WO2018091613A1 - Compositions immunogènes et vaccinales pour utilisation contre une infection par bordetella bronchiseptica - Google Patents

Compositions immunogènes et vaccinales pour utilisation contre une infection par bordetella bronchiseptica Download PDF

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Publication number
WO2018091613A1
WO2018091613A1 PCT/EP2017/079515 EP2017079515W WO2018091613A1 WO 2018091613 A1 WO2018091613 A1 WO 2018091613A1 EP 2017079515 W EP2017079515 W EP 2017079515W WO 2018091613 A1 WO2018091613 A1 WO 2018091613A1
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WIPO (PCT)
Prior art keywords
cyaa
immunogenic composition
bordetella
bordetella bronchiseptica
adenylate cyclase
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PCT/EP2017/079515
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English (en)
Inventor
Renaud Nalin
Séverine BOULLIER
Alain Bousquet-Melou
Patrick Cornille
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Ecole Nationale Vétérinaire de Toulouse
Cyanimal IP
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Priority claimed from US15/354,964 external-priority patent/US20180133301A1/en
Priority claimed from EP16199413.2A external-priority patent/EP3323426A1/fr
Application filed by Ecole Nationale Vétérinaire de Toulouse, Cyanimal IP filed Critical Ecole Nationale Vétérinaire de Toulouse
Publication of WO2018091613A1 publication Critical patent/WO2018091613A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/02—Bacterial antigens
    • A61K39/099—Bordetella
    • 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
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55561—CpG containing adjuvants; Oligonucleotide containing 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
    • A61K2039/572—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 cytotoxic 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]

Definitions

  • the present invention relates to the field of immunology, and in particular to the field of immunogenic and vaccine compositions. It relates to such compositions for use against Bordetella bronchiseptica infection and in particular against canine tracheobronchitis commonly named kennel cough.
  • Bordetella bronchiseptica (B. bronchiseptica) is a small, Gram-negative, rod-shaped bacterium of the genus Bordetella and closely related to B. pertussis, the obligate human pathogen that causes pertussis (whooping cough).
  • B. bronchiseptica Humans are not natural carriers of B. bronchiseptica, which typically infects the respiratory tracts of animals and especially mammals animals such as cats, dogs, pigs, cattle, etc...
  • B. bronchiseptica and Pasteurella multocida act synergistically to cause atrophic rhinitis, a disease resulting in arrested growth and distortion of the turbinate in the nasal terminus snout.
  • B. bronchiseptica causes tracheobronchitis, conjunctivitis, and rhinitis (upper respiratory tract infection - URI), mandibular lymphadenopathy, and pneumonia.
  • URI can also be caused by herpesvirus, calicivirus, Mycoplasma or Chlamydia bacteria.
  • B. bronchiseptica causes tracheobronchitis, commonly named kennel cough or bordetellosis, which is highly contagious respiratory disease typified by inflammation of the trachea and bronchi.
  • the symptoms are a persistent cough, retching, watery nasal discharge and can be in severe cases, pneumonia, inappetence, fever, lethargy and even death.
  • B. bronchiseptica seems to be the major cause of this disease, others pathogens such as canine adenovirus, parainfluenza virus, and mycoplasma can also cause the symptoms alone or in combination.
  • Vaccination of the non-human animals to prevent tracheobronchitis is commonly used but as and especially by vaccine against B. bronchiseptica.
  • Bordetella bronchiseptica vaccines licensed in the United States for use in dogs: a killed injectable vaccine for subcutaneous use, Bronchicine®CAe (Zoetis), a live attenuated vaccine for intranasal administration, Bronchi-shield®III (Boehringer Ingelheim Vetmedica), Vanguard® (Zoetis), Nobivac® (Merck Animal Health) and a live attenuated vaccine to be given orally, Bronchi- Shield®ORAL (Boehringer Ingelheim Vetmedica).
  • Bronchi- Shield®ORAL Boehringer Ingelheim Vetmedica.
  • a comparative study has been made of protective immunity provided by oral, intranasal and parenteral Canine Bordetella bronchiseptica vaccines by Larson et al.
  • the killed injectable vaccine Bronchicine®CAe was shown to significantly reduce clinical disease signs.
  • the live attenuated intranasally administered vaccine, Bronchi- shield® III was considered superior in reducing clinical disease compared to the killed injectable vaccine.
  • Live attenuated vaccines have the advantage to induce immunity after a single dose and have been shown to provide protection after only 72 hours.
  • intranasal vaccines are more difficult to administer than an injectable product, and are therefore less popular with veterinarians.
  • the oral Bordetella vaccine, Bronchi-Shield®ORAL provided immunity that was similar to that induced by the intranasal product (Larson et al., Intern J Appl Res Vet Med, Vol. 11, No. 3, 2013).
  • live attenuated vaccines A disadvantage with live attenuated vaccines is that their protection is not really long lasting, so a second and possibly a third vaccination with a live attenuated vaccine must be necessary. Furthermore, while live attenuated vaccines induce local immunity, they may cause significant vaccination reaction, in particular in the respiratory tract after spray vaccination.
  • the present invention generally relates to immunogenic compositions comprising Bordetella sp. Adenylate cyclase toxin (CyaA) for use for treating Bordetella bronchiseptica infections in non-human animals.
  • CyaA Adenylate cyclase toxin
  • the invention relates to immunogenic compositions comprising Bordetella sp. Adenylate cyclase toxin (CyaA) vector for use for treating Bordetella bronchiseptica infections in non-human animals.
