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WO2018189515A1 - Nouveau vaccin antipneumococcique - Google Patents

Nouveau vaccin antipneumococcique Download PDF

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Publication number
WO2018189515A1
WO2018189515A1 PCT/GB2018/050935 GB2018050935W WO2018189515A1 WO 2018189515 A1 WO2018189515 A1 WO 2018189515A1 GB 2018050935 W GB2018050935 W GB 2018050935W WO 2018189515 A1 WO2018189515 A1 WO 2018189515A1
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WO
WIPO (PCT)
Prior art keywords
proteins
pneumococcal
vaccine
capsular
mammal
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/GB2018/050935
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English (en)
Inventor
Stephen D. BENTLEY
Nicholas J. CROUCHER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Genome Research Ltd
Ip2ipo Innovations Ltd
Original Assignee
Imperial Innovations Ltd
Genome Research Ltd
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Filing date
Publication date
Application filed by Imperial Innovations Ltd, Genome Research Ltd filed Critical Imperial Innovations Ltd
Publication of WO2018189515A1 publication Critical patent/WO2018189515A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • C07K14/315—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Streptococcus (G), e.g. Enterococci
    • C07K14/3156—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Streptococcus (G), e.g. Enterococci from Streptococcus pneumoniae (Pneumococcus)

Definitions

  • the invention relates to a pneumococcal vaccine, to pharmaceutical compositions comprising said vaccine and to their uses in vaccination against pathogenic pneumococcal strains.
  • Streptococcus pneumoniae or pneumococcus
  • pneumococcus is a Gram-positive, alpha-hemolytic (under aerobic conditions) or beta-hemolytic (under anaerobic conditions), facultative anaerobic member of the genus Streptococcus.
  • alpha-hemolytic under aerobic conditions
  • beta-hemolytic under anaerobic conditions
  • facultative anaerobic member of the genus Streptococcus As a significant human pathogenic bacterium S.
  • pneumoniae was recognized as a major cause of pneumonia in the late 19th century, and is the subject of many humoral immunity studies.
  • S. pneumoniae resides asymptomatically in healthy carriers typically colonizing the respiratory tract, sinuses, and nasal cavity. However, the bacterium may become pathogenic and spread to other locations to cause disease, particularly in susceptible individuals with weaker immune systems, such as the elderly and young children.
  • S. pneumoniae is the main cause of community acquired pneumonia and meningitis in children and the elderly, and of septicemia in those infected with HIV.
  • the organism also causes many types of pneumococcal infections other than pneumonia. These invasive pneumococcal diseases include bronchitis, rhinitis, acute sinusitis, otitis media,
  • PCV pneumococcal conjugate vaccine
  • PPV pneumococcal polysaccharide vaccine
  • a pneumococcal vaccine comprising one or more proteins, or one or more nucleic acid molecules encoding said proteins, which are present on capsular pneumococcal strains and absent on non-capsular pneumococcal strains.
  • a pharmaceutical composition comprising a pneumococcal vaccine as described herein.
  • a method of preventing pneumococcal infection in a mammal which comprises administering to the mammal a therapeutically effective amount of a vaccine composition as described herein.
  • a method of inducing an immune response in a mammal wherein the method includes administering to the mammal, an effective amount of a vaccine composition described herein.
  • a kit of parts comprising a vaccine composition as described herein, a medical instrument or other means for administering the vaccine composition and instructions for use.
  • a pneumococcal vaccine comprising one or more proteins, or one or more nucleic acid molecules encoding said proteins, which are present on capsular pneumococcal strains and absent on non-capsular pneumococcal strains.
  • S. pneumoniae is only thought to be able to cause invasive disease when expressing a polysaccharide capsule.
  • Strains which lack the polysaccharide capsule are often referred to as nontypable since the typing method used to categorise members of the species relies on binding of antibodies with sera specific for different polysaccharide capsule structures.
  • the invention provides a vaccine which is able to specifically target only the pathogenic, capsular pneumococcal strains. Therefore, the nonpathogenic, non-capsular pneumococcal strains will be unaffected by treatment with the vaccine of the present invention.
