as adults aged 19-64 years with underlying medical conditions that increase the risk for pneumococcal disease. This vaccine is not recommended for children ⁇ 2 years of age, due to their immature immune system.
  • heptavalent conjugate vaccine (PCV7) Prevnar® was approved in the USA in 2000 and contains capsular polysaccharides from serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F, and are individually conjugated to a protein carrier; nontoxic diphtheria cross-reactive material CRM- 197.
  • PCV7 heptavalent pneumococcal conjugate vaccine 7 (PCV7) for the pediatric population has significantly decreased the incidence of IPD in both children and non-vaccinated adults.
  • PCV10 Synflorix ®
  • PCV13 l3-valent pneumococcal polysaccharide -protein conjugate vaccine
  • PCV13 contains 2.2 pg of polysaccharide from each of 12 serotypes and approximately 4.4 pg of polysaccharide from serotype 6B. PCV13 is approved for use among children aged 6 weeks to 5 years and replaces PCV7, and for adults aged 50 years and older. PCV13 contains the seven serotypes included in PCV7 (serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F) and six additional serotypes (1, 3, 5, 6A, 7F, and 19A).
  • US20060228380A1 describes an immunogenic composition having 13 distinct polysaccharide -protein conjugates and optionally, an aluminum- based adjuvant, is described.
  • Each conjugate contains a capsular polysaccharide prepared from a different serotype of Streptococcus pneumoniae (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F) conjugated to a carrier protein.
  • the l5-valent pneumococcal polysaccharide-protein conjugate vaccine (PCV15) by Merck includes the serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F that are conjugated to CRM-197.
  • US8192746B2 assigned to Merck describes 15 -valent pneumococcal polysaccharide-protein conjugate vaccine compositions and the methods of manufacturing.
  • the present invention relates to a vaccine compositions that includes 15 types of pneumococcal capsular polysaccharides prepared from the cultures of Streptococcus pneumonia serotypes 1, 2, 3, 4, 5, 6A, 6B, 7F, 9V, 12F, 14, 18C, 19A, 19F & 23F.
  • the present invention also relates to vaccine composition comprising 15 types of pneumococcal capsular polysaccharides of different size and molecular weight conjugated to a common carrier protein CRM- 197.
  • the present invention relates to novel 15 valent pneumococcal polysaccharide conjugate vaccine composition comprising 15 distinct polysaccharide-protein conjugates, linker, carrier protein, aluminum based adjuvant and additives, and the process for manufacturing thereof.
  • aspects of the present invention relate to a novel multivalent immunogenic composition having distinct polysaccharide -protein conjugates and the process for manufacturing thereof.
  • aspects of the present invention also relate to a method of inducing an immune response to a Streptococcus pneumoniae capsular polysaccharide conjugate, comprising administering to a human a novel multivalent immunogenic composition having distinct polysaccharide-protein conjugates.
  • compositions comprising novel multivalent immunogenic composition including 15 valent pneumococcal polysaccharide conjugate vaccine composition for use in immunization or protection against pneumococcal disease and preventing pneumococcal disease in animals and human beings, including infants and young children.
  • aspects of the present invention also provide a multivalent Pneumococcal Polysaccharide conjugate vaccine composition which is Asia specific in terms of coverage of the serotypes prevalent in this region.
  • Serotypes 2 and 12F are selected in addition to the 13 global serotypes that are prevalent in India, Bangladesh and China and other Asian countries.
  • the present invention provides a solution to balance the increased risk of immunocompetition with the increased number of serotypes.
  • the present invention also relate to a vaccine compositions that includes 15 types of pneumococcal capsular polysaccharides prepared from the cultures of Streptococcus pneumonia serotypes 1, 2, 3, 4, 5, 6A, 6B, 7F, 9V, 12F, 14, 18C, 19A, 19F & 23F conjugated to a common carrier protein CRM-197.
  • aspects of the present invention also relate to novel 15 valent pneumococcal polysaccharide conjugate vaccine compositions comprising 15 distinct polysaccharide-protein conjugates, linker, carrier protein, aluminum based adjuvant and additives, and the process for manufacturing thereof.