  • the Bordetella sp. adenylate cyclase toxin (CyaA) vector is capable of retaining the binding activity of native CyaA through its N-terminal domain into target cells and translocate into the cytosol of the antigen-presenting cells (APC).
  • the adenylate cyclase toxin (CyaA) vector is suitable for delivering molecules, in particular Bordetella bronchiseptica antigens and for eliciting a protective immune response.
  • the present invention also relate to immunogenic compositions comprising a Bordetella sp. adenylate cyclase toxin (CyaA) vector carrying at least one antigen of Bordetella bronchiseptica.
  • a Bordetella sp. adenylate cyclase toxin (CyaA) vector carrying at least one antigen of Bordetella bronchiseptica.
  • FIGURES 1A and IB show clinical follow-up of puppies after Bordetella bronchiseptica challenge.
  • FIGURE 1A Clinical score determined every day for each dog after bacterial infection.
  • FIGURE IB Comparison of the number of coughing/day between each group of puppies (control group and vaccine group)
  • FIGURE 3A and 3B show humoral response against CyaA
  • FIGURE 4A, 4B, and 4C show immune response against Bsp22
  • the present invention generally relates to an immunogenic composition
  • the term "immunogenic composition” or “vaccine” or its equivalents relates to any composition comprising a Bordetella sp. adenylate cyclase toxin (CyaA) or a Bordetella sp. adenylate cyclase toxin (CyaA) vector, which can be used to elicit an immune response in a non-human animal.
  • the immunogenic composition is suitable for eliciting a T-cell immune response, and in a particular embodiment, Thl.
  • the immunogenic composition of the present invention can be used to treat a non-human animal susceptible to Bordetella bronchiseptica caused infections and/or diseases by means of administering the immunogenic composition.
  • an immunogenic composition according to the invention induces a response orientated toward Th-1 phenotype, characterized by IFNy production and IgG2 synthesis.
  • the Adenylate Cyclase toxin (CyaA) of Bordetella species in particular of Bordetella pertussis or Bordetella bronchiseptica is a 1706 residue-long protein (177 kDa).
  • adenylate cyclase toxin or “CyaA” or “native adenylate cyclase toxin (CyaA)” or “native CyaA” refer to the adenylate cyclase toxin protein from a Bordetella sp., such as the adenylate cyclase toxin protein from Bordetella pertussis (Accession number CPI 05197, SEQ ID NO: l), the adenylate cyclase toxin protein from Bordetella bronchiseptica (Accession number KDS81064, SEQ ID NO:2), the adenylate cyclase toxin protein from Bordetella hinzii (Accession number AAY57201, SEQ ID NO: l), or the adenylate cyclase toxin protein Bordetella parapertussis (Accession number CAB76450, SEQ ID
  • Bordetella sp. refers to Bordetella species.
  • the adenylate cyclase toxin (CyaA) is from Bordetella pertussis (SEQ ID NO: 1).
  • the adenylate cyclase toxin (CyaA) is from Bordetella bronchiseptica (SEQ ID NO: 2).
  • CyaA is a bifunctional protein that consists of an amino-terminal adenylate cyclase (AC) domain of about 400 residues (N-terminal part) and of a Repeats in ToXin (RTX) cytolysin moiety (Hly) of about 1300 residues (C-terminal part).
  • the Hly moiety inserts into cellular membranes and mediates translocation of the enzymatic AC domain into cell cytosol, where this binds calmodulin and catalyzes conversion of ATP to cAMP, thus subverting cellular signaling.
  • the AC domain appears to be a passive passenger that can be replaced by synthetic polypeptides that can also be delivered into cells by the Hly moiety.
  • the Adenylate cyclase toxin (CyaA) of Bordetella types, in particular of Bordetella pertussis has been described as a recombinant vector able to deliver efficiently polypeptides, such as antigens, into the cytosol of target sentinel cells commonly named Antigen Presenting Cells (APC).
  • APC Antigen Presenting Cells
  • CyaA is able to translocate its N-terminal domain directly across the plasma membrane of target cells, from the extracellular side into the cytosol (Guermonprez, P., Ladant, D., Karimova, G., Ullmann, A., and Leclerc, C. Direct delivery of the Bordetella pertussis adenylate cyclase toxin to the MHC class I antigen presentation pathway. J. Immunol.
  • the adenylate cyclase was modified by inactivating the enzymatic activity and rendering it permissive to harbor a variety of polypeptide vaccinal sequences or antigens. This was achieved without altering its high affinity to APC and its capability to translocate into the cytosol of the APC (Fayolle et al., In vivo induction of CTL responses by recombinant adenylate cyclase of Bordetella pertussis carrying viral CD8+ T cell epitopes. J Immunol. 1996;156(12):4697-706). CyaA recombinant vectors derived from Bordetella sp.
  • CyaA in particular of Bordetella pertussis, have been described as a recombinant vectors able to deliver polypeptides, such as antigens, into the cytosol of APC and were constructed by recombinant DNA technology, especially as described in WO 93/21324 or WO 02/22169.
  • These CyaA vectors are genetically modified adenylcyclase toxoids carrying modifications, such as point mutations, deletions or insertions, which can be obtained using usual site-directed or random mutagenesis techniques.
