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WO1999038529A1 - Composition vaccinale comprenant un lyophilisat de cellules entieres antigeniques usinees - Google Patents

Composition vaccinale comprenant un lyophilisat de cellules entieres antigeniques usinees Download PDF

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Publication number
WO1999038529A1
WO1999038529A1 PCT/GB1999/000287 GB9900287W WO9938529A1 WO 1999038529 A1 WO1999038529 A1 WO 1999038529A1 GB 9900287 W GB9900287 W GB 9900287W WO 9938529 A1 WO9938529 A1 WO 9938529A1
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WO
WIPO (PCT)
Prior art keywords
cells
vaccine composition
lyophilisate
milled
bacterial
Prior art date
Application number
PCT/GB1999/000287
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English (en)
Inventor
Roderick Peter Hafner
Original Assignee
Provalis Uk Limited
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Provalis Uk Limited filed Critical Provalis Uk Limited
Priority to AU22897/99A priority Critical patent/AU2289799A/en
Publication of WO1999038529A1 publication Critical patent/WO1999038529A1/fr

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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
    • A61K39/105—Delta proteobacteriales, e.g. Lawsonia; Epsilon proteobacteriales, e.g. campylobacter, helicobacter
    • 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
    • A61K39/0002—Fungal antigens, e.g. Trichophyton, Aspergillus, Candida
    • 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
    • A61K39/102—Pasteurellales, e.g. Actinobacillus, Pasteurella; Haemophilus
    • 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
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/52—Bacterial cells; Fungal cells; Protozoal cells
    • A61K2039/521—Bacterial cells; Fungal cells; Protozoal cells inactivated (killed)
    • 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
    • A61K2039/541—Mucosal route
    • A61K2039/542—Mucosal route oral/gastrointestinal
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a vaccine composition and, in particular, to a vaccine composition which elicits a mucosal immune response and protects against infections of mucosal membranes.
  • Mucosal membranes such as those lining the gastrointestinal tract, respiratory tract, the urogen al tract, the eye and the mammary gland, are protected by the common mucosal immune system, which is characterised by the sub-epithelial distribution of both diffuse and aggregated collections of ly ⁇ hoid tissue. Induction of mucosal immune responses for orally dosed products occurs primarily within the Peyer's patches of die gastrointestinal tract with the predominant flow of effector cells from the gut to other mucosal sites via the intestinal lymphatics, mesenteric lymph nodes and the blood.
  • the dome of the Peyer's patch is covered by specialised membranous epithelial cells called microfold, or M, cells, which are capable of sampling antigen from the gastrointestinal tract and transporting the sample antigen without degradation to the underlying lymphoid tissue.
  • M membranous epithelial cells
  • B cells contain germinal centres which give rise primarily to precursor IgM and IgG B cells.
  • Intestinally derived B and T effector cells traffic preferentially from the Peyer's patch to sites within the mucosal immune system, such as the gut itself, the airways, the mammary glands, urogenital tract and eyes and ears.
  • infection depend upon the nature of the immunogen (vaccine) and the invading pathogen. Examples of the responses that may be elicited are given below.
  • IgA antibody produced by IgA plasma cells is transported across the epithelial membrane into the mucosal fluid by a specialised transport system. However, some of this IgA antibody, which is produced in the sub-epithelial tissue, returns to the blood system by the regional lymphatics.
  • IgA in the mucosal immune system is distinct from IgA systemically in that it consists of two IgA molecules linked by a special connecting protein. It also has attached to it a protein called a secretory component, which protects the molecule against degradation in the hostile environment found at mucosal sites. This unique molecule is called secretory IgA (slgA).
  • secretory IgA secretory IgA
  • An important property of slgA is that it does not activate the classical complement pathways. This is important because activation of complement results in the induction of significant inflammatory mechanisms.
  • the principle mechanism by which slgA protects the mucosal linings is by the inhibition of attachment of pathogens to the mucosal epithelial cells, thereby controlling the initial colonisation. This function prevents the establishment f infection at the target site. IgA probably has a lesser role in modulating established colonisation.
  • IgG whether derived from the serum, or mucosal, may also fulfil a protective
  • Antigen-stimulated CD4 positive T H 1 cells from the Peyer's patch may migrate from the gut-associated lymphoid tissue to, for example, the bronchus lumen. Following reactivation at this site due to exposure to the specific antigen of the pathogen, 99/38529 1
  • secreted cytokines may initiate (or contribute to) a sequence of events involving activated alveolar macrophages leading ultimately to increased polymorphonuclear neutrophil recruitment and activation.
