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WO2020157772A1 - Compositions vaccinales à base de conjugués polysaccharide-protéine pneumococcique multivalentes - Google Patents

Compositions vaccinales à base de conjugués polysaccharide-protéine pneumococcique multivalentes Download PDF

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Publication number
WO2020157772A1
WO2020157772A1 PCT/IN2020/050093 IN2020050093W WO2020157772A1 WO 2020157772 A1 WO2020157772 A1 WO 2020157772A1 IN 2020050093 W IN2020050093 W IN 2020050093W WO 2020157772 A1 WO2020157772 A1 WO 2020157772A1
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Prior art keywords
polysaccharide
psaa
conjugated
crm197
vaccine composition
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PCT/IN2020/050093
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English (en)
Inventor
Rajendar Burki
Rajan Sriraman
Ramesh Venkat Matur
Narender Dev MANTENA
Mahima DATLA
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Biological E Limited
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Publication of WO2020157772A1 publication Critical patent/WO2020157772A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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
    • 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
    • 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
    • A61K2039/60—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
    • A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
    • A61K2039/6031—Proteins
    • A61K2039/6068—Other bacterial proteins, e.g. OMP
    • 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

Definitions

  • the present invention relates to multivalent pneumococcal polysaccharide-protein conjugates vaccine composition
  • vaccine composition comprising pneumococcal capsular polysaccharide of one or more Streptococcus pneumoniae serotypes conjugated to one or more carrier proteins.
  • Streptococcus pneumoniae (“pneumococcus”) is a gram-positive bacterium that causes invasive diseases, such as pneumonia, bacteremia and meningitis, and diseases associated with colonization, such as acute otitis media (e.g., colonization of middle ear). These pneumococcus- induced diseases result in morbidity and mortality, particularly in persons less than 24 months old and greater than 60 years old. The rate of pneumococcal pneumonia in the U.S. for persons over 60 years of age is estimated to be 3 to 8 per 100,000. In 20% of cases, pneumococcal pneumonia leads to bacteremia and meningitis collectively having a mortality rate close to 30% despite antibiotic treatment.
  • Pneumococcal vaccines may be administered to prevent infections.
  • Current vaccines include multivalent pneumococcal polysaccharide (comprises pneumococcal polysaccharides from two or more serotypes) and multivalent pneumococcal polysaccharide protein conjugates.
  • the protective efficacy of the pneumococcal polysaccharide vaccine is known to be related to the concentration of antibody generated against a capsular polysaccharide.
  • Pneumococcus cells are encapsulated with a polysaccharide giving rise to more than 90 different pneumococcus serotypes. The capsule is the principal virulence determinant for pneumococci, as it not only protects the cell’s inner surface from complement mediated cell lysis, it is also poorly immunogenic.
  • Pneumovax®23 is a multivalent pneumococcal polysaccharide vaccine and contains capsular polysaccharides from 23 pneumococcal serotypes including 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.
  • the multivalent pneumococcal polysaccharide vaccines that have been licensed so far proved valuable in preventing pneumococcal disease in adults, particularly, the elderly and those at high-risk. However, infants and young children respond poorly to these pneumococcal polysaccharide vaccines.
  • Prevnar®-7 is a pneumococcal polysaccharide-protein conjugate vaccine and includes the seven most frequently isolated pneumococcal polysaccharide serotypes (e.g., 4, 6B, 9V, 14, 18C, 19F, and 23F conjugated to CRM197). Since the use of Prevnar®-7 began in the United States in 2000, there has been a significant reduction in invasive pneumococcal disease (IPD) in children.
  • IPD invasive pneumococcal disease
  • Prevenar-13® containing thirteen serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F conjugated to CRMi97 , was developed and approved due to the limitations in serotype coverage with Prevnar®-7 in certain regions of the world.
  • Synflorix® is a pneumococcal vaccine that includes ten polysaccharide serotypes - wherein polysaccharide from serotypes 1, 4, 5, 6B, 7, 9V, 14, 23F are conjugated to protein D (PD), serotype 18C conjugated to tetanus toxoid (TT) and serotype 19F conjugated to diphtheria toxoid (DT).
  • PD protein D
  • TT tetanus toxoid
  • DT diphtheria toxoid
  • U.S. Patent No. 5,360,897 discloses an immunogenic conjugate composition comprising a reductive amination product of an intact capsular polymer of the bacterial pathogen Streptococcus pneumoniae having at least two carbonyl groups and a bacterial toxin or toxoid, said vaccine comprising a cross-linked conjugate in which there is a direct covalent linkage between the capsular polymer and the toxin or toxoid.
  • U.S. Patent No. 5,693,326 provides a generalized method for preparing a conjugate vaccine wherein for activating viral, fungal or bacterial polysaccharides, an organic cyanylating agent is used selected from the group l-cyano-4-(dimethylamino)-pyridinium tetrafluoroborate, N-cyanotriethyl-ammonium tetrafluoroborate, and p-nitrophenylcyanate, to form an activated carbohydrate and is subsequently coupled to the protein or carrier protein.
  • an organic cyanylating agent selected from the group l-cyano-4-(dimethylamino)-pyridinium tetrafluoroborate, N-cyanotriethyl-ammonium tetrafluoroborate, and p-nitrophenylcyanate
  • U.S. Patent No. 5,854,416 discloses amino acid and DNA sequences of 37-kDa protein from S. pneumonia known as PsaA (Pneumococcal surface adhesion A).
  • U.S. Patent No. 7,862,823 discloses a multivalent conjugate vaccine composition comprising pneumococcal capsular polysaccharides with at least two different carrier proteins, such as DT and TT.
  • U.S. Patent No. 8,192,746 discloses a 15-valent pneumococcal polysaccharide -protein conjugate vaccine composition having capsular polysaccharides from serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F conjugated to CRM197 .
  • U.S. Patent No. 8,808,708, and U.S. Patent No. 8,603,484 describes a 13-valent immunogenic composition consisting polysaccharide -protein conjugates wherein serotypes consist of 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F, and carrier protein CRM197.
  • U.S. Patent Publication No. 2010/0074922 A1 discloses an immunogenic composition containing 10 or more serotypes wherein 19F capsular saccharide is conjugated to DT, serotype 18C capsular saccharide is conjugated to tetanus toxoid and serotypes 1, 4, 5, 6B, 7F, 9V, 14 and 23F capsular saccharides are conjugated to Protein D isolated from Haemophilus influenzae.
  • U.S. Patent Publication No. 2010/0239604 describes an immunogenic composition comprising multivalent Streptococcus pneumoniae capsular saccharide conjugates from serotypes 19A and 19F wherein serotype 19A is conjugated to a first bacterial toxoid and 19F is conjugated to a second bacterial toxoid and 2-9 of the Streptococcus pneumoniae capsular saccharides are conjugated to protein D.
  • U.S. Patent Publication No. 2012/321658 A1 discloses an immunogenic composition wherein serotypes 1, 3, 19A and 19F linked to protein carrier(s) either directly or indirectly through a chemistry other than reductive amination, and one or more different saccharides is/are selected from a second group consisting of serotypes 4, 5, 6A, 6B, 7F, 9V, 14, 18C and 23F which is/are linked to a protein carrier(s) by reductive amination.