  • the vaccine of the invention would not aim to use the immune response alone to remove targeted pneumococci, as previous designs have done, but instead put them at a competitive disadvantage with divergent unencapsulated pneumococci (also termed classic non-typeable pneumococci 1 ; these may also be regarded as pneumococci-like streptococci), such that they were eliminated from the population through the combination of vaccine- induced immunity and displacement through competition with the divergent unencapsulated pneumococci or pneumococcus-like streptococci.
  • divergent unencapsulated pneumococci also termed classic non-typeable pneumococci 1 ; these may also be regarded as pneumococci-like streptococci
  • the vaccine of the present invention to induce an adaptive immune response at the mucosal surface, which could be protective against carriage and non-invasive, as well as invasive, pneumococcal disease, particularly if a probiotic were provided to the recipient at the same time.
  • the one or more proteins are selected from one or more of:
  • transcriptional regulator PIcR putative; sucrose-6-phosphate hydrolase; L-fucose isomerase; carbamate kinase; surface anchored beta-galactosidase; capsule biosynthesis integral membrane regulatory protein Wzg; surface anchored endo-alpha-N- acetylgalactosaminidase; and ABC transporter iron-binding protein.
  • References herein to "transcriptional regulator PIcR, putative" include the product of the plcR gene which is a transcriptional regulator and has a cluster of orthologous genes (COG) designation of CLS01686, using the scheme defined in Croucher et al (2015) Sci. Data 2: 150058.
  • references herein to "sucrose-6-phosphate hydrolase” include the product of the sacC gene which is involved in carbohydrate metabolism and has a cluster of orthologous genes (COG) designation of CLS01545, using the scheme defined in Croucher et al (2015) Sci. Data 2. 150058.
  • References herein to "L-fucose isomerase” include the product of the fuel gene which is involved in carbohydrate metabolism and has a cluster of orthologous genes (COG) designation of CLS01869, using the scheme defined in Croucher et al (2015) Sci. Data 2: 150058.
  • references herein to "carbamate kinase” include the product of the arcC gene which is involved in carbohydrate metabolism and has a cluster of orthologous genes (COG) designation of CLS01862, using the scheme defined in Croucher et al (2015) Sci. Data 2. 150058.
  • References herein to "surface anchored beta-galactosidase” include the product of the bgaA gene which is a surface-associated degradative enzyme and has a cluster of orthologous genes (COG) designation of CLS00596, using the scheme defined in Croucher et al (2015) Sci. Data 2. 150058.
  • capsule biosynthesis integral membrane regulatory protein Wzg include the product of the wzg gene which is a surface-associated enzyme involved in regulation of capsule production and has a cluster of orthologous genes (COG) designation of CLS00362, using the scheme defined in Croucher et al (2015) Sci. Data 2: 150058.
  • COG orthologous genes
  • references herein to "surface anchored endo-alpha-N-acetylgalactosaminidase” include the product of the eng gene which is a surface-associated degradative enzyme and has a cluster of orthologous genes (COG) designation of CLS00380, using the scheme defined in Croucher et al (2015) Sci. Data 2: 150058.
  • COG orthologous genes
  • ABSC transporter iron-binding protein examples include the product of the piaA gene which is the substrate binding protein from an iron transporter and is involved in iron acquisition and has a cluster of orthologous genes (COG) designation of CLS00926, using the scheme defined in Croucher et al (2015) Sci. Data 2: 150058.
  • COG orthologous genes
  • the pneumococcal vaccine comprises two or more of said proteins. In a further embodiment, the pneumococcal vaccine comprises three or more of said proteins.
  • the pneumococcal vaccine comprises four or more of said proteins. In a further embodiment, the pneumococcal vaccine comprises five or more of said proteins. In a further embodiment, the pneumococcal vaccine comprises six or more of said proteins. In a further embodiment, the pneumococcal vaccine comprises seven or more of said proteins.
  • the pneumococcal vaccine comprises all eight of said proteins.
  • a pharmaceutical composition comprising a pneumococcal vaccine as described herein.
  • the vaccine composition comprises one or more proteins which are present on capsular pneumococcal strains and absent on non-capsular pneumococcal strains.
  • the vaccine composition comprises one or more nucleic acid molecules encoding said one or more proteins described herein.
  • nucleic acid molecules typically refer to DNA or RNA.
  • the one or more nucleic acid molecules comprise one or more oligonucleotides encoding said one or more proteins.
  • said one or more proteins function as antigens within the vaccine composition and provide the function of being immunogenic (i.e. generating an immune response within the individual). It is envisaged that either the full length proteins or nucleic acids described herein will be present within the vaccine composition or fragments of said proteins or nucleic acids may suitably be employed.