  • Neutrophils are able to phagocytose pathogens and inactivate them.
  • a vaccine composition in order to provide protection against mucosal infections, must contain an active agent which is capable of being absorbed from the gastrointestinal tract by the M cells of the Peyer's patches and transported into the lymphatic system where it can elicit an immune response.
  • Vaccines which protect against infections of mucosal surfaces are known, for example from EP-A-0225329, which describes a non-adjuvanted composition comprising killed bacteria.
  • the killed bacterial cells should be released close to die Peyer's patches so that proteolytic damage to the surface antigens of the killed cells is minimised.
  • Transit time through the human small intestine is typically several hours and the Peyer's patches are distributed evenly along it and this means that the vaccine should ideally be formulated for sustained release.
  • Formulation of a solid dosage product requires particles of the active material to be granulated to approximately equal size to that of the tablet excipients so as to allow good blending characteristics and even distribution of the active material throughout the product. The rate of release of particles from such a granulated material can then be controlled by the use of appropriate polymers.
  • the stresses involved in the granulation process are not compatible with maintaining immunogenicity of the vaccine materials.
  • a vaccine composition comprising a milled lyophilisate of antigenic whole cells can achieve sustained release of the cells over the length of the small intestine without the problems associated with granulation.
  • a vaccine composition comprising a lyophilisate of antigenic whole cells milled to a particle size of from about 20 to 350 ⁇ m.
  • composition of the invention is effective as a vaccine because it would have been expected that particles of from about 20 to 350 ⁇ m would be too large to be taken up into the Peyer's patches.
  • effectiveness of the vaccine appears to arise from the fact that, under the conditions which prevail in the gastrointestinal tract, individual cells gradually peel from the surface of the milled particles. It is these cells which are taken up into the Peyer's patches and which trigger the immune response.
  • the peeling of cells from the surface of the lyophilised particles has been observed experimentally when the milled lyophilisate is dispersed in a buffer which simulates the conditions found in the gastrointestinal tract.
  • the vaccine composition is particularly advantageous because the gradual peeling off of the cells from the particles is, in effect, sustained release of individual cells along the length of the small intestine.
  • the present invention has all the advantages of a sustained release vaccine product without die risk of destroying the antigenicity of the antigenic whole cells.
  • the term "vaccine” refers to a composition for pharmaceutical or veterinary use which either prevents colonisation by an organism expressing the antigen contained in the antigenic whole cells or, in subjects 5
  • the particles may be milled to a size of from about 20 to 350 ⁇ m, it is preferred that the particles are within the range of about 20 to 250 ⁇ m. The best results are achieved when the particles are up to 150 ⁇ m in size.
  • the antigenic whole cells may be killed bacterial or yeast cells and the particular species of cell used will, of course, depend upon die condition against which the patient is being immunised.
  • suitable species include Haemophilus influenzae, Pseudomonas species (such as P. aeruginosa and P. cepaceia), E. coli (both enteropathogenic and enterotoxigenic), Streptococcus species (such as S. pneumoniae, S. mitis, S. mutans, S. viridans and S. pyogenes), Staphylococcus aureus, Mycobacterium tuberculosis (such as Bacille Calmette-Guerin, BCG), Corynebacterium parvum, Candida species (such as C.
  • albicans C. cruzzi and C. glabrata
  • other causative agents of genitourinary tract infections for example Chlamydia trachomatis and Neisseria gonnorhoea, Helicobacter pylori
  • bacteria known to cause respiratory exacerbations in diseased populations for example Diplococcus pneumoniae, Klebsiella pneumoniae, Klebsiella ozaenae and Branhamella catarrhalis
  • bacteria known to cause meningitis for example Neisseria meningitidis, bacteria which cause whooping cough, cholera, diphtheria and typhoid and organisms related to any of the above.
  • Other suitable species will be familiar to those skilled in the art.
  • the antigenic whole cells may be of an organism which has been genetically modified so as to be antigemc.
  • Organisms which may be modified in this way include Lactococcus lactis which may be genetically modified to express antigenic elements.
  • antigenic whole cells may be recombinant organisms. 6
  • the genetically modified or recombinant organisms may include antigens from one or more of the species mentioned above.
  • a further type of antigenic whole cell which may be useful in the present invention is a bacterial or eukaryotic cell onto which a virus has been adsorbed.