  • IN 140/DEL/2011 describes a Streptococcus pneumonia vaccine comprising either of (a) 7 or more (b) 10 or more polysaccharides from different serotypes conjugated to at least 2 or more carrier proteins selected from a group comprising DT, diphtheria toxoid, CRM197, and tetanus toxoid.
  • WO Publication No. 2013/191459 A1 discloses a conjugated 15 valent composition comprising different serotypes of Streptococcus pneumoniae derived from a capsular polysaccharide 1, 2, 3, 4, 5, 6A, 6B, 7F, 9N, 9V, 14, 18C, 19A, 19F and 23F conjugated to CRM197.
  • WO Publication No. 2014/092377 A1 discloses a 13 valent composition wherein 12 serotypes are selected from 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F and the last serotype is either 2 or 9N conjugated to CRM197.
  • WO Publication No. 2014/092378 A1 describes an immunogenic conjugate composition where 12 serotypes are selected from 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F and remaining one from 22F or 33F conjugated to CRM197.
  • WO Publication No. 2016/207905 A2 discloses a multivalent Pneumococcal conjugate vaccine (PCV) composition
  • PCV Pneumococcal conjugate vaccine
  • composition comprising: 1) at least 12 capsular polysaccharides selected from serotypes 1, 3, 4, 5, 6B, 7F, 9N, 9V, 15B, 14, 18C, 19A, 19F, 22F, 23F and 33F of Streptococcus pneumoniae activated with CDAP and conjugated to carrier protein CRM197, and 2) a pharmaceutically acceptable carrier, wherein the composition does not contain capsular polysaccharide from serotype 6A.
  • CN 101590224 describes a 14 valent pneumococcal polysaccharide-protein conjugate vaccine containing serotypes 1, 2, 4, 5, 6A, 6B, 7F, 9N, 9V, 14, 18C, 19A, 19F and 23F conjugated to CRM19 7 .
  • Cisokaku No. CN 103623401 discloses a 14 multivalent pneumococcal capsular polysaccharide-protein conjugate composition wherein said 14 different serotypes are 1, 3, 4, 5, 6A, 6B, 9V, 14, 18C, 19A, 19F, 22F, 23F and 33F conjugated to CRM197.
  • Cisokawa, CN 103656631 provides a multivalent pneumococcus capsular polysaccharide -protein conjugate composition is prepared from capsular polysaccharides of pneumococcus of 24 different serotypes and a carrier protein in a covalent linkage manner, wherein the 24 different serotypes are 1, 2, 3, 4, 5, 6A, 6B, 7F, 8, 9N, 9V, 10A, 11 A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F conjugated to CRM19 7 .
  • the 24 different serotypes are 1, 2, 3, 4, 5, 6A, 6B, 7F, 8, 9N, 9V, 10A, 11 A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F conjugated to CRM19 7 .
  • Cisokawa, CN 103656632 discloses a multivalent pneumococcal capsular polysaccharide composition containing serotype 6A and at least one extra serotype selected from the group consisting of 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F conjugated to CRM19 7 .
  • Cipheral Patent Application Publication No. CN 104069488 discloses a multivalent pneumococcus capsular polysaccharides of 14 different serotypes and carrier protein, wherein the 14 serotypes include 1, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F and 33F conjugated to CRM197.
  • Anderson P et al, (2003, Vaccine; 21 (13-14): 1554-9) discloses a comparative study of tetravalent conjugate vaccines with each polysaccharide types 6A, 14, 19F, and 23F separately coupled to tetanus toxoid or diphtheria CRM197 or a mixture of halved doses of polysaccharide types 6A, 14, 19F, and 23F separately coupled to tetanus toxoid and diphtheria CRM197.
  • Nurkka et al. discloses a study of the immunogenicity and safety of an 11-valent pneumococcal protein D conjugate vaccine where no priming effect was observed for serotype 3 in infants who had received three doses of the vaccine followed by a booster dose of either the same vaccine or a pneumococcal polysaccharide vaccine.
  • the multivalent pneumococcal conjugate vaccine compositions of the present invention offer an improved immune response over the naive multivalent pneumococcal vaccines and existing pneumococcal conjugate vaccines.
  • the present invention provides a 20 valent pneumococcal conjugate vaccine composition, comprising capsular polysaccharides from serotype of Streptococcus pneumoniae conjugated to a carrier protein, wherein the serotypes comprise 1, 3, 4, 5, 6A, 6B, 6C/6D, 7F, 9V, 11A, 12F, 14, 15A, 18C, 19A, 19F, 22F, 23A, 23F and 35B.
  • the present invention also provides a 20 valent pneumococcal conjugate vaccine composition, comprising capsular polysaccharide from serotype of Streptococcus pneumoniae conjugated to a carrier protein, wherein the serotypes comprise 1, 3, 4, 5, 6A, 6B, 6C/6D, 7F, 9V, 11A, 12F, 14, 15A, 18C, 19A, 19F, 22F, 23A, 23F and 35B wherein the carrier protein is selected from CRM197, PsaA, Tetanus toxoid, Diphtheria toxoid or combination of CRM197 and PsaA or combination of CRM197 and Tetanus toxoid or combination of CRM197 and Diphtheria toxoid or combination of PsaA and Tetanus toxoid or combination of PsaA and Diphtheria toxoid or combination of CRM197, PsaA and Tetanus toxoid or combination of CRM197, PsaA and Tetanus
  • the present invention provides a 20 valent pneumococcal conjugate vaccine composition, comprising capsular polysaccharides from serotype of Streptococcus pneumoniae conjugated to a carrier protein, wherein the serotypes comprise 1, 3, 4, 5, 6A, 6B, 6C/6D, 7F, 9V, 11A, 12F, 14, 15A, 18C, 19A, 19F, 22F, 23A, 23F and 35B wherein the carrier protein is CRM197.
  • the present invention provides a 20 valent pneumococcal conjugate vaccine composition, comprising capsular polysaccharides from serotype of Streptococcus pneumoniae conjugated to a carrier protein, wherein the serotypes comprise 1, 3, 4, 5, 6A, 6B, 6C/6D, 7F, 9V, 11A, 12F, 14, 15A, 18C, 19A, 19F, 22F, 23A, 23F and 35B wherein the carrier protein is PsaA.
  • the present invention provides a 20 valent pneumococcal conjugate vaccine composition, comprising capsular polysaccharides from serotype of Streptococcus pneumoniae conjugated to a carrier protein, wherein the serotypes comprise 1, 3, 4, 5, 6A, 6B, 6C/6D, 7F, 9V, 11A, 12F, 14, 15A, 18C, 19A, 19F, 22F, 23A, 23F and 35B wherein the carrier protein is CRM 197 and PsaA.
  • the present invention also provides a 20 valent pneumococcal conjugate vaccine composition, comprising capsular polysaccharides from serotype of Streptococcus pneumoniae conjugated to a carrier protein, wherein the serotypes comprise 1, 3, 4, 5, 6A, 6B, 6C/6D, 7F, 9V, 11A, 12F, 14, 15A, 18C, 19A, 19F, 22F, 23A, 23F and 35B wherein at least 13 polysaccharides are conjugated to first carrier protein, at least 3 polysaccharides are conjugated to second carrier protein, wherein the first and second carrier protein is CRM 197 and Tetanus toxoid.