  • the vaccine composition additionally comprises one or more adjuvants.
  • adjuvant refers to a compound that, when used in
  • Modification of the immune response can include intensification or broadening the specificity of either or both antibody and cellular immune responses. Modification of the immune response can also mean decreasing or suppressing certain antigen-specific immune responses.
  • At least about 1 ⁇ g and up to about 20 ⁇ g adjuvant is present within the vaccine composition.
  • suitable adjuvants include: alum; aluminum hydroxide; aluminum phosphate; calcium phosphate hydroxide; paraffin oil; killed bacteria such as
  • the vaccine composition additionally comprises one or more capsular polysaccharides.
  • the capsular polysaccharides are selected from serotypes: 1 , 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F of S. pneumoniae.
  • the capsular polysaccharides are selected from serotypes: 1 , 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F of S. pneumoniae.
  • the capsular polysaccharides are selected from serotypes: 1 , 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F of S. pneumoniae.
  • polysaccharides are selected from serotypes: 1 , 3, 4, 5, 6B, 7F, 9N, 9V, 14, 15B, 18C, 19A, 19F, 22F, 23F and 33F of S. pneumoniae.
  • the vaccine composition additionally comprises a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof, in which the immunogen (i.e. one or more proteins as defined herein) is/are suspended or dissolved.
  • the immunogen i.e. one or more proteins as defined herein
  • Pharmaceutically acceptable carriers include but are not limited to, water for injection, saline solution, buffered saline, dextrose, water, glycerol, sterile isotonic aqueous buffer, and combinations thereof.
  • the carrier may include water, saline, alcohol, a fat, a wax, a buffer or combinations thereof.
  • Pharmaceutically acceptable carriers, diluents, and other excipients are described in detail in Remington's Pharmaceutical Sciences (Mack Pub. Co. N.J. current edition).
  • the formulation should suit the mode of administration.
  • the formulation is suitable for administration to humans, preferably is sterile, non-particulate and/or non-pyrogenic.
  • the vaccine composition can include one or more diluents, preservatives, solubilizers and/or emulsifiers.
  • the vaccine composition can include minor amounts of wetting or emulsifying agents, or pH buffering agents to improve vaccine efficacy.
  • the composition can be a solid form, such as a lyophilized powder suitable for reconstitution, a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder.
  • Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium
  • the vaccine composition can include antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • antibacterial agents such as benzyl alcohol or methyl paraben
  • antioxidants such as ascorbic acid or sodium bisulfite
  • chelating agents such as ethylenediaminetetraacetic acid
  • buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • Administration of the vaccine composition can be systemic or local.
  • compositions described herein are administered intramuscularly, intravenously,
  • compositions may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucous, colon, conjunctiva, nasopharynx, oropharynx, vagina, urethra, urinary bladder and intestinal mucosa, etc.) and may be administered together with other biologically active agents.
  • epithelial or mucocutaneous linings e.g., oral mucous, colon, conjunctiva, nasopharynx, oropharynx, vagina, urethra, urinary bladder and intestinal mucosa, etc.
  • intranasal or other mucosal routes of administration of a composition may induce an antibody or other immune response that is substantially higher than other routes of administration.
  • intranasal or other mucosal routes of administration of a composition described herein may induce an antibody or other immune response at the site of immunization.
  • the vaccine composition has a volume of between about 50 ⁇ and about 500 ⁇ .
  • a method of preventing pneumococcal infection in a mammal which comprises administering to the mammal a therapeutically effective amount of a vaccine composition as described herein.
  • references herein to "pneumococcal infection” refer to infection by Streptococcus pneumoniae.
  • References herein to "effective amount” refer to a dose which is sufficient or most likely to elicit antibodies such that the immunized subject has reduced severity of infection.
  • a method of inducing an immune response in a mammal wherein the method includes administering to the mammal, an effective amount of a vaccine composition described herein.