  • composition of the invention may contain cells of a single species or a mixture of species.
  • the vaccine of the present invention may be used to protect against bacterial, viral or fungal infections of any mucosal surface, for example the surfaces lining the gastrointestinal tract (including the buccal cavity), the middle ear, the eustachian tubes, respiratory tract (including the nose and the nasopharynx), the urogenital tract, the eye and the mammary gland.
  • Killed whole cell vaccines have, in the past, been particularly useful for the prophylaxis of infections of the lungs and respiratory tract and the vaccine of the present invention is also of particular use in this field.
  • the vaccine of the present invention has a dual use and thus, for example, in a patient with a chronic lung disease such as cystic fibrosis, chronic bronchitis or bronchiectasis, a vaccine composition of the invention containing whole killed cells of Haemophilus influenzae or Pseudomonas aeruginosa or genetically modified or recombinant cells containing antigens from these organisms can prevent colonisation of the patient with Haemophilus influenzae or Pseudomonas aeruginosa.
  • a vaccine composition of the invention containing whole killed cells of Haemophilus influenzae or Pseudomonas aeruginosa or genetically modified or recombinant cells containing antigens from these organisms can prevent colonisation of the patient with Haemophilus influenzae or Pseudomonas aeruginosa.
  • the composition may be used to prevent acute infection of the patients by Haemophilus influenzae or Pseudomonas aeruginosa, although it will not necessarily clear the colonising organism. Acute infection by these organisms considerably worsens the prognosis of patients with severe lung disease.
  • the vaccine can either be used to prevent initial colonisation by an infecting organism or to reduce the incidence of acute infections in a patient already colonised by the orgamsm.
  • Vaccine compositions according to the invention may be used to prevent bacterial conjunctivitis, oral or vaginal thrush, which is caused by infection with Candida species, infection of the gastrointestinal tract with Helicobacter pylori, which can lead to inflammation and ulceration of the lining of the gastrointestinal tract, otitis media, meningitis, tonsillitis, pharyngitis, tuberculosis, secondary bacterial infections for example those occurring after a cold, diarrhoea caused, for example, by organisms such as E. coli, S. typhi and V. cholerae, pneumonia, conditions caused by Corynebacterium parvum and other sexually transmitted diseases.
  • the vaccine composition may contain an adjuvant but, in many cases, it is preferable not to include one.
  • Adjuvants are well known to those skilled in the art of vaccine formulation and it would be a relatively simple matter to choose one which is suitable.
  • the killed cells in the vaccine may elicit a sufficient antigenic response so as not to require an adjuvant.
  • compositions in which the antigenic whole cells are genetically modified or recombinant organisms or which include viruses adsorbed onto cells may, in some cases require an adjuvant.
  • an adjuvant Those skilled in the art can easily determine whether or not an adjuvant is necessary using known methods and without undue experimentation.
  • the vaccine composition of the present invention is intended for oral administration and may be formulated in any suitable manner.
  • the milled lyophilisate may be encapsulated in hard or soft capsules or may be mixed with an excipient and tabletted.
  • Sugars are especially suitable tabletting excipients and examples include lactose, sucrose, mannitol and sorbitol.
  • other known tabletting excipients such as microcrystalline cellulose or dicalcium phosphate may be included in addition to or instead of sugars.
  • the particle size of the milled lyophilisate is maintained in tabletting, indicating that the material retains substantial strength.
  • the lyophilisate may be supplied as a powder which may be packaged in single-dose sachets.
  • the vaccine composition of the present invention may be used in a method of preventing the colonisation of mucosal surfaces by an infecting organism, the method comprising immunising a patient at risk of such infection with a vaccine composition comprising a lyophilisate of antigemc whole cells milled to a particle size of from about 20 to 350 ⁇ m.
  • composition is also of use in a method for the prevention of acute infections by an organism in an individual already colonised by that orgamsm, the method comprising immunising a patient at risk of such infection with a vaccine composition 9/38529 _
  • the present invention provides the use of a lyophilisate of antigenic whole cells milled to a particle size of from about 20 to 350 ⁇ m in the preparation of a vaccine composition for preventing colonisation of mucosal surfaces by an infecting organism expressing an antigen which is the same as the antigen of the lyophilisate or for preventing acute infection by the organism in a previously colonised patient.