  • a 20 valent pneumococcal conjugate vaccine composition comprising capsular polysaccharides from serotype of Streptococcus pneumoniae conjugated to a carrier protein, wherein the serotypes comprise 1, 3, 4, 5, 6A, 6B, 6C/6D, 7F, 9V, 11A, 12F, 14, 15A, 18
  • the present invention also provides a 20 valent pneumococcal conjugate vaccine composition, comprising capsular polysaccharides from serotype of Streptococcus pneumoniae conjugated to a carrier protein, wherein the serotypes comprise 1, 3, 4, 5, 6A, 6B, 6C/6D, 7F, 9V, 11A, 12F, 14, 15A, 18C, 19A, 19F, 22F, 23A, 23F and 35B wherein at least 13 polysaccharides and carrier protein is Tetanus toxoid.
  • the present invention also provides a 20 valent pneumococcal conjugate vaccine composition, comprising capsular polysaccharides from serotype of Streptococcus pneumoniae conjugated to a carrier protein, wherein the serotypes comprise 1, 3, 4, 5, 6A, 6B, 6C/6D, 7F, 9V, 11A, 12F, 14, 15A, 18C, 19A, 19F, 22F, 23A, 23F and 35B wherein at least 13 polysaccharides are conjugated to first carrier protein, at least 3 polysaccharides are conjugated to second carrier protein and at least one polysaccharide is conjugated to third carrier protein, wherein the first, second and third carrier protein is CRM 197 , PsaA and Tetanus toxoid.
  • the serotypes comprise 1, 3, 4, 5, 6A, 6B, 6C/6D, 7F, 9V, 11A, 12F, 14, 15A, 18C, 19A, 19F, 22F, 23A, 23F and 35B wherein at least
  • Figure 1 SEC-HPLC chromatogram illustrating conjugation reaction kinetics of (a) serotype 3 and (b) serotype 6B with PsaA.
  • Figure 2 SEC-HPLC chromatogram illustrating conjugation reaction kinetics of (a) serotype 6A-CRM 197 and (b) serotype 6A with PsaA.
  • Figure 3 SEC-HPLC chromatogram illustrating conjugation reaction kinetics of (a) serotype 6C-CRM 197 and (b) serotype 6C-PsaA.
  • Figure 4 SEC-HPLC chromatogram illustrating conjugation reaction kinetics of (a) serotype I IA-CRM 197 and (b) serotype HA-PsaA.
  • Figure 5 SEC-HPLC chromatogram illustrating conjugation reaction kinetics of (a) serotype I2F-CRM 197 and (b) serotype 12F-PsaA.
  • Figure 6 SEC-HPLC chromatogram illustrating conjugation reaction kinetics of (a) serotype 15A-CRMi 97 and (b) serotype 15A-PsaA.
  • Figure 7 SEC-HPLC chromatogram illustrating conjugation reaction kinetics of (a) serotype 22F-CRMi 97 and (b) serotype 22F-PsaA.
  • Figure 8 SEC-HPLC chromatogram illustrating conjugation reaction kinetics of (a) serotype 23A-CRMi 97 and (b) serotype 23A-PsaA.
  • Figure 9 SEC-HPLC chromatogram illustrating conjugation reaction kinetics of (a) serotype 35B-CRMi 97 and (b) serotype 35B-PsaA.
  • Figure 10 IgG titer values of vaccinated animals at the pre-immunization stage and after immunization with Formulation of Example 2.
  • references herein to "one embodiment,” “an embodiment,” or similar formulations means that a particular feature of a composition, a composition, a method, or a characteristic described in connection with the embodiment may be included in at least one embodiment of the present technology. Thus, the appearances of such phrases or formulations herein are not necessarily all referring to the same embodiment. Furthermore, various particular features, compositions, methods, or characteristics may be combined in any suitable manner in one or more embodiments.
  • capsulear polysaccharide refers to a layer of polysaccharide external to but contiguous with the cell wall of Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 6C or 6D, 7F, 9V, 11A, 12F, 14, 15A, 18C, 19A, 19F, 22F, 23A, 23F and 35B.
  • the terms“immunogenic composition” and“vaccine composition” are used interchangeably.
  • carrier protein refers to any protein to which the peptide is coupled or attached or conjugated, typically for the purpose of enhancing or facilitating the detection of the antigen by the immune system.
  • carrier proteins include, but are not limited to CRM197, PsaA, Diphtheria toxoid and Tetanus toxoid.
  • conjugate or“conjugated” as used herein is used to mean that a Streptococcus pneumoniae capsular polysaccharide is covalently bonded to a carrier protein.
  • adjuvant refers to the non-antigenic component of the vaccine that enhances the immune response of the antigens of the vaccine by facilitating the contact between the antigen and the immune system by influencing the type and the quality of the immune response generated against an antigen.
  • the adjuvant causes prolonged immune responses against the antigens and also may serve to decrease toxicity of certain antigens or provide solubility to certain antigens.
  • the term“pharmaceutically acceptable carrier(s)” refers to one or more optional components which may be added to the vaccine formulation for administration of the antigens and/or viruses which does not itself induce the production of antibodies harmful to the individual receiving the composition, and which may be administered without undue toxicity.
  • Suitable carriers may be large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, and inactive virus particles.
  • the term includes one or more excipient, stabilizer, diluents, buffers or surfactants, lyophilization excipient or a combination thereof.
  • pharmaceutically acceptable or pharmacologically acceptable is meant a material which is not biologically or otherwise undesirable, i.e., the material may be administered to an individual in a formulation or composition without causing any undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • the present invention provides a 20-valent pneumococcal conjugate vaccine composition
  • the present invention provides a pneumococcal conjugate vaccine composition comprising pneumococcal polysaccharides where one or more of the pneumococcal polysaccharides are native pneumococcal polysaccharides.
  • the present invention provides a pneumococcal conjugate vaccine composition
  • a pneumococcal conjugate vaccine composition comprising pneumococcal polysaccharides where one or more of the pneumococcal polysaccharides are fragmented, each fragmented pneumococcal polysaccharide having an average molecular weight less than that of a native pneumococcal polysaccharide.
  • the present invention provides a pneumococcal conjugate vaccine composition
  • a pneumococcal conjugate vaccine composition comprising pneumococcal polysaccharides where one or more of the pneumococcal polysaccharides are directly coupled to an amino group of the carrier protein or are coupled to the amino group by a spacer wherein the spacer is selected from the group consisting of cystamine, cysteamine, hexane diamine, adipic acid dihydrazide (ADH), ED AC or EDC and the like.
  • ADH adipic acid dihydrazide
  • CRM 197 is a variant of diphtheria toxin and is by itself non-toxic (i.e., toxoid).
  • CRM197 is isolated from cultures of Corynebacterium diphtheriae strain C7 (b 197) grown in casamino acids and yeast extract-based medium.
  • CRM197 may be prepared recombinantly in accordance with the methods described in U.S. Pat. No. 5,614,382.
  • CRM197 is prepared recombinantly in accordance with the methods known in the literature or may be performed according to the procedure described in PCT publications WO 2016/079755.