  • aspects of the present invention also relate to a pharmaceutical vaccine composition according to the present invention for use in the treatment or prevention of diseases or disorders caused due to Streptococcus Pneumonia including bacteremia, acute otitis media, pneumonia, invasive pneumococcal disease (IPD) such as meningitis and septicemia.
  • the methods of the invention can be used for the prevention and/or reduction of primary clinical syndromes caused by S. pneumoniae including both invasive infections (meningitis, pneumonia, and bacteremia), and noninvasive infections (acute otitis media, and sinusitis).
  • Fig. 1 depicts the ELISA Geometric Mean Titer (GMT's) for PCV-15 vaccine against various serotypes of S. pneumoniae.
  • Fig 2 depicts the opsonophagocytosis assay (OPA) Geometric Mean Titer (GMT's) for PCV-15 vaccine against various serotypes of S. pneumoniae.
  • OPA opsonophagocytosis assay
  • GTT's Geometric Mean Titer
  • Fig 3 depicts the immunogenicity profile in healthy adults in terms of ELISA GMT & ELISA GMR (geometric mean ratio) values for PCV-15 vaccine against various serotypes of S. pneumoniae.
  • treating refers to administering a therapy in an amount, manner, or mode effective to improve a condition, symptom, or parameter associated with a disorder.
  • treatment refers to the treatment of a disease or medical condition in a human patient which includes:
  • prophylaxis or the term “ameliorating” refers to preventing a disorder or preventing progression of a disorder, to either a statistically significant degree or to a degree detectable to one skilled in the art.
  • composition of the invention refers to a dose required to elicit antibodies that significantly reduce the likelihood or severity of infectivitiy of S. pneumoniae during a subsequent challenge.
  • PCV 15 means 15 Valent pneumococcal Polysaccharide Conjugate Vaccine.
  • the present invention relates to a novel multivalent immunogenic composition having distinct polysaccharide-protein conjugates and the process for manufacturing thereof.
  • the present invention also relates to novel 15 valent pneumococcal polysaccharide conjugate vaccine composition
  • novel 15 valent pneumococcal polysaccharide conjugate vaccine composition comprising 15 distinct polysaccharide-protein conjugates, linker, carrier protein, aluminum based adjuvant and additives, and the process for manufacturing thereof and method of using the same.
  • the present invention also relate to a method of inducing an immune response to a Streptococcus pneumoniae capsular polysaccharide conjugate, comprising administering to a human a novel multivalent immunogenic composition having distinct polysaccharide-protein conjugates.
  • the present invention also relates to compositions comprising novel multivalent immunogenic composition including 15 valent pneumococcal polysaccharide conjugate vaccine composition for use in immunization or protection against pneumococcal disease and preventing pneumococcal disease in animals and human beings, including infants and young children.
  • the present invention describes an injectable vaccine composition containing 15 distinct capsular polysaccharide -protein conjugates, wherein the polysaccharides are obtained from individual serotypes of Streptococcus pneumonia.
  • a common carrier protein is used in the conjugation process.
  • the 15 distinct capsular polysaccharides are selected from serotypes 1, 2, 3, 4, 5, 6A, 6B, 7F, 9V, 12F, 14, 18C, 19A, 19F and 23F of Streptococcus pneumonia.
  • a common protein is used as a carrier in all the individual polysaccharide conjugates.
  • the protein may be a non-toxic form of Diphtheria Toxin, called CRM-197.
  • the present invention provides a multivalent Pneumococcal Polysaccharide conjugate vaccine composition which is Asia specific in terms of coverage of the serotypes prevalent in this region. Serotypes 2 and 12F selected in addition to the 13 global serotypes are prevalent in India, Bangladesh and China. Accordingly, the present invention describes a vaccine composition comprising 15 distinct capsular polysaccharides selected from serotypes 1, 2, 3, 4, 5, 6A, 6B, 7F, 9V, 12F, 14, 18C, 19A, 19F and 23F of Streptococcus pneumonia, conjugated to a common carrier protein, the CRM- 197.
  • Carrier proteins are preferably proteins that are non-toxic and non-reactogenic and obtainable in sufficient amount and purity.