  • the vaccine composition of the present invention is relatively simple to prepare and the method of preparation comprises the steps of:
  • preparing a suitable quantity of cells of the required organism by fermentation i. killing the organism by a method which enables antigenicity to be maintained; iii. washing and harvesting the killed cells by any suitable method; iv. lyophilising the harvested killed cells; and ii. milling the cake of killed cells to a particle size of about 20 to 350 ⁇ m.
  • Further optional steps include filling the milled lyophilisate into capsules or mixing the milled lyophilisate with a suitable excipient and tabletting.
  • Suitable methods of killing the cells include treatment with formaldehyde and the killed cells may be harvested by centrifugation.
  • FIGURE 1 is a plot showing the number of live bacteria recovered from bronchoalveolar lavage fluid in non immunised rats and in rats immunised with either a freshly prepared suspension of formalin-killed P. aeruginosa or with a milled lyophilisate of P. aeruginosa and subsequently challenged with live bacteria.
  • FIGURE 2 is a plot showing the number of live bacteria recovered from lung homogenate in non immunised rats and in rats immunised with either a freshly prepared suspension of formalin killed P. aeruginosa or with a milled lyophilisate of P. aeruginosa and subsequently challenged with live bacteria.
  • FIGURE 3 is a plot showing the in vitro proliferative response to l.O ⁇ g of P. aeruginosa antigen for non immunised rats and rats immunised with either a freshly prepared suspension of formalin killed P. aeruginosa or with a milled lyophilisate of P. aeruginosa and subsequently challenged with live bacteria.
  • FIGURE 4 is a plot showing the in vitro proliferative response to l.O ⁇ g concanavalin A for non immunised rats and rats immunised with either a freshly prepared suspension of formalin killed P. aeruginosa or with a milled lyophilisate of P. aeruginosa and subsequently challenged with live bacteria.
  • FIGURE 5 is a plot showing the extent of P. aeruginosa-speciRc antibody response in the serum of non immunised rats and rats immunised with either a freshly prepared suspension of formalin killed P. aeruginosa or with a milled lyophilisate of P. aeruginosa and subsequently challenged with live bacteria.
  • FIGURE 6 is a plot showing the extent of P. aeruginosa-specific antibody response in bronchoalveolar lavage fluid of non immunised rats and rats immunised with either a freshly prepared suspension of formalin killed P. aeruginosa or witii a milled lyophilisate of P. aeruginosa and subsequently challenged with live bacteria.
  • FIGURE 7 shows milled lyophilisate particles immediately after dispersion in deionised water and with a magmfication of x50.
  • FIGURE 8 is a close up (magnification x 1000) of the edge of one of the particles of Figure 7 and shows individual cells gradually being released from the surface of the particle.
  • FIGURE 9 is a similar view to Figure 8 (magnification x 1000) but taken two to three hours after dispersion of the lyophilisate particles in the deionised water.
  • FIGURE 10 is a plot showing the particles size profile of the lyophilisate when first dispersed in deionised water.
  • FIGURE 11 is a plot which is similar to Figure 10 but which shows the particles size profile of the lyophilisate one hour after dispersion in deionised water.
  • Titanium dioxide 27.250% w/w
  • a culture broth of P. aeruginosa is used to inoculate two 500ml flasks of Tryptone Soya Broth which is incubated aerobically at 37°C. Once the OD660,,,,, reaches a value greater than 4, two 500ml flasks are used to inoculate a fermenter containing 30L of Tryptone Soya Broth with a suitable quantity of Antifoam CTM.
  • the fermenter is controlled to maintain an oxygen tension of at least 40% and the cells grown until an OD660,,,, of 5-6 is reached.
  • the seed fermenter is used to inoculate a fermenter containing 400L of Tryptone Soya Broth.
  • the fermenter is controlled to maintain an oxygen tension of at least 40% and d e cells grown until an OD ⁇ O ⁇ , of 5-6 is reached.
  • the cells are then killed by addition of formaldehyde to a final concentration of 1 % followed by incubation for 10-12 hours.
  • the contents of the fermenter are then transferred to a holding tank and held for a further 6-8 hours before harvesting using a centrifuge.
  • the resulting cell paste is frozen to -70°C and lyophilised using a shelf temperature of -20°C and a condenser temperature of -51°C and a pressure of 0.13mBar.
  • the secondary drying cycle is initiated by ramping the shelf temperature up by 5°C increments to a maximum of 15°C. 13
  • the lypophilisate is milled using a FritschTM variable speed rotor mill fitted with a 200 micron trapezoidal screen operating at 12000 rpm and a feed rate of 20g/min.