  • the mammal is a human. In another embodiment, the mammal is selected from: an adult such as an elderly adult greater than 65 years old; an infant less than 1 year old; a toddler between 1 and 2 years old; or a young child between 2 and 5 years old.
  • the vaccine composition is administered in a single dose regimen. In another embodiment, the vaccine composition is administered in a two dose regimen that includes a first and a second dose. In one embodiment, the second dose is administered at least about 1 week, 2 weeks, 3 weeks, 1 month or 1 year after the first dose. In another embodiment, the vaccine composition is administered in a three dose regimen.
  • kits of parts comprising a vaccine composition as described herein, a medical instrument or other means for administering the vaccine composition and instructions for use.
  • the vaccine composition is packaged in a hermetically sealed container such as an ampoule or sachette indicating the quantity of composition.
  • the composition is supplied as a liquid.
  • the composition is supplied as a dry sterilized lyophilized powder or water free concentrate in a hermetically sealed container, wherein the composition can be reconstituted, for example, with water or saline, to obtain an appropriate concentration for administration to a subject.
  • the vaccine composition When the vaccine composition is systemically administered, for example, by subcutaneous or intramuscular injection, a needle and syringe, or a needle-less injection device can be used.
  • the vaccine formulation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • Prodigal 5 and Glimmer 6 and the protein sequences translated and aligned using BLAT 7 . These were grouped into 'clusters of orthologous genes' (COGs) using COGtriangles 8 and custom scripts 2 . Concatenation of the 'core' COGs allowed a phylogeny to be constructed using RAxML 9 , and a population clustering to be generated with BAPS 10 .
  • the first step was to use this analysis of population structure to identify a set of
  • the second step was confirming the antigenic distinctiveness of SC12 through analysis of immunoglobulin G binding to pneumococcal proteins expressed in ' fro 11 .
  • This study can be used to identify eight antigenic proteins that were ubiquitous in encapsulated pneumococci, but absent from SC12 streptococci (Table 1).
  • PiaA the substrate binding protein from an iron transporter.
  • Eng a cell-wall associated endo-alpha-/V- acetylgalactosaminidase
  • BgaA a beta galactosidase
  • Wzg an integral membrane protein.
  • Three are involved in carbohydrate metabolism: ArcC, a carbamate kinase; Fuel, an L- fucose isomerase; and SacC, a sucrose-6-phosphate hydrolase.
  • PlcR a transcriptional regulator
  • the third step was identifying that encapsulated and unencapsulated pneumococci frequently co-circulate in the same populations, and therefore are likely to compete with one another. This has been inferred from large-scale genomics projects such as the survey of the Maela refugee camp, where unencapsulated pneumococci were very common 12 .
  • the following description illustrates the general principles of the invention described herein:
  • the identification of antigens that might facilitate the replacement of the encapsulated pneumococcal population by unencapsulated pneumococci or pneumococci-like streptococci would first require a collection of genetic data on a set of pneumococci and pneumococci- like organisms.
  • Protein coding sequences could be predicted in an automated manner using software such as Glimmer 6 or Prodigal 5 , or determined manually 13 , based on the genetic data. The encapsulation status of these bacteria may be inferred from the presence of protein coding sequences associated with the synthesis of pneumococcal capsules 14 , else determined experimentally using antisera, polymerase chain reactions, microarrays, or other genotyping method 15,16 .
  • the proteins encoded by protein coding sequences can be predicted through conventional nucleic acid to amino acid sequence translation software 17 . The predicted proteins can be clustered into groups likely to perform similar functions based on similarity of protein sequence following pairwise alignment using algorithms such as
  • GET_HOMOLOGUES 19 COGtriangles 8 or TribeMCL 20 .
  • Those proteins that are unique to, or enriched in, the unencapsulated pneumococci or pneumococci-like streptococci can then be identified by quantifying the distribution of sequences encoding orthologous proteins in the genetic data associated with encapsulated and unencapsulated bacteria.
  • the subset of those proteins likely to be viable vaccine antigens can then be identified on the basis of in silico immunogenicity prediction 24 and/or direct experimental evidence of surface exposure, such as proteomics 21 or immunological work in mammals 22,23 , or identification of particular functional motifs associated with secretion, bacterial surface association, or immunogenicity in mammals 11 .