  • a carrier protein can be conjugated or joined with a S. pneumoniae polysaccharide to enhance immunogenicity of the polysaccharide.
  • Suitable carrier proteins used in the present invention can include inactivated bacterial toxins such as diphtheria toxoids, tetanus toxoid, pertussis toxoid, cholera toxoid, E. coli LT, E. coli ST, and exotoxin A from Pseudomonas aeruginosa.
  • CRM-197 is used as the carrier protein.
  • CRM- 197 is a nontoxic protein molecule produced by point mutation of the original C. Diphtheriae strain (PW8). This protein is immunologically similar to native Diphtheria toxin but without toxicity. The mutant strain is grown in an animal free, amino acid rich medium with controlled iron levels under aerobic conditions in a fermenter, separated and purified. CRM- 197 may be prepared recombinantly in accordance with U.S. Pat. No. 5,614,382, which is hereby incorporated by reference.
  • Capsular polysaccharides from individual serotypes of Streptococcus pneumonia are prepared by standard techniques known to those in the art.
  • the strains belonging to serotypes 1, 2, 3, 4, 5, 6A, 6B, 7F, 9V, 12F, 14, 18C, 19A, 19F and 23F are purified using standard techniques known in the art.
  • the purification process of capsular polysaccharides from S. pneumonia culture broth comprising serotypes 1, 2, 3, 4, 5, 6A, 6B, 7F, 9V, 12F, 14, 18C, 19A, 19F & 23F comprises of the following steps:
  • the supernatant is further passed through 0.2micron filter to reduce the bioburden.
  • the cell-free supernatant is concentrated and dia-filtered using 100 KDa UF cassette and the retentate is collected for further processing.
  • the retentate is subjected to multistep Ethanol precipitation to purify the polysaccharide.
  • the partially purified Polysaccharide is further purified from contaminating proteins and nucleic acid impurities on Q-Sepharose (anion exchange) column. lOmM Phosphate buffer at pH 8.0 is used as a mobile phase. Polysaccharide is eluted from the column by salt gradient.
  • the polysaccharide pool is dia-filtered against 3 ⁇ 40, concentrated, sterile filtered and stored at
  • the individual polysaccharides are broken down by mechanical high pressure homogenization to a pre-determined molecular size by HPLC-GPC-MALS. All the polysaccharides are de-sized to a molecular weight range between 200 - 400 KDa. After size reduction, individual polysaccharides are activated with N-cyano4-dimethyl-aminopyridinium tetrafluoroborate (CDAP) in the presence of triethylamine (TEA) for a period of time. The resulting O-cyanylated polysaccharide is immediately derivatized with Adipicdihydrazide (ADH) at pH 8.5-9.0 for 8-10 hrs at 5-10 degree centigrade. The reaction mixture (PS-ADH) is dia-filtered against MES buffer pH 5.6 - 6.2 and stored at 4°C.
  • CDAP N-cyano4-dimethyl-aminopyridinium tetrafluoroborate
  • TAA triethylamine
  • Linker molecules are often introduced between the saccharide and the protein to reduce a steric hindrance and facilitate interaction between both moieties.
  • the conjugation method and linker used together with saccharide chain length, type of carrier protein and saccharide to protein ratios are the significant conjugation variables that can affect the yield, quality and persistence of antibody response elicited in humans.
  • the currently available PCV’s like Prevenarl3 and Synflorix are prepared using conjugation chemistries without the use of any linker molecule.
  • conjugate vaccines such as Hib and Typhoid conjugates are prepared with Adipicdihydrazide (ADH) which is a six carbon linker molecule widely used.
  • ADH Adipicdihydrazide
  • Final conjugation is achieved by mixing the PS-ADH solution with CRM- 197 in MES buffer in the ratio of 2: 1 in the presence of N-(3-dimethylaminopropyl)-N-ethylcarbodiimide HC1 (EDC).
  • EDC N-(3-dimethylaminopropyl)-N-ethylcarbodiimide HC1
  • the conjugation reaction is continued under agitation, pH and temperature control.