  • CRM197 may be purified by ultrafiltration, ammonium sulphate precipitation, and ion-exchange chromatography, methods well known in the art.
  • the present invention provides a pneumococcal conjugate vaccine composition
  • a pneumococcal conjugate vaccine composition comprising one or more pneumococcal polysaccharides of serotypes conjugated to PsaA a carrier protein wherein the PsaA carrier protein is a modified PsaA and does not include wild-type hydrophobic N-terminal leader peptide and includes 290 amino acids.
  • Carrier proteins are non-toxic and non-reactogenic proteins that are obtainable in a sufficient amount and purity.
  • the present invention provides a pneumococcal conjugate vaccine composition comprising one or more carrier proteins conjugated to one or more Streptococcus pneumoniae polysaccharides (also referred to herein as“pneumococcal polysaccharides”).
  • Streptococcus pneumoniae polysaccharides also referred to herein as“pneumococcal polysaccharides”.
  • pneumococcal conjugate vaccine composition comprising pneumococcal capsular polysaccharide serotypes each individually conjugated to a carrier protein, referred to herein as polysaccharide-protein conjugates and/or conjugates.
  • pneumococcal vaccine is a multivalent pneumococcal polysaccharide-protein conjugate vaccine (also referred to herein as multivalent conjugate vaccine, conjugate vaccine, and/or polysaccharide-protein conjugate vaccine).
  • the present invention provides a process for preparing and/or administering the same to a subject in need thereof.
  • the pneumococcal conjugate vaccine composition is a 20 valent immunogenic composition comprising capsular polysaccharide from serotype of Streptococcus pneumoniae conjugated to a carrier protein, wherein the serotypes comprise 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F, 6C/6D, 11 A, 12F, 15A, 22F, 23A, and 35B wherein the carrier protein is CRM197, PsaA, Tetanus toxoid, Diphtheria toxoid or combination of CRM197, PsaA or CRM197, PsaA and Tetanus toxoid.
  • the carrier protein is CRM197, PsaA, Tetanus toxoid, Diphtheria toxoid or combination of CRM197, PsaA or CRM197, PsaA and Tetanus toxoid.
  • a combination of the carrier protein used which includes two or more carrier proteins, such as PsaA, CRM197, Diphtheria toxoid and tetanus toxoid (TT).
  • carrier protein such as PsaA, CRM197, Diphtheria toxoid and tetanus toxoid (TT).
  • some polysaccharides are conjugated to CRM197 as carrier protein and some polysaccharides are conjugated to PsaA or TT and the like.
  • the present invention provides a pneumococcal polysaccharide- protein conjugate vaccine composition
  • a pneumococcal polysaccharide- protein conjugate vaccine composition comprising pneumococcal polysaccharides selected from serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F, 6C/6D, 11A, 12F, 15A, 22F, 23A, and 35B.
  • the selected pneumococcal polysaccharides are each conjugated individually to carrier protein CRM197.
  • the present invention provides a pneumococcal polysaccharide- protein conjugate vaccine composition
  • a pneumococcal polysaccharide- protein conjugate vaccine composition comprising pneumococcal polysaccharides selected from serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F, 6C/6D, 11A, 12F, 15A, 22F, 23A, and 35B.
  • the selected pneumococcal polysaccharides are each individually conjugated to carrier protein wherein a first portion of the selected pneumococcal polysaccharides are conjugated to CRM197 and a second portion of the selected pneumococcal polysaccharides are conjugated to PsaA.
  • the present invention provides a 20 valent pneumococcal conjugate vaccine composition, the composition comprising capsular polysaccharides from serotype of Streptococcus pneumoniae conjugated to a carrier protein, wherein the serotypes comprise 1, 3, 4, 5, 6A, 6B, 6C/6D, 7F, 9V, 11A, 12F, 14, 15A, 18C, 19A, 19F, 22F, 23A, 23F and 35B wherein at least 13 polysaccharides are conjugated to first carrier protein, at least 3 polysaccharides are conjugated to second carrier protein and at least one polysaccharide is conjugated to third carrier protein, wherein the first, second and third carrier protein is CRM197, PsaA and Tetanus toxoid respectively.
  • the present invention provides a pneumococcal polysaccharide- protein conjugate vaccine composition
  • a pneumococcal polysaccharide- protein conjugate vaccine composition comprising pneumococcal polysaccharides selected from serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F, 6C/6D, 11A, 12F, 15A, 22F, 23A, and 35B.
  • the selected pneumococcal polysaccharides are each individually conjugated to carrier protein wherein at least 3 polysaccharides are conjugated to TT, a portion of the selected pneumococcal polysaccharides are conjugated to CRM197 and another portion of the selected pneumococcal polysaccharides are conjugated to PsaA.
  • the present invention provides a pneumococcal polysaccharide- protein conjugate vaccine composition
  • the composition is a 20 valent vaccine composition comprising capsular polysaccharide from Streptococcus pneumonia serotypes 1, 4, 5, 6B, 6C or 6D, 7F, 9V, 11A, 12F, 14, 18C, 19A and 19F conjugated to CRM197 and capsular polysaccharide from Streptococcus pneumonia serotypes 3, 6A, 15A, 22F, 23A, 23F and 35B conjugated to PsaA.
  • the present invention also provides a 20 valent pneumococcal conjugate vaccine composition, comprising capsular polysaccharides from serotype of Streptococcus pneumoniae conjugated to a carrier protein, wherein the serotypes comprise 1,
  • the present invention provides a pneumococcal polysaccharide- protein conjugate vaccine composition, wherein the composition is a 20 valent vaccine composition comprising capsular polysaccharide from Streptococcus pneumoniae serotypes 1,
  • the pneumococcal polysaccharides useful in the compositions of the present invention may be extracted from one or more microorganisms (e.g. Streptococcus pneumoniae ) according to conventional methods.
  • pneumococcal polysaccharides may be prepared according to known procedures.
  • purification of the pneumococcal polysaccharides may be performed according to the procedure described in PCT publication WO 2016/174683 Al.
  • the extracted pneumococcal polysaccharides may be purified according to conventional methods and may be used in its native form.
  • the extracted and purified pneumococcal polysaccharides may be fragmented to obtain one or more portions of the pneumococcal polysaccharide, each portion of the pneumococcal polysaccharide having an average molecular weight less than that of the extracted and purified pneumococcal polysaccharides.
  • the present invention provides a pneumococcal conjugate vaccine composition comprising pneumococcal polysaccharides, each pneumococcal polysaccharide having an average molecular weight in between about 150 kDa and 2000 kDa.
  • the present invention provides a pneumococcal conjugate vaccine composition
  • a pneumococcal conjugate vaccine composition comprising one or more pneumococcal capsular polysaccharide serotypes each individually conjugated to a carrier protein, such as a polysaccharide-protein conjugate wherein each polysaccharide-protein conjugate has a molecular weight of about 1,500 kDa to about 15,000 kDa.
  • the extracted and purified pneumococcal polysaccharides may be activated prior to conjugation to one or more carrier proteins.
  • the extracted and purified pneumococcal polysaccharides may be activated (e.g., chemically) prior to conjugation to one or more carrier proteins.
  • one or more of the activated pneumococcal polysaccharides may be conjugated to an individual carrier protein.