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  • Genetics & Genomics (AREA)
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  • Gastroenterology & Hepatology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

L'invention concerne un vaccin antipneumococcique, des compositions pharmaceutiques comprenant ledit vaccin et leurs utilisations dans la vaccination contre des souches pneumococciques pathogènes.
PCT/GB2018/050935 2017-04-10 2018-04-09 Nouveau vaccin antipneumococcique Ceased WO2018189515A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB1705733.2 2017-04-10
GBGB1705733.2A GB201705733D0 (en) 2017-04-10 2017-04-10 Novel pneumococcal vacine
US201762589430P 2017-11-21 2017-11-21
US62/589,430 2017-11-21

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WO2018189515A1 true WO2018189515A1 (fr) 2018-10-18

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008127094A2 (fr) * 2007-04-12 2008-10-23 Stichting Katholieke Universiteit, More Particularly The Radboud University Nijmegen Medical Center Nouveaux facteurs de virulence de streptococcus pneumoniae

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008127094A2 (fr) * 2007-04-12 2008-10-23 Stichting Katholieke Universiteit, More Particularly The Radboud University Nijmegen Medical Center Nouveaux facteurs de virulence de streptococcus pneumoniae

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ANDERSON RICHARD J ET AL: "In vivoscreen of genetically conservedStreptococcus pneumoniaeproteins for protective immunogenicity", VACCINE, ELSEVIER, AMSTERDAM, NL, vol. 34, no. 50, 2 November 2016 (2016-11-02), pages 6292 - 6300, XP029824223, ISSN: 0264-410X, DOI: 10.1016/J.VACCINE.2016.10.061 *
JOMAA M ET AL: "Immunization with the iron uptake ABC transporter proteins PiaA and PiuA prevents respiratory infection with Streptococcus pneumoniae", VACCINE, ELSEVIER, AMSTERDAM, NL, vol. 24, no. 24, 12 June 2006 (2006-06-12), pages 5133 - 5139, XP028010666, ISSN: 0264-410X, [retrieved on 20060612], DOI: 10.1016/J.VACCINE.2006.04.012 *
JUSTIN A. THORNTON ET AL: "Differential Bacterial Gene Expression during Experimental Pneumococcal Endophthalmitis", OPHTHALMIC RESEARCH, vol. 53, no. 3, 1 January 2015 (2015-01-01), CH, pages 149 - 161, XP055478015, ISSN: 0030-3747, DOI: 10.1159/000371713 *
NICHOLAS J. CROUCHER ET AL: "Diverse evolutionary patterns of pneumococcal antigens identified by pangenome-wide immunological screening", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 114, no. 3, 17 January 2017 (2017-01-17), US, pages E357 - E366, XP055477978, ISSN: 0027-8424, DOI: 10.1073/pnas.1613937114 *

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