  • the conjugate is purified by one or more of a variety of techniques known in the art.
  • the preferred purification methods are GPC column chromatography, diafiltration, sterile filtration.
  • the purified polysaccharide conjugates are then stored at less than l0°C, preferably below 4°C.
  • the PS/protein ratio of the final conjugate is fixed to be in the range of 0.5-2.5.
  • Preparation of conjugate can be carried out using any technique known in the art.
  • manufacturing of the immunogenic conjugates is described wherein the 15 different polysaccharides (serotype 1, 2, 3, 4, 5, 6A, 6B, 7F, 9V, 12F, 14, 18C, 19A, 19F and 23F) are covalently linked to the common carrier protein CRM-197.
  • the method comprises of the following steps:
  • PS polysaccharides
  • the de-sized individual polysaccharide is activated by reacting with l-Cyano-4- dimethylaminopyridinium tetrafluoroborate (CDAP), an organic cyanalating compound to introduce cyanyl ester on the polysaccharide.
  • Activation is carried out at a pH of 10-10.5, temperature 4 - 10 deg C and duration of 2 - 5 mins.
  • the purified conjugate is dia-filtered against normal saline with TWEEN-80, pH 5.8 - 6.5, sterile filtered using 0.2 micron capsule filter and stored at 2-8 deg C.
  • each vaccine dose serves as an amount that induces an immunoprotective response without significant, adverse effects. Such amount can vary depending upon the pneumococcal serotype. Generally, each dose will comprise 0.1 to 100 pg of each polysaccharide, particularly 0.1 to 10 pg, and more particularly 1 to 5 pg. Effective amounts of conjugates for a particular vaccine can be ascertained by standard studies involving observation of appropriate immune responses in subjects.
  • compositions of the invention can be administered to a subject by one or more methods such as orally, parenterally, transmucosally, transdermally, intramuscularly, intravenously, intra- dermally, intra-nasally, subcutaneously, intra-peritonealy etc.
  • administration of the compositions of the present invention can include one or more of: injection via the intramuscular, intraperitoneal, intradermal or subcutaneous, intranasal routes; or via mucosal administration to the oral/alimentary, respiratory or genitourinary tracts.
  • compositions of the present invention can be solid, semisolid or liquid compositions.
  • the compositions can be tablets, capsules, pills, granules, pellets, solutions, suspensions, dispersions, emulsions, oils and the like.
  • Pharmaceutically acceptable liquid formulations may contain as carrier aqueous or non-aqueous solutions, suspensions, emulsions or oils.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • compositions can also contain other ingredients, including but not limited to adjuvants, excipients, diluents, carriers, suspending agents, surfactants, chelating agents, salts, buffers, solvents, vehicles, peptides, amino acids, stabilizers, preservatives, antioxidants, isotonicity agents, thickening agents, emulsifying agents, wetting agents, non-viral vectors, and transfection facilitating compounds.
  • other ingredients including but not limited to adjuvants, excipients, diluents, carriers, suspending agents, surfactants, chelating agents, salts, buffers, solvents, vehicles, peptides, amino acids, stabilizers, preservatives, antioxidants, isotonicity agents, thickening agents, emulsifying agents, wetting agents, non-viral vectors, and transfection facilitating compounds.
  • Suitable vehicles include, but are not limited to, water, buffered saline, polyols (e.g., glycerol, propylene glycol, polyethylene glycol), dextrose solutions, sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils of animal, vegetable, or synthetic origin, (e.g., peanut oil, soybean oil, olive oil, sunflower oil, fish-liver oil, marine oil, lipid from milk or eggs), Polysorbate-80.
  • polyols e.g., glycerol, propylene glycol, polyethylene glycol
  • dextrose solutions sodium chloride solution
  • Ringer's dextrose, dextrose and sodium chloride lactated Ringer's and fixed oils of animal, vegetable, or synthetic origin, (e.g., peanut oil, soybean oil, olive oil, sunflower oil, fish-liver oil, marine oil, lipid from milk or eggs), Polysorbate-80.
  • the formulations of the invention also contain an adjuvant.