  • CyaA recombinant vectors are constructed by inserting deliver polypeptides into the AC domain at selected residues such as 224-225 or 228-229 or 235-236 or 317-318 as described in EP0637335, but also at 107-108 or 132-133 or 137-138 or 232-233 or 235- 236 or 317-318 or 319-320 or 335-336 or 336-337 as described in EP1725259.
  • a new generation of CyaA recombinant vectors are constructed by truncating the AC domain such as between residues 1 to 373 or residues 1 to 372 as described in EP1317282B1, residues 1 to 300 as described in EP1489092 Al, residues 184 to 320 as EP2875130 Al, residues 228 to 320 as described in EP2690172 Al or residues 224 to 235 as described in EP2351580 Al.
  • the CyaA Hly domains were demonstrated to bind specifically to the ⁇ ⁇ 2 integrin (CDllb/CD18) (WO02/22169) through its CDllb subunit (Osicka R et al., 2015, eLife, 4:e 10766) and so exhibit the capacity to target T-cell epitopes of choice into the CDllb(+) subpopulation of dendritic cells.
  • Immunization of mice with a recombinant CyaA bearing appropriate epitopes led to the induction of strong CD8(+) CTL responses, conferring full protection against a lethal viral challenge and an efficient prophylactic and therapeutic antitumor immunity.
  • fragments of CyaA encompassing residues 373 to 1706 contain the structure essentially required for interaction with the CD lib/CD 18 receptor. More specifically, the amino acid sequence extending from residues 1166 to 1281 comprise a determinant for interaction with the CD lib/CD 18 receptor, and more particularly that amino sequence extending from residues 1208 to 1243 are described as critical for the interaction of the toxin with CD lib/CD 18 in EP1489092 A1 and EP1633776 Al.
  • CyaA recombinant vectors are then constructed by combining deletion of AC domain residues such as residues 1 to 300 combined with minor modification of the Hly domain such as acetylation of the Lysine 860 and Lysine 963 residues as illustrated in EP1633776A1 or substitution of the Glutamic acid 570 residue by a glutamine residue and the Lysine 860 by arginine residue as described in EP2233569B1.
  • CyaA recombinant vector used under clinical development is GTL001 (known as ProCervix® in Europe) developed by Genticel as a first- in-class bivalent Human papillomavirus (HPV) therapeutic vaccine candidate in women infected with HPV 16 and/or HPV 18, before the appearance of papillomavirus related cervical lesions or cancer.
  • This vaccine consists of two CyaA proteins carrying E7 antigens of HPV 16 and HPV 18 inserted in the CyaA AC domain.
  • Jiri Masin et al. (Negatively charges residues of the segment linking the enzyme and cytolysin moieties restrict the membrane -permeabilizing capacity of adenylate cyclase toxin, Nature, Scientific Reports 6, Article number:29137) describes that a mutation on a specific part of the Hly domain (between residues 400 to 500 of the CyaA) and especially a substitution of amino acid 445, 446 and 448, have positive impact on the pore forming capacity of the CyaA without altering its AC translocation capacity across target cell plasma membrane.
  • CyaA recombinant vectors can be constructed by combining deletion of AC domain residues with mutation on the Hly domain and especially by amino acid substitution of the residues 445 by an Asparagine (D445N), the residue 446 by an Asparagine (D446N) and of the residue 448 by a Glutamine (E448Q) .
  • CyaA vector excludes the native adenylate cyclase toxin.
  • Adenylate cyclase toxin (CyaA) vector means genetically modified adenylate cyclase toxin (CyaA) of Bordetella sp, by at least one mutation and/or at least one deletion and/or at least one insertion in the native sequence of Bordetella sp (SEQ ID No: 1, 2 or 3).
  • genetically modifications are deletion in the AC domain of at least 100 amino acids, 200 amino acids, 300 amino acids, more preferably 360 amino acids to 370 amino acids and even more preferably 373 amino acids in the AC domain.
  • located in the Hly domain of CyaA are substitutions and especially substitution of amino acid 445, 446 and 448, and even more preferably substitution of the residues 445 by an Asparagine (D445N), the residue 446 by an Asparagine (D446N) and of the residue 448 by a Glutamine (E448Q)
  • This Adenylate cyclase toxin (CyaA) vector have an amino acid sequence percentage of identity of at least 75% with the amino acid sequence of a native CyaA protein (i.e. CyaA such as SEQ ID NO: l, SEQ ID NO:2 or SEQ ID NO:3) or a fragment thereof, preferably of at least 79%, at least 80%, or at least 85%, still preferably of at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of identity.
  • CyaA such as SEQ ID NO: l, SEQ ID NO:2 or SEQ ID NO:3
  • a fragment thereof preferably of at least 79%, at least 80%, or at least 85%, still preferably of at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of identity.
  • This Adenylate cyclase toxin (CyaA) vector still possesses high affinity to target Antigen Presenting Cells and capability to translocate into the cytosol of the APC and capacity for the delivery of molecules of interest, in particular Bordetella bronchiseptica antigen.
  • adenylate cyclase toxin (CyaA) vector is a genetically modified adenylate cyclase toxin (CyaA) of Bordetella pertussis.
  • the adenylate cyclase toxin (CyaA) vector is a genetically modified adenylate cyclase toxin (CyaA) of Bordetella bronchiseptica.
  • Adenylate cyclase toxin (CyaA) vector comprises or consist of the amino acid sequence of the adenylate cyclase (CyaA) of Bordetella bronchiseptica or Bordetella pertussis wherein a Bordetella bronchiseptica antigen is inserted in the N terminal part and the AC domain is deleted of at least 100 amino acids, 200 amino acids, 300 amino acids, more preferably 360 amino acids, more preferably 370 amino acids and even more preferably 373 amino acids.