  • the conjugates may be prepared by known techniques.
  • the pneumococcal polysaccharides may be chemically activated and subsequently conjugated to carrier proteins according to known techniques, such as those described in U.S. Pat. Nos. 4,365,170, 4,673,574 and 4,902,506.
  • pneumococcal polysaccharides can be activated by oxidation of a terminal hydroxyl group to an aldehyde with an oxidizing agent, such as periodate (e.g., sodium periodate, potassium periodate, or periodic acid) by random oxidative cleavage of one or more vicinal hydroxyl groups of the carbohydrates and formation of one or more reactive aldehyde groups.
  • an oxidizing agent such as periodate (e.g., sodium periodate, potassium periodate, or periodic acid)
  • the pneumococcal polysaccharides may also be activated by CDAP (l-cyano-4- dimethylamino-pyridinium tetrafluoroborate) and subsequently conjugated to one or more carrier proteins such as PsaA, CRM197 or combination thereof.
  • CDAP l-cyano-4- dimethylamino-pyridinium tetrafluoroborate
  • pneumococcal polysaccharides activated with CDAP to form a cyanate ester may be directly conjugated to one or more carrier proteins or conjugated using a spacer (e.g., linker).
  • the spacer may couple to an amino group on the carrier protein.
  • the spacer may be cystamine or cysteamine, which generates a thiolated polysaccharide that may be coupled to the carrier protein through a thioether linkage to a maleimide-activated carrier protein (e.g., using GMBS) or a haloacetylated carrier protein (e.g., using iodoacetimide, ethyl iodoacetimide HC1, SIAB, SIA, SBAP, and/or N-succinimidyl bromoacetate.
  • a maleimide-activated carrier protein e.g., using GMBS
  • a haloacetylated carrier protein e.g., using iodoacetimide, ethyl iodoacetimide HC1, SIAB, SIA, SBAP, and/or N-succinimidyl bromoacetate.
  • the cyanate ester is coupled using hexane diamine or adipic acid dihydrazide (ADH) and an amino- derivitized saccharide is conjugated to a carrier protein using carbodiimide (e.g. ED AC or EDC) chemistry via a carboxyl group on the protein carrier.
  • ADH hexane diamine or adipic acid dihydrazide
  • carbodiimide e.g. ED AC or EDC
  • Such conjugates are described in PCT Publication No. WO 93/15760, PCT Publication No. WO 95/08348, PCT Publication No. WO 96/29094, and Chu et al., 1983, Infect. Immunity 40:245-256.
  • Suitable activation and/or coupling techniques for use with the polysaccharide- protein conjugates and vaccine compositions of the present invention include use of carbodiimides, hydrazides, active esters, norborane, p-nitrobenzoic acid, N- hydroxysuccinimide, S— NHS, EDC, TSTU, and other methods described in PCT Publication No. WO 98/42721.
  • conjugation may involve a carbonyl linker which may be formed by reaction of a free hydroxyl group of the saccharide with CDI (See Bethell et al., 1979, J. Biol. Chem. 254:2572-4; Hearn et al., 1981, J. Chromatogr.
  • the anomeric terminus may be reduced to a primary hydroxyl group, optional protection/deprotection of the primary hydroxyl group, reaction of the primary hydroxyl group with CDI to form a CDI carbamate intermediate and coupling the CDI carbamate intermediate with an amino group on a protein.
  • sized pneumococcal polysaccharides e.g., about 6 mL of sized polysaccharide at a concentration of about 10 mg/mL
  • CDAP e.g., about 100 mg/mL in acetonitrile (w/v)
  • the pH of the polysaccharide solution may be adjusted as necessary (e.g., to about 9.25 with about 0.2M triethylamine and stirred for 3 minutes at room temperature).
  • PsaA e.g., about 4 mL of a solution having a concentration of about 15 mg/mL
  • PsaA may be added slowly to the activated pneumococcal polysaccharides (e.g., in a ratio of about 1 to about 1 (Ps: Carrier protein)).
  • the pH of the reaction may be adjusted (e.g., to about 9.05 using 0.2M trimethylamine) and the reaction may be continued (e.g., by stirring for 5 hours at room temperature).
  • the reaction mixture may be quenched (e.g., by addition of an excess concentration of glycine).
  • the reaction mixture may be diafiltered using a membrane (e.g., a 100 K MWCO membrane) and may be purified by size-exclusion chromatography.
  • the diafiltered and purified fractions may be analyzed using SEC-MALLS, and an anthrone method.
  • the analyzed fractions containing conjugates may be pooled and sterile filtered (e.g., using 0.2 pm filters).
  • the polysaccharide-protein conjugates may be purified (e.g., enriched with respect to the amount of polysaccharide -protein conjugate) by a variety of techniques.
  • conjugates may be compounded to formulate the pneumococcal polysaccharide-protein conjugate compositions of the present invention, which may be used as vaccines.
  • the pneumococcal polysaccharide -protein conjugate compositions of the present invention further comprise one or more of the following: a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent, a buffer, a preservative, a stabilizer, an adjuvant, and/or a lyophilization excipient.
  • a pharmaceutically acceptable carrier for example, a pharmaceutically acceptable diluent, a buffer, a preservative, a stabilizer, an adjuvant, and/or a lyophilization excipient.
  • the pneumococcal polysaccharide-protein conjugate compositions of the present invention may comprise a pharmaceutically acceptable carrier.
  • the present invention provides a method for preparing a polysaccharide-protein conjugate of the pneumococcal vaccine composition described herein wherein the method further comprises formulating the polysaccharide-protein conjugate into the pneumococcal vaccine composition including an adjuvant, an excipient, and a buffer.
  • the present invention provides a method for preparing a polysaccharide-protein conjugate of the pneumococcal vaccine composition described herein wherein the adjuvant is aluminum phosphate.
  • the present invention provides a method of treating a subject in need thereof comprising, administering a pneumococcal vaccine composition described herein to the subject in need thereof.
  • the subject has a disease mediated by Streptococcus pneumoniae, such as invasive pneumococcal disease (IPD).
  • IPD invasive pneumococcal disease
  • the subject is a human, such as an infant (less than about 1 year of age), a toddler (about 12 months to about 24 months of age), a young child (about 2 years to about 5 years of age), an older child (about 5 years to about 13 years of age), an adolescent (about 13 years to about 18 years of age), an adult (about 18 years to about 65 years of age), or an elder (more than about 65 years of age).
  • the present disclosure provides a method of inducing an immune response to a Streptococcus pneumoniae capsular polysaccharide conjugate comprising administering an immunologically effective amount of the pneumococcal conjugate vaccine composition described herein to a subject.
  • method of inducing an immune response to a Streptococcus pneumoniae capsular polysaccharide conjugate comprising administering the pneumococcal conjugate vaccine composition described herein to the subject systemically, subcutaneously, and/or mucousally.
  • an amount of each conjugate in a dose of the vaccine compositions of the present invention is an amount sufficient to induce an immunoprotective response, such as an immunoprotective response without significant, adverse effects. While the amount of each conjugate may vary depending upon the pneumococcal serotype, each dose of the vaccine compositions may comprise about 0.1 pg to about 50 pg of each pneumococcal polysaccharide, about 0.1 pg to about 10 pg, or about 1 pg to about 5 pg of each pneumococcal polysaccharide conjugated to each carrier protein comprising about 1.5 pg to about 5 pg of carrier protein.