  • Adjuvants typically increase inflammation and activate the compliment cascade, possibly creating particulate multivalency, as well as allowing increased exposure of the antigen by lengthening its release into the injection site.
  • Adjuvants include synthetic emulsions (oil-in-water), alum (aluminum hydroxide gel or aluminum phosphate), lipid formulations, and cytokine-based adjuvants like type-one interferon.
  • the adjuvant is an aluminum salt.
  • the aluminum salt adjuvant may be an alum -precipitated vaccine or an alum -adsorbed vaccine.
  • Aluminum-salt adjuvants are well known in the art and are described, for example, in Harlow, E. and D. Lane (1988; Antibodies: A Laboratory Manual Cold Spring Harbor Laboratory) and Nicklas, W. (1992; Aluminum salts. Research in Immunology 143:489-493).
  • the aluminum salt includes, but is not limited to, hydrated alumina, alumina hydrate, alumina trihydrate (ATH), aluminum hydrate, aluminum trihydrate, alhydrogel, Superfos, Amphogel, aluminum (III) hydroxide, aluminum hydroxyphosphate sulfate (Aluminum Phosphate Adjuvant (APA)), amorphous alumina, trihydrated alumina, or trihydroxyaluminum.
  • the adjuvant is an aluminum-based adjuvant, such as aluminum phosphate, aluminum sulfate or aluminum hydroxide.
  • the adjuvant is aluminum phosphate.
  • the present invention can contain as adjuvant aluminum salt in an amount of 10 pg, 15 pg, 20 pg, 25 pg, 30 pg, 50 pg, 70 pg, 100 pg, 125 pg, 150 pg, 200 pg, 300 pg, 500 pg, or 700 pg, or 1, 1.2, 1.5, 2, 3, 5 mg or more and fractions thereof.
  • the formulations of the invention may also contain isotonicity agent.
  • the isotonicity agent may be ionic or a non-ionic.
  • the examples of isotonicity agents include but are not limited to NaCl, CaCl2, KC1 and MgCl2, mannitol, sorbitol and glycerol etc and mixtures thereof.
  • the formulations of the invention may also contain buffer.
  • the buffer used in the present invention may be selected from monobasic acids such as acetic, benzoic, gluconic, glyceric and lactic; dibasic acids such as aconitic, adipic, ascorbic, carbonic, glutamic, malic, succinic and tartaric, polybasic acids such as citric and phosphoric; and bases such as ammonia, diethanolamine, glycine, triethanolamine, and TRIS and mixtures thereof.
  • the formulations of the invention may also contain a surfactant.
  • Preferred surfactants include, but are not limited to: the polyoxyethylene sorbitan esters surfactants (commonly referred to as the Tweens), especially polysorbate 20 and polysorbate 80; copolymers of ethylene oxide (EO), propylene oxide (PO), and/or butylene oxide (BO), sold under the DOWLAXTM tradename, such as linear EO/PO block copolymers; octoxynols, which can vary in the number of repeating ethoxy (oxy-l,2-ethanediyl) groups, with octoxynol-9 (Triton X-100, or t- octylphenoxypolyethoxyethanol) being of particular interest; (octylphenoxy)polyethoxyethanol (IGEPAL CA-630/NP-40); phospholipids such as phosphatidylcholine (lecithin); nonylphenol e
  • the formulations of the invention may also contain a preservative.
  • Preservatives used in the present invention can be selected from those known in the art including but not limited to ethanol, phenols, benzoates, parabens, sorbates, thimerosal, ethyl mercury, benzyl alcohol, 2- phenoxyethanol, Sodium benzoate, methylparaben (MP), ethylparaben (EP), propylparaben (PP) and n-butylparaben (BP) and the like and mixtures thereof.
  • MP methylparaben
  • EP ethylparaben
  • PP propylparaben
  • BP n-butylparaben
  • the formulations of the invention may also contain a stabilizer to maintain effectiveness by keeping the antigen and other vaccine components stable during storage. Stabilizers also prevent the vaccine components adhering to the side of the vaccine vial.
  • stabilizers include sugars, amino acids or salts of amino acids, proteins, lactose and sucrose, glycine, monosodium glutamate, human or bovine serum albumin, gelatin and the like and mixtures thereof.