  • the milled material is blended witii die tablet core excipients using a drum blender and compressed using a rotary tablet press fitted witii 9mm tooling.
  • the resulting tablets are enteric coated in a perforated drum coater, applying the enteric coat components from an ethanol/water suspension.
  • Example 2 Using the general method of Example 1, a milled lyophilisate of Candida albicans was prepared. 175-250mg of the lyophilisate was filled into white opaque size 1 gelatin capsules. The capsules were gelatin banded and enteric coated with the following coating composition.
  • Example 2 Using the general method of Example 1, a milled lyophilisate of Helicobacter pylori was prepared. 5mg of the lyophilisate was mixed wim 100-250mg of lactose and O 99/38529 14
  • the capsules were gelatin banded and enteric coated with the following coating composition.
  • SPF Specific pamogen free P. aeruginosa were grown overnight on a nutrient agar plate and harvested into PBS. The cell concentration was adjusted to 10 10 /mL by comparison of optical density at 405nm with a standard regression curve. An equal volume of 2% parafo ⁇ naldehyde in PBS was added and the suspension incubated for 2h at 37°C. Following three washes with PBS, the live P. aeruginosa was resuspended in PBS to 10 ,0 mL. The actual concentration of live bacteria was checked by plating out 20 ⁇ L of serial dilutions onto nutrient agar plates, incubation overnight at 37°C and then counting the CFU.
  • P. aeruginosa were killed using formalin and a freshly prepared suspension of the killed bacteria was used as a "gold standard". The gold standard was compared for effectiveness in an animal model against a milled lyophilisate of P. aeruginosa prepared using the method described in Example 1.
  • rats Fourteen days after immunisation, rats were infected by intra-tracheal instillation of 5 x 10 8 live bacterial in 50 ⁇ L of PBS. Rats were killed 4 hours later by intraperitoneal overdose of sodium pentobarbitone. Blood was collected by heart- 99/38529 j 6
  • Triplicate cultures were set up containing 2 x 10 5 cells/200 ⁇ L/well in flat-bottom 96 well tissue culture plates. Cultures contained no antigen, P. aeruginosa antigen (Pa antigen) at 0. l ⁇ g/mL or
  • Live bacteria recovered is shown in Figures 1 and 2 and mean bacterial clearance in Table 2.
  • the number of live bacteria in both immunised groups is significantly lower than in the non-immune group ( Figure 1 and Table 2).
  • the milled lyophilisate immunised group was not significantly different from the gold standard immunised group.
  • % bacterial clearance is defined as:
  • the in vitro proliferative response is shown in Figures 3 and 4.
  • the response to 1.O ⁇ g Pa antigen of immunised groups is not significantly different from that of the non-immune group and die test groups are not significantly different from the gold standard ( Figure 3).
  • the immunised groups are not significantly different from me non-immune group or from each other ( Figure 4).
  • the P. aeruginosa-specific antibody response is shown in Figures 5 and 6. Serum P. aeruginosa-specific IgG, IgA and IgM are significantly higher in the immumsed groups than the non-immune group ( Figure 5). There is no significant difference between the group immunised with milled lyophilisate and die gold standard group.
  • the BAL IgA of the Pa milled lyophilisate immunised group is sigmficantly higher than that of the gold standard immunised group.
  • the BAL IgG and IgM of die milled lyophilisate immunised group are not significantly different from those of the gold standard.
  • the bacterial clearance assay is the most relevant assay to perform as it is an actual measure of protection against infection.
  • the proliferation and antibody assays provide extra information about die immune status of the rats following immunisation.
  • Milled lyophilisate particles were dispersed in distilled water and observed under a light microscope.
  • Figure 7 shows die particles immediately after dispersion.
  • Figure 8 shows a close up of the edge of one of die particles with individual bacterial cells gradually being released from the surface. After 2-3 hours, the large milled particles break up into smaller particles about 20-3 ⁇ m across, which continue to release individual cells (Figure 9)
  • Figures 10 and 11 demonstrate me behaviour of a milled lyophilisate dispersed in deionised water.
  • Figure 10 shows the particle size profile of the material when first dispersed in deionised water. The majority of the material is in the 100-200 ⁇ m particle size range witii only a small quantity between 1 and lO ⁇ m.
  • Figure 11 shows the same material after one hour. There has been a significant decrease in die material with a particle size of between 100 and 200 ⁇ m and a noticeable increase in the material with a particle size of 1 to lO ⁇ m. Importantiy, a significant proportion of the material remains with a particle size of 100 to 200 ⁇ m, providing a reservoir of material for ongoing release.