  • the immunogenic composition comprising a Bordetella sp.
  • Adenylate cyclase toxin (CyaA) vector carries at least one antigen of Bordetella bronchiseptica.
  • the term "antigen” generally refers to a protein, a peptide or a polypeptide, which contains at least one epitope to which a cognate antibody can selectively bind; or that can stimulate the production of antibodies or T-cell responses, or both, in an non-human animal, including compositions that are injected or absorbed into this non-human animal.
  • the immune response may be generated to the whole molecule, or to one or more various portions of the protein, the peptide or the polypeptide (e.g., an epitope or hapten).
  • antigen includes all related antigenic epitopes.
  • An antigen is recognized by antibodies, T-cell receptors or other elements of specific humoral and/or cellular immunity.
  • antigen includes all related antigenic epitopes.
  • the antigen can be derived, obtained, or isolated from bacteria, more particularly from Bordetella bronchiseptica
  • the antigen can consist in a full-length antigen of Bordetella bronchiseptica or an antigenic fragment(s).
  • the antigen of Bordetella bronchiseptica is selected from Bsp22, pertactin, filamentous hemagglutinin (FHA), BteA (also named BopC), or any antigen of Bordetella bronchiseptica involved in bacterial colonization or in virulence.
  • Bsp22 a self-associating tip complex protein from the type III secretion system (T3SS) of Bordetella bronchiseptica.
  • pertactin is an autotransporter protein of Bordetella bronchiseptica (Inatsuka et al., Pertactin is required for Bordetella species to resist neutrophil-mediated clearance, infection and immunity, July 2010, p. 2901-2909).
  • the filamentous hemagglutin is an adhesin of Bordetella bronchiseptica (Romero et al., Filamentous hemagglutinin of Bordetella pertussis: a key adhesion with immunomodulatory properties? Future Microbiol. (2014) 9(12), 1339-1360).
  • BteA also named BopC is a protein secreted from the Bordetella bronchiseptica type III secretion system (Kuwae et al., BteA Secreted from the Bordetella bronchiseptica Type III Secretion System Induces necrosis through an Actin Cytoskeleton Signaling Pathway and Inhibits Phagocytosis by Macrophages, PLOS ONEDOI: 10.1371/journal.pone.0148387, February 2016), (Kuwae et al., BopC is a novel type III effector secreted by Bordetella bronchiseptica and has a critical role in type Ill- dependent necrotic cell death, the journal of biological chemistry vol. 281, NO. 10, pp. 6589-6600, March 10, 2006).
  • the antigen of Bordetella bronchiseptica is the Bsp22 antigen.
  • Bsp22 antigen includes whole Bsp22 antigen and any Bsp22 antigenic fragments.
  • amino acid sequence of Bsp22 antigen is described in SEQ ID No: 4.
  • Bsp22 antigen is conjugated to a linker.
  • amino acid sequence of Bsp22 antigen conjugated to the linker is described in SEQ ID No: 5.
  • Bsp22 antigen is any polypeptide having an amino acid identity between 60% and 100%, preferably more than 80% and even preferably more than 90%, with a part of SEQ ID NO:5 having the same size.
  • the sequence of the Bordetella bronchiseptica adenylate cyclase toxin (CyaA) vector carrying the Bsp22 antigen from Bordetella bronchiseptica is as set forth in SEQ ID NO: 6.
  • the immunogenic composition further comprises at least one adjuvant.
  • adjuvant refers to a compound or mixture that enhances the immune response when administered together with an immunogen or antigen.
  • the adjuvant is chosen among Complete Freund's Adjuvant (CFA), Incomplete Freund's Adjuvant (IFA), montanide ISA (incomplete seppic adjuvant), muramyl peptides such as muramyl dipeptide (MDP) MDP-Lys (L18) (N.sup..alpha.-acetylemuramyl-L- alanyl-D-isoglutaminyl-N.sup.esteoroyl-L— lysine), zinc sulphate, colloidal iron hydroxide, calcium phosphate or calcium chloride, CpG oligodeoxynucleotides (CPG ODN) such as CPG ODN 1826 and CPG ODN 2007, MF59 which is a detergent stabilized oil-in water emulsion containing 5% squalene (w/v)
  • CFA Complete Freund'
  • Span 80 (w/v) and 0.5% Span (w/v) in water, polysaccharides (such as Inulin) and liposomes (such as cationic liposomes, ISCOMs), molecules which have the capacity to activate T-cell immune response, PRP (Pathogen Recognition Receptors), such as adjuvants that bind or are agonists to TLR (Toll like receptor) 3, 4, 7, 8 and/or 9 on immune cells (such as APC).
  • PRP Pathogen Recognition Receptors
  • the adjuvant is a TLR ligand, in particular a TLR ligand selected from the group consisting of TLR ligands of class 3, such as Poly IC, Poly-ICLC, TLR ligands of class 4, such as MPL or GLA, TLR ligands of class 9, such as CpG, and TLR ligands of class 7/8, such as Imiquimod.
  • TLR ligands of class 3 such as Poly IC, Poly-ICLC
  • TLR ligands of class 4 such as MPL or GLA
  • TLR ligands of class 9 such as CpG
  • TLR ligands of class 7/8 such as Imiquimod.
  • adjuvant is Poly-ICLC.