  • the formulations of the present invention are manufactured by methods known in the art. Manufacturing methods used in the art for parenteral, sterile, liquid, solution, suspension, emulsion dosage forms may be used for preparing the vaccine composition of the present invention.
  • the methods of the present invention can be used for the prevention and/or reduction of primary clinical syndromes caused by S. pneumoniae including both invasive infections (meningitis, pneumonia, and bacteremia), and noninvasive infections (acute otitis media, and sinusitis).
  • the present invention provides use of a pharmaceutical vaccine composition according to the present invention for use in the treatment or prevention of diseases or disorders caused due to Streptococcus Pneumonia including bacteremia, acute otitis media, pneumonia, invasive pneumococcal disease (IPD) such as meningitis and septicemia.
  • IPD invasive pneumococcal disease
  • compositions of the present invention are suitable for use with infants, toddlers, young children, older children, adolescents and adults and elderly patients.
  • a composition of the present invention can be administered as a single inoculation once, twice, three times or four times or more, adequately spaced apart at 1, 2, 3, 4, 5, or 6 month intervals or any combination thereof.
  • the present invention provides a process of making a vaccine composition
  • a vaccine composition comprising Individual serotype specific polysaccharide conjugates wherein each 0.5 ml of the vaccine composition contains 2.2 micro grams of individual serotype specific polysaccharides in the conjugated form except for serotype 6B which is at 4.4 micro grams; about 35-40 micro grams of CRM-197 as carrier protein; 0.5 mg of aluminum phosphate in gel-form; 4.5 mg sodium chloride and 0.1 mg Tween 80 as excipients and 5 mg of 2 -phenoxy ethanol as preservative.
  • the final pH of the bulk vaccine is adjusted to 6.8 ⁇ 0.4.
  • the vaccine is filled in Glass vials either as single dose (0.5 ml) or multi dose (2.5 ml).
  • the composition of the present invention is packed into a suitable container such as a glass container, bottle, vial, ampoule, prefilled syringe, prefilled injection or auto injector and other suitable packaging materials.
  • a suitable container such as a glass container, bottle, vial, ampoule, prefilled syringe, prefilled injection or auto injector and other suitable packaging materials.
  • the vaccine composition can be filled in suitable containers described above either as single dose (0.5 ml) or multi dose (1 ml, 1.5 ml, 2 ml, 2.5 ml, 3 ml, 3.5 ml, 4 ml, 4.5 ml, 5 ml and higher doses) containers.
  • the present invention provides use of a pharmaceutical vaccine composition according to the present invention for treatment or prevention of diseases or disorders caused due to Streptococcus Pneumonia including bacteremia, acute otitis media, pneumonia, invasive pneumococcal disease (IPD) such as meningitis and septicemia.
  • Streptococcus Pneumonia including bacteremia, acute otitis media, pneumonia, invasive pneumococcal disease (IPD) such as meningitis and septicemia.
  • IPD invasive pneumococcal disease
  • Stability studies were carried out to establish the quality of immunogenic vaccine composition with respect to time under the influence of a variety of environmental factors. Stability studies were performed to determine shelf-life, storage conditions and evaluate the potency of the vaccine during storage for up to 48 months as per the World Health Organization (WHO) guidelines (World Health Organization, WHO/BS/06.2049, Guidelines on Stability Evaluation of Vaccines, 2006.) Stability studies were carried out to determine various parameters including but not limited to visual description, response to specific antisera, pH, Saccharide content (in pg/ml), CRM- 197 Protein Content (in pg/ml), Sterility of the vaccine composition during and after exposure to real time conditions (2-8 degree centigrade), accelerated conditions (25 ⁇ 2 degree centigrade; 60 ⁇ 5% relative humidity) and stressed conditions (35 ⁇ 2 degree centigrade; 60 ⁇ 5% relative humidity).