  • the present invention provides a pneumococcal conjugate vaccine composition
  • a pneumococcal conjugate vaccine composition comprising pneumococcal polysaccharides and carrier proteins, the pneumococcal conjugate vaccine composition having a percent ratio of protein to polysaccharide (protein/PS) of about 0.3 to about 2.0 protein/PS, preferably, 0.5 to 1.5.
  • the purified polysaccharides before conjugation have a molecular weight of between 10 kDa and 2,000 kDa. In other such embodiments, the polysaccharide has a molecular weight of between 50 kDa and 2,000 kDa.
  • the present invention provides pneumococcal polysaccharide- protein conjugate vaccine compositions comprising one or more polysaccharide-protein conjugates having a molecular weight ranging between about 1,000 kDa to about 10,000 kDa, about 1,500 kDa to about 15,000 kDa, about 2,000 kDa to about 20,000 kDa, about 2,500 kDa to about 25,000 kDa, or about 3,000 kDa to about 30,000 kDa.
  • the present invention provides a 20 valent pneumococcal conjugate vaccine composition
  • a 20 valent pneumococcal conjugate vaccine composition comprising capsular polysaccharides from serotype of Streptococcus pneumoniae conjugated to a carrier protein, wherein the serotypes comprise 1, 3, 4, 5, 6A, 6B, 6C/6D, 7F, 9V, 11A, 12F, 14, 15A, 18C, 19A, 19F, 22F, 23A, 23F and 35B and the carrier protein is CRM197, PsaA and Tetanus toxoid, wherein each polysaccharide conjugate having a molecular weight ranging between about 1,000 kDa to about 30,000 kDa and the ratio of protein to polysaccharide (protein/PS) of about 0.3 to about 2.0 protein/PS, preferably, 0.5 to 1.5.
  • the present invention provides a 20 valent pneumococcal conjugate vaccine composition
  • a 20 valent pneumococcal conjugate vaccine composition comprising capsular polysaccharides from serotype of Streptococcus pneumoniae conjugated to a carrier protein, wherein the serotypes comprise 1, 3, 4, 5, 6A, 6B, 6C/6D, 7F, 9V, 11A, 12F, 14, 15A, 18C, 19A, 19F, 22F, 23A, 23F and 35B and the carrier protein is CRM197, PsaA and Tetanus toxoid, wherein each polysaccharide conjugate having a molecular weight ranging between about 1,000 kDa to about 15,000 kDa and the ratio of protein to polysaccharide (protein/PS) of 0.5 to 1.5.
  • the present invention provides a 20 valent pneumococcal conjugate vaccine composition
  • a 20 valent pneumococcal conjugate vaccine composition comprising capsular polysaccharides from serotype of Streptococcus pneumoniae conjugated to a carrier protein, wherein the serotypes comprise 1, 3, 4, 5, 6A, 6B, 6C/6D, 7F, 9V, 11A, 12F, 14, 15A, 18C, 19A, 19F, 22F, 23A, 23F and 35B and the carrier protein is a combination of CRM197 and PsaA, wherein each polysaccharide conjugate having a molecular weight ranging between about 1,000 kDa to about 15,000 kDa and the ratio of protein to polysaccharide (protein/PS) of 0.5 to 1.5.
  • the pneumococcal polysaccharide-protein conjugate vaccine compositions of the present invention may be manufactured using known methods.
  • the pneumococcal polysaccharide-protein conjugate vaccine compositions may be formulated with a pharmaceutically acceptable diluent or vehicle, e.g. water or a saline solution.
  • the pneumococcal polysaccharide-protein conjugate vaccine compositions may further include one or more of the following: a buffer, a preservative or a stabilizer, polysorbate, an adjuvant such as an aluminum compound, e.g. an aluminium hydroxide, an aluminium phosphate or an aluminium hydroxyphosphate, and/or a lyophilization excipient.
  • any one of the above compounds in the pneumococcal polysaccharide-protein conjugate vaccine compositions of the present invention may be selected as a function of the mode and route of administration to a subject in need thereof and may further be based on standard pharmaceutical practices.
  • the present invention provides a method for preparing a 20 valent pneumococcal polysaccharide -protein conjugate composition
  • a 20 valent pneumococcal polysaccharide -protein conjugate composition comprising pneumococcal polysaccharides selected from serotypes 1, 3, 4, 5, 6A, 6B, 6C/6D, 7F, 9V, 11A, 12F, 14, 15A, 18C, 19A, 19F, 22F, 23A, 23F, and 35B wherein the carrier protein is CRM197.
  • the method for preparing the 20 valent pneumococcal polysaccharide -protein conjugate composition comprises the steps of;
  • the present invention provides a method for preparing a twenty valent pneumococcal polysaccharide -protein conjugate composition
  • a twenty valent pneumococcal polysaccharide -protein conjugate composition comprising pneumococcal polysaccharides selected from serotypes 1, 3, 4, 5, 6A, 6B, 6C, 7L, 9V, 11A, 12L, 14, 15A, 18C, 19 A, 19L, 22L, 23A, 23L and 35B wherein serotypes 3, 6A, 6B, 6C, 11A, 12L, 15A, 23A, 22L and 35B are conjugated to PsaA and serotypes 1, 4, 5, 7L, 9V, 14, 18C, 19A, 19L, 23L, are conjugated to CRM19 7 .
  • the method for preparing the twenty valent pneumococcal polysaccharide-protein conjugate composition comprises the steps of:
  • the invention provides a 20-valent vaccine composition, wherein the composition is a 20 valent pneumococcal polysaccharide-protein conjugate composition comprising pneumococcal polysaccharides selected from serotypes 1, 3, 4, 5, 6A, 6B, 6C, 7L, 9V, 11 A, 12F, 14, 15A, 18C, 19A, 19F, 22F, 23 A, 23F and 35B, wherein serotypes 1, 4, 5, 6B, 6C or 6D, 7F, 9V, 14, 18C, 22F, 19A, 19F and 23F are conjugated to CRM197 and capsular polysaccharide from Streptococcus pneumonia serotypes 3, 6A, 11A, 12F, 15A, 23A and 35B are conjugated to PsaA.
  • the composition is a 20 valent pneumococcal polysaccharide-protein conjugate composition comprising pneumococcal polysaccharides selected from serotypes 1, 3, 4, 5, 6A, 6B, 6
  • the invention provides a 20-valent vaccine composition, wherein the composition is a 20 valent pneumococcal polysaccharide-protein conjugate composition comprising pneumococcal polysaccharides selected from serotypes 1, 3, 4, 5, 6A, 6B, 6C, 7F, 9V, 11 A, 12F, 14, 15A, 18C, 19A, 19F, 22F, 23A, 23F and 35B, wherein serotypes 1, 4, 5, 7F, 9V, 14, 18C, 19A, 19F and 23F are conjugated to CRM197 and capsular polysaccharide from Streptococcus pneumonia serotypes 3, 6A, 6B, 6C or 6D, 11A, 12F, 15A, 22F, 23A and 35B conjugated to PsaA.