  • Poly-ICLC can be purchased from Oncovir Inc, (WA, US) as HiltonolTM.
  • the immunogenic composition as defined herein may be combined or mixed with at least one immunopotentiator, such as at least another adjuvant, or a surfactant or immunomodulatory substances, such as cytokines or chemokines, or a growth factors such as such as GM-CSF or a combination thereof.
  • at least one immunopotentiator such as at least another adjuvant, or a surfactant or immunomodulatory substances, such as cytokines or chemokines, or a growth factors such as such as GM-CSF or a combination thereof.
  • the immunogenic composition as defined herein and the immunopotentiator are both put in contact with the host, at the same or different time and/or by the same or different modes of administration, preferably at the same site of contact.
  • mixed means that the immunogenic composition as defined herein and the immunopotentiator are in the same formulation when administered.
  • the immunogenic composition comprises a Bordetella bronchiseptica adenylate cyclase toxin (CyaA) vector carrying a Bsp22 antigen, a Poly-ICLC as adjuvant and optionally some pharmaceutically/veterinary-acceptable carriers.
  • CyaA Bordetella bronchiseptica adenylate cyclase toxin
  • Immunogenic composition and vaccines encompassed by the present invention can further include one or more pharmaceutically/veterinary-acceptable carriers.
  • pharmaceutically/veterinary-acceptable refers to those compounds, materials, excipients, compositions or dosage forms which are, within the scope of sound medical judgment suitable for use in contact with the tissues of subjects, especially veterinary subjects, without excessive toxicity, irritation, allergic response or other problem complications commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically/veterinary acceptable carriers include but are not limited to solvents, dispersion media, coatings, stabilizing agents, diluents, preservatives, antibacterial and antifungal agents, isotonic agents, adsorption delaying agents, and the like.
  • Diluents can include water, saline, dextrose, ethanol, glycerol and the like.
  • Isotonic agents can include sodium chloride, dextrose, mannitol, sorbitol and lactose, among others known to those skilled in the art.
  • Stabilizers include albumin.
  • Preservatives include merthiolate.
  • the immunogenic composition is for use for treating a Bordetella bronchiseptica infection in a non-human animal
  • treatment or “method of treating” or its equivalent is not intended as an absolute term and, when applied to, for example, infection refers to a procedure or course of action that is designed to reduce or eliminate or to alleviate the symptoms of an infection.
  • a “treatment” or a “method of treating” infection does not necessarily mean that the infection will, in fact, be eliminated, be reduced, or that the symptoms of infection will, in fact be alleviated. Often, a "treatment” or a "method of treating” infection will be performed even with a low likelihood of success but is nevertheless deemed to induce an overall beneficial course of action.
  • the term "treatment” also includes the prevention of an infection. Instead, prevention, e.g., of Bordetella bronchiseptica infection, refers to delay on onset, reduced frequency of symptoms, or reduced severity of symptoms associated with the disorder. Prevention therefore refers to a broad range of prophylactic measures that will be understood by those in the art. In some circumstances, the frequency and severity of symptoms is reduced to non-pathological levels.
  • the term "treatment” also includes a prophylactic treatment of non-human animals. A prophylactic treatment aims at preventing the Bordetella bronchiseptica infection of said non-human animal and/or preventing the apparition, the development and/or the occurrence of a pathological state and /or symptoms in said non-human animal.
  • the prophylactic treatment encompasses vaccination.
  • non-human animal encompasses, and preferably is, a non-human mammal such as for example a canine, a feline, a bovine, an ovine, a porcine, a camelid or an equine.
  • the non-human animal is a canine or a feline.
  • the immunogenic composition is for use for treating canine tracheobronchitis, commonly named kennel cough.
  • the immunogenic composition is administered in a non-human animal by different routes: by oral or per oral administration, oronasal administration, parenteral administration, intranasal administration, respiratory administration.
  • Oral or per oral administration refers to the introduction of the immunogenic composition of the invention, into the non-human animal body through or by way of the mouth and involves swallowing or transport through the oral mucosa (e.g., sublingual or buccal absorption) or both.
  • Intratracheal is also a means of oral or peroral administration.
  • Oronasal administration refers to the introduction of the immunogenic composition of the invention, into the non-human animal body through or by way of the nose and the mouth, as would occur, for example, by placing one or more droplets in the nose. Oronasal administration involves transport processes associated with oral and intranasal administration.
  • Parenteral administration refers to the introduction of the immunogenic composition of the invention, into the non-human animal body through or by way of a route that does not include the digestive tract.
  • Parenteral administration includes subcutaneous, intramuscular, intraarterial, and intravenous administration.
  • parenteral administration excludes administration routes that primarily involve transport of the substance through mucosal tissue in the mouth, nose, trachea, and lungs.
  • Intrasal administration refers to the introduction of the immunogenic composition of the invention, into the non-human animal body through or by way of the nose, and involves transport of the substance primarily through the nasal mucosa.
  • Respiratory administration refers to the introduction of the immunogenic composition of the invention, into the non-human animal body through or by way of inhalation of a nebulized (atomized) substance.
  • respiratory administration the primary transport mechanism involves absorption of the atomized substance through the mucosa in the trachea, bronchi, and lungs and is therefore different than intranasal or peroral administration.
  • the immunogenic compositions defined herein may be in a solid form (capsule, powder, tablet, pill, suppository, quick release tablet, gastro-resistant tablet, delayed release tablet), a powder form, preferably after lyophilization (lyophilized form or lyophilized powder form) which needs to be reconstituted for example with diluents(s) before injection, or in a liquid form, such as an injectable solution or injectable suspension.