  • WHO World Health Organization
  • Each 0.5 ml of the vaccine composition contains 2.2 micro grams of individual serotype specific polysaccharides except for serotype 6B which is at 4.4 micro grams; about 20 micro grams to 50 micro grams of CRM-197 as carrier protein; 0.01 to 10 mg of aluminum phosphate; 2 mg to 10 mg of sodium chloride and 0.01 mg to 1 mg of tween 80, 1 mg to 10 mg of 2-phenoxyethanol and water for injection.
  • the final pH of the bulk vaccine is adjusted to 6.8 ⁇ 0.4.
  • the vaccine is filled in Glass vials either as single dose (0.5 ml) or multi dose (2.5 ml).
  • Each 0.5 ml of the vaccine composition contains 2.2 micro grams of Pneumococcal polysaccharide for serotypes 1, 2, 3, 4, 5, 6A, 7F, 9V, 12F, 14, 18C, 19A, 19F& 23F and 4.4 micro grams for serotype 6B.
  • the Pneumococcal polysaccharides are conjugated to about 35 micro grams to 40 micro grams of CRM- 197 carrier protein with adipic acid linker and adsorbed on 0.125 mg of aluminium phosphate.
  • the Pneumococcal polysaccharides are formulated into a sterile parenteral composition by suitable filtration, sterilization and mixing with 4.5 mg of sodium chloride and 0.1 mg of tween 80, 5 mg of 2-phenoxyethanol and water for injection.
  • the final pH of the bulk vaccine is adjusted to 6.8 ⁇ 0.4.
  • the vaccine is filled in Glass vials either as single dose (0.5 ml) or multi dose (2.5 ml).
  • the vaccine composition was evaluated in Rabbits for its serotype specific IgG antibody response by EFISA and functional antibody assay by opsonophagocytosis assay (OPA). Rabbits were immunized with 0.5 ml of the vaccine composition by IM route on day 0, l5th day and 30th day. All animals were bled on the 60th day and sera separated and stored at -20°C. Then serotype specific geometric mean titer (GMT) for IgG levels (in pg/mL) of the various serotypes of Streptococcus Pneumoniae were measured by EFISA and results are given in figure 1. The serotype specific GMT values measured by EFISA were from about 40 pg/mF to about 130 pg/mF. The serotype specific GMT values measured by OPA were from about 20 to about 650 and results are given in figure 2.
  • GTT geometric mean titer
  • the serotype specific GMT values measured by EFISA were from about 40 pg/

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Abstract

La présente invention concerne une composition vaccinale immunogène multivalente ayant des conjugués polysaccharide-protéine distincts qui comprennent 15 types de polysaccharides capsulaires pneumococciques préparés à partir des cultures de sérotypes 1, 2, 3, 4, 5, 6A, 6B, 7F, 9V, 12F, 14, 18C, 19A, 19F, 23F de Streptococcus pneumoniae. La présente invention concerne une nouvelle composition vaccinale de conjugué polysaccharide pneumococcique 15-valent comprenant 15 conjugués polysaccharide-protéine distincts, un liant, une protéine porteuse, un adjuvant à base d'aluminium et des additifs, et son procédé de fabrication.
PCT/IB2019/053921 2018-05-14 2019-05-13 Vaccin conjugué de polysaccharide pneumococcique 15-valent WO2019220304A1 (fr)

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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
US11642406B2 (en) 2018-12-19 2023-05-09 Merck Sharp & Dohme Llc Compositions comprising Streptococcus pneumoniae polysaccharide-protein conjugates and methods of use thereof
US11951165B2 (en) 2016-12-30 2024-04-09 Vaxcyte, Inc. Conjugated vaccine carrier proteins
US11998599B2 (en) 2016-12-30 2024-06-04 Vaxcyte, Inc. Polypeptide-antigen conjugates with non-natural amino acids

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US11951165B2 (en) 2016-12-30 2024-04-09 Vaxcyte, Inc. Conjugated vaccine carrier proteins
US11998599B2 (en) 2016-12-30 2024-06-04 Vaxcyte, Inc. Polypeptide-antigen conjugates with non-natural amino acids
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
US12016914B2 (en) 2018-12-19 2024-06-25 Merck Sharp & Dohme Llc Compositions comprising Streptococcus pneumoniae polysaccharide-protein conjugates and methods of use thereof

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