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Abstract

On décrit une composition vaccinale pour la prévention d'infections bactériennes ou fongiques de surfaces muqueuses. La composition vaccinale comprend un lyophilisat de cellules entières antigéniques usinées dans une taille des particules comprise entre environ 20 et 350 νm. Le vaccin peut contenir des organismes tueurs, tels que Haemophilus influenzae ou Pseudomonas aeruginosa, qui peuvent par exemple empêcher efficacement que ces organismes n'envahissent des patients atteints de maladies pulmonaires chroniques ou, s'agissant de patients déjà atteints, d'empêcher la survenue d'une infection aiguë de l'appareil respiratoire.
PCT/GB1999/000287 1998-01-28 1999-01-28 Composition vaccinale comprenant un lyophilisat de cellules entieres antigeniques usinees WO1999038529A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU22897/99A AU2289799A (en) 1998-01-28 1999-01-28 Vaccine composition comprising milled lyophilisate of antigenic whole cells

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Application Number Priority Date Filing Date Title
GBGB9801870.8A GB9801870D0 (en) 1998-01-28 1998-01-28 Vaccine composition
GB9801870.8 1998-01-28

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Cited By (8)

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WO2000044402A1 (fr) * 1999-01-29 2000-08-03 Galagen, Inc. Composition pharmaceutique comprenant un antigene selectionne, antigene de l'espece candida et procedes connexes
WO2001087332A1 (fr) * 2000-05-19 2001-11-22 Pneumobiotics, Pty, Ltd Compositions et procedes de traitement des infections muqueuses
US6541001B1 (en) 1999-08-24 2003-04-01 Teva Pharmaceutical Industries, Ltd. Vaccine composition and method of using the same
US6592869B2 (en) 1999-08-24 2003-07-15 Teva Pharmaceutical Industries, Ltd. Vaccine composition and method of using the same
WO2006017895A1 (fr) * 2004-08-17 2006-02-23 Hunter Immunology Pty Limited Vaccins à virus inactivé oraux et procédé de production de vaccins à virus inactivé oraux
DE102004046391A1 (de) * 2004-09-24 2006-04-06 Bioveta Ag Neuer Impfstoff für veterinäre und humanmedizinische Prophylaxe und Therapie
US7871627B2 (en) * 2001-12-11 2011-01-18 Institut Pasteur Gram positive bacteria preparations for the treatment of disease comprising an immune dysregulation
US7914799B2 (en) * 2001-08-27 2011-03-29 Immunitor USA, Inc. Anti-fungal composition

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000044402A1 (fr) * 1999-01-29 2000-08-03 Galagen, Inc. Composition pharmaceutique comprenant un antigene selectionne, antigene de l'espece candida et procedes connexes
US6541001B1 (en) 1999-08-24 2003-04-01 Teva Pharmaceutical Industries, Ltd. Vaccine composition and method of using the same
US6592869B2 (en) 1999-08-24 2003-07-15 Teva Pharmaceutical Industries, Ltd. Vaccine composition and method of using the same
US7192588B2 (en) 1999-08-24 2007-03-20 Teva Pharmaceutical Industries, Ltd. Vaccine composition and method of using the same
WO2001087332A1 (fr) * 2000-05-19 2001-11-22 Pneumobiotics, Pty, Ltd Compositions et procedes de traitement des infections muqueuses
US8637051B2 (en) * 2000-05-19 2014-01-28 Hunter Immunology Limited Compositions and methods for treatment of mucosal infections
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US7871627B2 (en) * 2001-12-11 2011-01-18 Institut Pasteur Gram positive bacteria preparations for the treatment of disease comprising an immune dysregulation
US8404250B2 (en) 2001-12-11 2013-03-26 Institut Pasteur Gram positive bacteria preparations for the treatment of diseases comprising an immune dysregulation
WO2006017895A1 (fr) * 2004-08-17 2006-02-23 Hunter Immunology Pty Limited Vaccins à virus inactivé oraux et procédé de production de vaccins à virus inactivé oraux
US7858073B2 (en) 2004-08-17 2010-12-28 Hunter Technology Limited Oral killed vaccines and method for providing same
DE102004046391A1 (de) * 2004-09-24 2006-04-06 Bioveta Ag Neuer Impfstoff für veterinäre und humanmedizinische Prophylaxe und Therapie

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