  • the immunogenic composition of the invention is administered to a non-human animal subcutaneously in a liquid form.
  • the immunogenic composition of the invention is administered to a non-human animal with another vaccine, selected from vaccines for treating others pathogens in Bordetella bronchiseptica infection such as pasteurella multocida, herpesvirus, calicivirus, mycoplasma, chlamydia, adenovirus and parainfluenza virus alone or in combination.
  • the immunogenic composition of the invention can be administered to the non-human animal in one dose or in multiple doses.
  • Dose refers to the immunogenic composition given to a subject.
  • a “first dose” or “priming dose” refers to the dose of such composition given on day 0.
  • a “second dose” or a “third dose” or an “annual dose” refers to an amount of such composition given subsequent to the first dose, which can be but is not required to be the same vaccine or immunogenic composition as the first dose.
  • a particular regimen that may be adopted is a repeated administration protocol, especially in a protocol which encompasses two rounds or more of administration.
  • the immunogenic composition is administered in one dose, followed by subsequent doses.
  • the immunogenic composition is administered in one dose, followed by a second dose.
  • the immunogenic composition is administered in first dose, followed by a second dose, the second dose is given 3 weeks after the first dose.
  • the first dose and the second dose are administered subcutaneously.
  • the present invention also relates to an immunogenic composition comprising a Bordetella sp. adenylate cyclase toxin (CyaA) for use for treating a Bordetella bronchiseptica caused infection and / or related disease.
  • a Bordetella sp. adenylate cyclase toxin CyaA
  • the Bordetella bronchiseptica caused infection and / or related disease is tracheobronchitis, commonly named kennel cough.
  • the adenylate cyclase toxin is from Bordetella bronchiseptica.
  • the invention also concerns a method for treating of a non-human animal presenting with a Bordetella bronchiseptica infection or suspected to have a Bordetella bronchiseptica infection comprising (a) the administration of an effective amount of the immunogenic composition of the present invention into said non-human animal, possibly as multiple administered doses, and (b) the follow up of the condition of said non-human animal.
  • the invention also concerns a method for treating of a non-human animal presenting with a Bordetella bronchiseptica infection or suspected to have a Bordetella bronchiseptica infection comprising (a) the administration of an effective amount of the immunogenic composition of the present invention into said non-human animal, possibly as multiple administered doses, and (b) the follow up of the condition of said non-human animal, possibly as multiple administered doses.
  • An "effective amount" of the immunogenic composition of the invention refers to the effective amount sufficient to prevent, reduce, eliminate, control, treat or inhibit the Bordetella bronchiseptica infection and/or the symptoms.
  • controlling is intended to refer to all processes wherein there may be a slowing, interrupting, arresting, or stopping the progression of the diseases and conditions described herein, but does not necessarily indicate a total elimination of all disease and condition symptoms.
  • the doses used for the administration can be adapted as a function of various parameters, in particular as a function of the mode of administration used, of the relevant pathology, or alternatively of the desired duration of treatment.
  • the form of the pharmaceutical composition, the route of administration, the dosage and the regimen naturally depend on the condition to be treated, the severity of the illness, the age, weight, and sex of the subject, etc.
  • the ranges of effective doses provided below are not intended to limit the invention and represent preferred dose ranges. However, the preferred dose can be tailored to the individual subject, as is understood and determinable by one of skill in the art, without undue experimentation.
  • the amount of active agent present in the immunogenic composition of tbe present invention will vary depending upon the particular active agent used, as well as the intended subject for administration of the composition, and route of administration.
  • the immunogenic composition of the present invention will comprise from about 0.01% to about 90% by weight active agent, preferably from about 10% to about 60% and more preferably, from about 30% to about 50%, based upon the total weight of the immunogenic composition taken as 100% by weight.
  • the invention concerns a method for treating an infection in a non-human animal preferably in a canine and/or a feline, wherein the method comprises administering an effective amount of the immunogenic composition of the present invention to a non- human animal, preferably a canine or a feline, in need of such treatment.
  • the present invention relates to a method for treating a Bordetella bronchiseptica infection and related diseases preferably, a method for treating canine tracheobronchitis infection commonly called kennel cough, wherein the method comprises administering a therapeutically effective amount of the immunogenic composition of the invention to a canine or a feline in need of such treatment. All the embodiments disclosed above for the immunogenic composition are encompassed in this aspect.
  • the present invention relates to a method for treating a Bordetella bronchiseptica infection and related diseases in a non-human animal, preferably, a method for treating canine tracheobronchitis infection commonly called kennel cough comprising administering to said non-human animal a Bordetella sp.
  • Adenylate cyclase toxin CyaA
  • a Bordetella bronchiseptica adenylate cyclase toxin CDadenylate cyclase toxin
  • the present invention relates to the use of Bordetella sp. preferably Bordetella bronchiseptica adenylate cyclase toxin (CyaA) vector for the treatment of Bordetella bronchiseptica infections and more preferably the canine tracheobronchitis infection commonly called kennel cough.
  • Bordetella sp preferably Bordetella bronchiseptica adenylate cyclase toxin (CyaA) vector for the treatment of Bordetella bronchiseptica infections and more preferably the canine tracheobronchitis infection commonly called kennel cough.