  • the composition is a 20 valent pneumococcal polysaccharide-protein conjugate composition comprising pneumococcal polysaccharides selected from serotypes 1, 3, 4, 5, 6A, 6B, 6C
  • the present invention provides a method for preparing a twenty valent pneumococcal polysaccharide -protein conjugate composition
  • a twenty valent pneumococcal polysaccharide -protein conjugate composition comprising pneumococcal polysaccharides selected from serotypes 1, 3, 4, 5, 6A, 6B, 6C, 7F, 9V, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F, 33F, 35B and 45 wherein at least serotypes 3, 6A, 6B, 6C, 11A, 12F, 15A, 22F, 23A and 35B wherein the carrier protein is PsaA.
  • the method for preparing the twenty valent pneumococcal polysaccharide-protein conjugate composition comprises the steps of;
  • compositions of the present invention may be formulated into a unit dose vial, multiple-dose vial, or a pre-filled syringe.
  • the compositions of the present invention may further comprise one or more preservative(s) selected from thiomersal, 2-phenoxyethanol, m-cresol, benzyl alcohol, benzoic acid and the like or mixture thereof, in an amount which may range from about 2 to 14 mg/mL.
  • the present invention also provides an immunogenic composition (e.g., a vaccine), such as a pneumococcal polysaccharide-protein conjugate composition, administered as a single dose of about 0.5 mL formulated to contain at least the following: about 2.2 to 4.4 pg of each pneumococcal polysaccharide serotypes, about 1 pg to about 10 pg of PsaA per serotype, about 2 pg to about 5 pg of CRM197 for each serotype, about 0.2 mg to about 1 mg of an adjuvant (e.g., aluminum phosphate), and one or more excipients (e.g., sodium chloride, and/or a buffer).
  • an adjuvant e.g., aluminum phosphate
  • excipients e.g., sodium chloride, and/or a buffer.
  • compositions of the present invention may be administered to a subject in need thereof by any number of conventional routes used in the field of vaccines.
  • compositions of the present invention may be administered systemically, such as parenterally (e.g. subcutaneously, intramuscularly, intradermally and/or intravenously) or mucosally (e.g., orally and/or nasally).
  • the present invention also provides methods of inducing an immune response in a subject in need thereof to one or more Streptococcus pneumoniae capsular polysaccharides conjugated to one or more carrier proteins.
  • the methods for inducing the immune response comprising administering an immunologically effective amount of the compositions described herein to the subject in need thereof.
  • an "effective amount" of the compositions described in the present disclosure refers to an amount required to elicit an immune response in the subject to which the composition was administered.
  • the immune response is characterized by the presence of one or more Streptococcus pneumoniae antigen- specific antibodies in the host that significantly reduce the likelihood or severity of infection of Streptococcus pneumoniae during a subsequent challenge.
  • Polysaccharide CRM197 conjugates for pneumococcal serotypes 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F were prepared as per the procedure described in PCT publication No. WO 2016/207905.
  • Polysaccharide CRM197 conjugates for pneumococcal serotypes 6A, 6C, 11A, 12F, 15A, 22F, 23A and 35B were prepared as per the procedure mentioned below:
  • reaction mixture was diafiltered and concentrated using 100 kDa MWCO TFF membrane. Concentrate was purified by size-exclusion chromatography. The fractions were analyzed by SEC-MALLS, anthrone method and fractions containing conjugates were pooled and sterile filtered with 0.2 pm filters.
  • CRM 197 protein using CDAP chemistry
  • reaction mixture was diafiltered and concentrated using 100 kDa MWCO TFF membrane. Concentrate was purified by size-exclusion chromatography. The fractions were analyzed by SEC-MALLS, anthrone method and fractions containing conjugates were pooled and sterile filtered with 0.2 pm filters.
  • CRM 197 protein using CDAP chemistry
  • reaction mixture was diafiltered and concentrated using 100 kDa MWCO TFF membrane. Concentrate was purified by size-exclusion chromatography. The fractions were analyzed by SEC-MALLS, anthrone method and fractions containing conjugates were pooled and sterile filtered with 0.2 pm filters.
  • CRM 197 protein using CDAP chemistry
  • the reaction mixture was diafiltered and concentrated using 100 kDa MWCO TFF membrane.
  • the concentrate was purified by size-exclusion chromatography.
  • the fractions were analyzed by SEC-MALLS, anthrone method and fractions containing conjugates were pooled and sterile filtered with 0.2 pm filters.
  • CRM 197 protein using CDAP chemistry
  • the reaction mixture was diafiltered and concentrated using 100 kDa MWCO TFF membrane.
  • the concentrate was purified by size-exclusion chromatography.
  • the fractions were analyzed by SEC-MALLS, anthrone method and fractions containing conjugates were pooled and sterile filtered with 0.2pm filters.
  • CRM 197 protein using CDAP chemistry
  • the reaction mixture was diafiltered and concentrated using 100 kDa MWCO TFF membrane.
  • the concentrate was purified by size-exclusion chromatography.
  • the fractions were analyzed by SEC-MALLS, anthrone method and fractions containing conjugates were pooled and sterile filtered with 0.2 pm filters.
  • CRM 197 protein using CDAP chemistry
  • the reaction mixture was diafiltered and concentrated using 100 kDa MWCO TFF membrane.
  • the concentrate was purified by size-exclusion chromatography.
  • the fractions were analyzed by SEC-MALLS, anthrone method and fractions containing conjugates were pooled and sterile filtered with 0.2pm filters.
  • CRM 197 protein using CDAP chemistry
  • reaction mixture was diafiltered and concentrated using 100 kDa MWCO TFF membrane. Concentrate was purified by size-exclusion chromatography. The fractions were analysed by SEC-MALLS, anthrone method and fractions containing conjugates were pooled and sterile filtered with 0.2pm filters.
  • Example 2 Formulation of Pneumococcal Capsular Polysaccharide-protein conjugate vaccine (20- valent PCV)
  • a 20 valent conjugated vaccine was formulated as 0.5 mL dose containing 3 pg of Serotype 1, 2.2 pg of each pneumococcal polysaccharide from serotypes 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19 A, 19F, 23F, 6C, 11A, 12F, 15A, 22F, 23A, 35B and 4.4 pg of 6B conjugated to 45- 50 pg CRM 197 Protein. All the conjugates were adsorbed on to aluminum phosphate gel equivalent to 0.5 mg Al 3+ per dose of 0.5 ruL. A 0.9% w/v saline was used as diluent and vehicle for the formulation and the final formulation was adjusted to pH 6 using 1 N hydrochloric acid.
  • the formulation was mixed for 2 hours under constant stirring. After 2 hours of blending, the formulated blend was aseptically filled at 0.58 mL fill volume per vial into the 3 mL sterile non-siliconized vials, closed with sterile 13 mm rubber stoppers and sealed with 13 mm sterile pink-colored flip off aluminum seals, followed by optical inspection and labelling of filled vials. From the lot, some vials were randomly picked up and analyzed for the appearance, pH, Osmolality, total poly and protein content (pg/SHD), %Adsorption, aluminum content (mg/SHD) as given in Table 1 below. The product appearance is Whitish suspension in which the mineral carriers tends to settle down slowly.