  • the present invention concerns the use of an immunogenic composition
  • an immunogenic composition comprising a Bordetella sp. adenylate cyclase toxin (CyaA) vector with at least one Bordetella bronchiseptica antigen for the treatment of Bordetella bronchiseptica infection in a non-human animal.
  • the present invention relates to the use of an immunogenic composition for the treatment of a Bordetella bronchiseptica infection comprising a Bordetella sp.
  • adenylate cyclase toxin (CyaA) vector with a Bordetella bronchiseptica antigen for the treatment of the canine tracheobronchitis infection commonly called kennel cough All the embodiments disclosed above for the immunogenic composition are encompassed in this aspect.
  • the present invention related to the use of Bordetella sp. preferably Bordetella bronchiseptica adenylate cyclase toxin (CyaA) vector for the manufacture of a pharmaceutical preparation for the treatment of the canine tracheobronchitis infection commonly called kennel cough.
  • Bordetella sp. preferably Bordetella bronchiseptica adenylate cyclase toxin (CyaA) vector for the manufacture of a pharmaceutical preparation for the treatment of the canine tracheobronchitis infection commonly called kennel cough.
  • CeA Bordetella bronchiseptica adenylate cyclase toxin
  • the present invention concerns the use of an immunogenic composition
  • an immunogenic composition comprising a Bordetella sp. adenylate cyclase toxin (CyaA) vector with at least one Bordetella bronchiseptica antigen for the manufacture of a pharmaceutical and/or vaccinal preparation for the treatment of an Bordetella bronchiseptica infection in a non-human animal. All the embodiments disclosed above for the immunogenic composition are encompassed in this aspect.
  • the invention relates to the use of an immunogenic composition for the manufacture of a pharmaceutical preparation for the treatment of a Bordetella bronchiseptica infection, comprising a Bordetella sp. adenylate cyclase toxin (CyaA) vector with at least one Bordetella bronchiseptica antigen for the treatment of the canine tracheobronchitis infection commonly called kennel cough.
  • aA Bordetella sp. adenylate cyclase toxin
  • Example 1 Construction, production and purification of CyaA toxoid.
  • Antigens The synthetic peptide corresponding to antigens such as Bsp22 of Bordetella Bronchiseptica (SEQ ID No: 4) was purchased from Polypeptide (Strasbourg, France).
  • Recombinant CyaA toxoid comprising the antigens such as Bsp22 (CyaA-Bsp22) genetically link to the N-terminal part of Bordetella Bronchiseptica CyaA protein (SEQ ID NO:6 ) were produced in E. coli XLl-Blue (Stratagen, an Agilent Technologies Company, USA) transformed with appropriate pT7CACTl -derived constructs (Osicka R. et al, 2000, Infect. Immun., 68: 247-256).
  • Exponential 500-ml cultures were grown at 37°C and induced by isopropyl ⁇ - ⁇ - ⁇ - ⁇ - galactopyranoside (IPTG, 1 mM) for 4 h before the cells were washed with 50 mM Tris- HC1 (pH 8.0), 150 mM NaCl, resuspended in 50 mM Tris-HCl (pH 8.0), 0.2 mM CaC12, and disrupted by sonication.
  • IPTG isopropyl ⁇ - ⁇ - ⁇ - ⁇ - ⁇ - galactopyranoside
  • the CyaA toxoid were eluted with 8 M urea, 50 mM Tris-HCl (pH 8.0), 2 M NaCl, diluted four times with 50 mM Tris-HCl (pH 8.0), 1 M NaCl buffer, and further purified on a phenyl-Sepharose column equilibrated with the same buffer. Unbound proteins were washed out with 50 mM Tris-HCl (pH 8.0), and the CyaA toxoid were eluted with 8 M urea, 50 mM Tris-HCl (pH 8.0), 2 mM EDTA and stored at - 20°C.
  • Beagle dogs were purchased from a licensed kennel for animal breeding and husbandry (CEDS, Centre d'Elevage du Domaine de Souches, France). Specific pathogen-free puppies were eight week old at their arrival. They were bred in a specific facility free of Bordetella bronchispetica. Before the beginning of the study, all the puppies were shown to be seronegative for Bordetella bronchiseptica. All dogs were dewormed and vaccinated against canine distemper virus, parvovirus, leptospirosis, infectious canine hepatitis and parainfluenza virus. They were housed in an accredited class II facility and were provided commercial dog food (VetCare Nutrition, Junior 10kg, Royal Canin) and tap water ad libitum.
  • Vaccination preparation, formulation and regimens Dogs were vaccinated with the CyaA-Bsp22 toxoid as prepared in Example 1.
  • Each vaccinated dog received 2 subcutaneous injections of 300 ⁇ g CyaA-Bsp22 toxoid (in Urea 2.4M) and 150 ⁇ g of Poly-ICLC (Oncovir) at 3 weeks interval ("vaccine group").
  • Control dogs received the same amount of adjuvant (Poly-ICLC) in 2.4M Urea ("control group").
  • the challenge preparation was an equal mix of the three bacterial strains, corresponding to a total of 8.0 109CFU/ml.
  • PBMC Peripheral Blood Mononuclear Cells
  • PBMC peripheral blood mononuclear cells
  • IFNy ELISPOT The cells were cultured in complete medium composed of Gibco® Roswell Park Memorial Institute (cRPMI) Medium 1640 containing GlutaMAX® (L-alanyl-L-glutamine) and HEPES, supplemented with 1% sodium pyruvate, 1% non-essentials aminoacids, 100 ⁇ g/ml streptomycin, 100 IU penicillin and 10% heat-inactivated Gibco® Fetal Bovin Serum (cat 10270, batch 41G7832K) at a concentration of 2 x 10 6 PBMC/ml.
  • cRPMI Gibco® Roswell Park Memorial Institute
  • PBMC peripheral blood mononuclear cells
  • PBMC peripheral blood mononuclear cells
  • bIFN -I equine IFN capture antibody
  • cells were cultured in complete medium as a negative control and in the presence of 50 ng/ml Phorbol 12-Myristate 13-Acetate and 1 ⁇ ionomycine calcium salt (Sigma-Aldrich) as a non-antigen specific positive controls to assess the functionality of the PBMC.
  • the antigen- specific cellular response against the vaccine was tested with 0.5 ⁇ g/well of CyaA or 0.5 ⁇ g/well of Bsp22.
  • the geometric mean of spot number was calculated (mean of triplicate). For the specific response against CyaA or Bsp 22, the data are presented as the number of spots per 10 6 cells after stimulation with CyaA (or Bsp22) minus the value obtained with the negative control obtained with medium alone the same day.
  • ELISA testing was performed every week, starting on the day of the first vaccination until day 70 post- vaccination to measure the level of total IgG, IgGl and IgG2 antibodies specific for CyaA and Bsp 22.
  • a 96 well MAXISORP plate (Nunc) was coated with 0.25 ⁇ g of purified CyaA or 0.5 ⁇ g Bsp 22 per well in carbonate buffer (pH 9.6) overnight at +4°C. Nonspecific sites were blocked with PBT/BSA (PBS + 0.1% Tween-20 + 1% Bovine Serum Albumin) for 2 hours at room temperature. Serial two-fold dilutions of sera were tested starting at 1/5000 until 1/40000. The first dilution that did not saturate the ELISA in vaccinated dogs was used to analyse the results. After 1 hour of incubation at room temperature, plates were washed five times with PBT.
  • PBT/BSA PBS + 0.1% Tween-20 + 1% Bovine Serum Albumin
  • a specific peroxidase-conjugated rabbit polyclonal anti-dog IgG secondary Ab (304-035-0030, Jackson Immuno Research) was added at 0.04 ⁇ g/well and incubated 1 hour of incubation at room temperature. After five washed, revelation was done with incubation with TMB Liquid Substrate System (Sigma).
  • the immunogenic composition comprising CyaA vector carrying Bsp22 antigen was confirmed to be safe.
  • Example 4 Efficacy of the immunogenic composition comprising CyaA vector carrying Bsp22 antigen
  • control puppies After infection, control puppies display clear clinical signs of tracheobronchitis, including spontaneous and induced coughing, nasal discharge and, for some of them, vomiting. All dogs spontaneously recovered from infection in three weeks.
  • the immunogenic composition comprising CyaA vector carrying Bsp22 antigen delays the outbreak of tracheobronchitis and reduces the duration and intensity of cough.
  • the immunogenic composition reduces the intensity and duration of clinical signs after experimental infection.
  • Example 5 immunogenicity of the immunogenic composition comprising CyaA vector carrying Bsp22 antigen
  • the IFNy production of PBMC after specific in vitro re- stimulation was quantified by ELISpot, in order to monitor the cellular response induced by CyaA.
  • the plated cells with Phorbol Myristate Acetate plus ionomycine were stimulated to induce a polyclonal T-cell activation (positive control) in order to assess the functionality of our assay.
  • Non-specific activation was detected with cells cultured in the presence of the medium only (negative control).
  • an average of 4.3 10 3 spots per 10 6 cells could be detected after PMA+Io stimulation (data not shown), while no spots were detected when cells were cultured in medium alone.
  • the humoral response induced against CyaA was monitored every week after the first vaccination (FIGURE 3). Over the course of the study, all vaccinated dogs developed a strong humoral response against the CyaA protein (FIGURE 3A). This response was detectable one week after the second vaccine injection and was significantly higher than in control dogs during the course of the study (p ⁇ 0.01). Interestingly, this humoral response was boosted by the virulent challenge in vaccinated puppies while the infection did not induce anti-CyaA antibody synthesis in non-vaccinated puppies.
  • the next step for the validation of the immunogenicity of the candidate vaccine is to demonstrate that it also induces a specific cellular response against the target antigen included in the vaccine i.e. the Bsp22 protein.
  • the IFNy production was thus quantified by ELISpot by PBMC after in vitro Bsp22 specific re-stimulation.

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Abstract

La présente invention concerne de manière générale une composition immunogène comprenant la toxine d'adénylate cyclase (CyaA) de Bordetella sp. pour utilisation à des fins de traitement des infections par Bordetella bronchiseptica chez des animaux non humains. Plus particulièrement, l'invention concerne une composition immunogène comprenant le vecteur de la toxine d'adénylate cyclase (CyaA) de Bordetella sp. pour utilisation à des fins de traitement des infections par Bordetella bronchiseptica chez des animaux non humains. La présente invention concerne également une composition immunogène comprenant un vecteur de la toxine d'adénylate cyclase (CyaA) de Bordetella sp. portant au moins un antigène de Bordetella bronchiseptica.
PCT/EP2017/079515 2016-11-17 2017-11-16 Compositions immunogènes et vaccinales pour utilisation contre une infection par bordetella bronchiseptica WO2018091613A1 (fr)

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