  • PsaA Preparation, Activation and Conjugation of PsaA with Pneumococcal Polysaccharide Serotype 3, 6A and 6B was prepared as per the disclosure of PCT Publication WO 2018/064444 Al.
  • the reaction mixture was diafiltered and concentrated using 100 kDa MWCO TFF membrane.
  • the concentrate was purified by size-exclusion chromatography.
  • the fractions were analyzed by SEC-MALLS, anthrone method and fractions containing conjugates were pooled and sterile filtered with 0.2pm filters.
  • the reaction mixture was diafiltered and concentrated using 100 kDa MWCO TFF membrane.
  • the concentrate was purified by size-exclusion chromatography.
  • the fractions were analyzed by SEC-MALLS, anthrone method and fractions containing conjugates were pooled and sterile filtered with 0.2pm filters.
  • the pH of the reaction was adjusted to 9.0 with 0.9mL of 0.2M triethylamine and the reaction was continued under stirring for 3-5 hours at room temperature followed by quenching of the reaction by adding excess concentration of glycine (100 mM).
  • the conjugation kinetics (Ligure 6b) of reactions were monitored using SEC- HPLC at each hour of the reaction.
  • the reaction mixture was diafiltered and concentrated using 100 kDa MWCO TEL membrane.
  • the concentrate was purified by size-exclusion chromatography.
  • the fractions were analyzed by SEC-MALLS, anthrone method and fractions containing conjugates were pooled and sterile filtered with 0.2pm filters.
  • the reaction mixture was diafiltered and concentrated using 100 kDa MWCO TFF membrane.
  • the concentrate was purified by size-exclusion chromatography.
  • the fractions were analyzed by SEC-MALLS, anthrone method and fractions containing conjugates were pooled and sterile filtered with 0.2pm filters.
  • the reaction mixture was diafiltered and concentrated using 100 kDa MWCO TFF membrane.
  • the concentrate was purified by size-exclusion chromatography.
  • the fractions were analyzed by SEC-MALLS, anthrone method and fractions containing conjugates were pooled and sterile filtered with 0.2pm filters.
  • the reaction mixture was diafiltered and concentrated using 100 kDa MWCO TFF membrane.
  • the concentrate was purified by size-exclusion chromatography.
  • the fractions were analyzed by SEC-MALLS, anthrone method and fractions containing conjugates were pooled and sterile filtered with 0.2pm filters.
  • Example 4 Formulation of Pneumococcal Capsular Polysaccharide-protein conjugate vaccine (20- valent PCV)
  • a 20 valent conjugated vaccine was formulated as 0.5 mL dose containing 3 pg of serotype 1, 2.2 pg of each pneumococcal polysaccharide from serotypes 4, 5, 6C, 7F, 9V, 14, 18C, 22F, 19A, 19F and 23F, and 4.4 pg of serotype 6B conjugated to -45-48 pg CRM197 Protein and conjugates of pneumococcal polysaccharide from serotypes 3, 6A, 11A, 12F, 15A, 23A and 35B with PsaA as disclosed in above examples.
  • the formulation was mixed for 2 hours under constant stirring. After 2 hours of blending, the formulated blend was aseptically filled at 0.58 mL fill volume per vial into the 3 mL sterile non-siliconized vials, closed with sterile 13 mm rubber stoppers and sealed with 13 mm sterile pink-colored flip off aluminum seals, followed by optical inspection and labelling of filled vials. From the lot, some vials were randomly picked up and analyzed for the appearance, pH, Osmolality, total poly and protein content (pg/SHD), %Adsorption, aluminum content (mg/SHD) as given in Table 2 below. The product appearance is Whitish suspension in which the mineral carriers tends to settle down slowly.
  • Example 5 Formulation of Pneumococcal Capsular Polysaccharide-protein conjugate vaccine (20- valent PCV)
  • a 20 valent conjugated vaccine was formulated as 0.5 mL dose containing 2.2 pg of each pneumococcal polysaccharide from serotypes 1, 4, 5, 7F, 9V, 14, 18C, 19A, 19F and 23F, conjugated to -45-48 pg CRM197 Protein and conjugates of pneumococcal polysaccharide from serotypes 3, 6A, 6B, 6C, 11A, 12F, 15A, 22F, 23A and 35B with PsaA as disclosed in above examples.
  • the formulation was mixed for 2 hours under constant stirring. After 2 hours of blending, the formulated blend was aseptically filled at 0.58 mL fill volume per vial into the 3 mL sterile nonsiliconized vials, closed with sterile 13 mm rubber stoppers and sealed with 13 mm sterile pink-colored flip off aluminum seals, followed by optical inspection and labelling of filled vials. From the lot, some vials were randomly picked up and analyzed for the appearance, pH, Osmolality, total poly and protein content (pg/SHD), %Adsorption, aluminum content (mg/SHD) as given in Table 3 below. The product appearance is Whitish suspension in which the mineral carriers tends to settle down slowly.
  • Rabbits were immunized (seven rabbits) with single human dose on days 1, 15 and 29. They were bled on days 0, 14, and 28 while the final bleed was collected on day 36. The sera samples received at different time points under frozen condition were aseptically aliquoted in sterile vials, labelled appropriately and stored frozen at -80°C.
  • Serotype specific antibody response was measured by Indirect EFISA. Briefly, specific pneumococcal polysaccharides received from ATCC, USA and SSI, Denmark were coated on Maxisorp EFISA plates and the unsaturated sites were blocked. The sera samples were pre adsorbed with CWPS Multi, added to the plate and diluted serially. Recombinant protein A/G peroxidase was added as the detection reagent. Finally, the color was developed using the HRP substrate, TMB. The reaction was stopped with 1.25M H2SO4 solution and absorbance was read at 450 nm in EFISA plate reader.
  • IgG geometric mean titers were calculated for pre-immune and day 36 sera of all the groups for all the different serotypes. Geometric mean fold rise was also calculated in day 36 sera of all the serotypes from different groups. The results obtained after immunizing with formulation disclosed in Example 2 is represented in the Figure 10. The IgG titer value of pre vaccinated animal was used to calculate Geometric Mean Fold Rise (GMFR) in serum IgG titer.
  • GMFR Geometric Mean Fold Rise
  • the serotype specific IgG titers were significantly high in all the groups as compared to pre-immune with geometric mean fold rise more than 4 for all the serotypes tested across different groups.
  • the experiment indicates that the composition containing different formulation is immunogenic in rabbits.

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Abstract

La présente invention concerne une composition vaccinale à base de conjugués polysaccharide-protéine pneumococcique multivalentes comprenant un polysaccharide capsulaire pneumococcique d'un ou de plusieurs sérotypes de Streptococcus pneumoniae conjugués à une ou plusieurs protéines porteuses.
PCT/IN2020/050093 2019-01-28 2020-01-28 Compositions vaccinales à base de conjugués polysaccharide-protéine pneumococcique multivalentes WO2020157772A1 (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
EP3980055A4 (fr) * 2019-06-05 2023-07-26 Merck Sharp & Dohme LLC Conjugué polysaccharide pneumococcique de sérotype 35b immunogène et de protéine, et procédé de conjugaison pour la fabrication de celui-ci

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