US20020187154A1 - Nontoxic mucosal adjuvant - Google Patents

Nontoxic mucosal adjuvant Download PDF

Info

Publication number
US20020187154A1
US20020187154A1 US10/163,448 US16344802A US2002187154A1 US 20020187154 A1 US20020187154 A1 US 20020187154A1 US 16344802 A US16344802 A US 16344802A US 2002187154 A1 US2002187154 A1 US 2002187154A1
Authority
US
United States
Prior art keywords
antigen
toxic
mucosal
adjuvant
mucosal adjuvant
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.)
Abandoned
Application number
US10/163,448
Other languages
English (en)
Inventor
Rino Rappuoli
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.)
GSK Vaccines SRL
Original Assignee
Chiron SRL
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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=10747021&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20020187154(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Chiron SRL filed Critical Chiron SRL
Priority to US10/163,448 priority Critical patent/US20020187154A1/en
Assigned to CHIRON S.P.A. reassignment CHIRON S.P.A. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: RAPPUOLI, RINO
Publication of US20020187154A1 publication Critical patent/US20020187154A1/en
Assigned to CHIRON S.R.L. reassignment CHIRON S.R.L. CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: CHIRON S.P.A.
Abandoned legal-status Critical Current

Links

Images

Classifications

    • 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
    • C07K14/24—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Enterobacteriaceae (F), e.g. Citrobacter, Serratia, Proteus, Providencia, Morganella, Yersinia
    • C07K14/245—Escherichia (G)
    • 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
    • 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic 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
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55544—Bacterial toxins
    • 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
    • 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
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S424/00—Drug, bio-affecting and body treating compositions
    • Y10S424/832—Drug, bio-affecting and body treating compositions involving bacterial toxin that has modified amino acid sequence

Definitions

  • the present invention relates to an adjuvant useful for the administration of vaccines to organisms.
  • the adjuvant of the invention allows the delivery of vaccines to mucosal surfaces to raise a secretory and systemic immune response.
  • an oral vaccine which may be fed to subjects is easier to administer on a large scale in the absence of specialised equipment, especially to subjects which may be difficult to handle or even locate, such as livestock and wild animals. The spread of infection by the re-use of needles in developing countries would thereby be avoided.
  • an oral vaccine may be provided in the form of an edible solid, which is easier to handle under extreme conditions and is more stable than liquid suspensions as currently used.
  • the secretory immune response mainly IgA-mediated, appears to be substantially separate from the systemic immune response.
  • Systemic vaccination is ineffective for raising a secretory immune response. This is a considerable disadvantage when considering immunisation against pathogens, which often enter the subject across a mucosal surface such as the gut or lung.
  • the apparent difficulty is largely due to a phenomenon known as oral tolerance.
  • the linings of the gut and the lungs are naturally tolerant to foreign antigens, which prevents an immune response being raised to ingested or inhaled substances, such as food and airborne particulate matter.
  • ADP-ribosylating bacterial toxins namely diphtheria toxin, pertussis toxin (PT), cholera toxin (CT), the E.coli heat-labile toxin (LT1 and LT2), Pseudomonas endotoxin A, C. botulinum C2 and C3 toxins as well as toxins from C. perfringens, C. spiriforma and C. difficile are potent toxins in man.
  • These toxins are composed of a monomeric, enzymatically active A subunit which is responsible for ADP-ribosylation of GTP-binding proteins, and a non-toxic B subunit which binds receptors on the surface of the target cell and delivers the A subunit across the cell membrane.
  • a subunit is known to increase intracellular cAMP levels in target cells, while the B subunit is pentameric and binds to GM1 ganglioside receptors.
  • CT cholera toxoid
  • CT induces systemic and mucosal immunity to co-administered antigens, in other words functions as a mucosal adjuvant
  • Elson Curr. Top. Microbiol. Immunal, 1989; 146: 29; Elson and Ealding, J. Immunol. 1984; 133: 2892-2897; Elson and Ealding, Ibid. 1984; 132: 2736-2741; Elson et al., J. Immunol. Methods 1934; 67: 101-118; Lycke and Homgren, Immunology 1986; 59: 301-338).
  • CTB was covalently coupled to horseradish peroxidase (HRP) and administered to mice intraduodenally. This gave rise to a powerful mucosal immune response to HRP (McKenzie and Halsey, J. Immunol 1984; 133: 1818-1824).
  • HRP horseradish peroxidase
  • CTB is not useful as a mucosal adjuvant.
  • a second approach to eliminating the toxicity of CT has been to mutate the CT holotoxin in order to reduce or eliminate its toxicity.
  • the toxicity of CT resides in the A subunit and a number of mutants of CT and its homologue, LT, comprising point mutations in the A subunit are known in the art. See, for example, International Patent Application W092/19265 (Amgen). It is accepted in the art that CT and LT are generally interchangeable, showing considerable homology.
  • an active mucosal adjuvant which may be used to increase the immunogenicity of an antigen when administered to a mucosal surface, such as orally or intranasally.
  • the present invention in a first aspect, provides a pharmaceutical composition comprising a non-toxic mucosal adjuvant in admixture with a second antigen.
  • the non-toxic mucosal adjuvant is a detoxified mutant of a bacterial ADP-ribosylating toxin, optionally comprising one or more amino acid additions, deletions or substitutions.
  • a mutant LT in accordance with the invention may possess an Arg7 to Lys7 substitution at position 7 of the A subunit, the so-called LTK7 mutant.
  • mutants are known to those skilled in the art and are preferred molecules for use in the present invention. Examples include PT mutated at position 129, in particular PT having a Glu 129->Gly mutation. Further mutants include PT mutated at one or both of Trp 26 and Arg 9, optionally in combination with the Glu 129 mutation.
  • the mutant used in the invention may moreover be a mutant wherein the mutation has been effected in a part of the molecule which results in the prevention of proteolytic cleavage of the A subunit of the toxin, such that enzymatic activity is not brought about.
  • Such mutants are described in Grant et al. Inf. and Immunity (1994) 62(10) 4270-4278.
  • the mutant may comprise an Arg 192->Gly mutation in LT or a corresponding mutation in another ADP-ribosylating toxin.
  • the mutant of the invention is preferably in the form of a holotoxin, comprising the mutated A subunit and the B subunit, which may be oligomeric, as in the wild-type holotoxin.
  • the B subunit is preferably not mutated.
  • a mutated A subunit may be used in isolation from the B subunit, either in an essentially pure form or complexed with other agents, which may replace the B subunit and/or its functional contribution.
  • the adjuvant of the invention is preferably administered in admixture with a suitable antigen against which it is desired to raise an immune response. If the antigen and the adjuvant are not in admixture, it is preferred that they be administered within a relatively short time of each other, at the same site of administration. It has been observed that the adjuvant effect provided by wild-type CT is short lived (see Lycke and Homgren, Immunology 1986; 59: 301-308).
  • the mucosal adjuvant of the invention may be administered, optionally in isolation from other antigens, as a boost following systemic or mucosal administration of a vaccine.
  • the precise formulation of the vaccine may vary in accordance with the nature of the immunogen.
  • the mucosal adjuvant may be similarly enclosed so that the antigen and the adjuvant may interact simultaneously with the mucosal immune system.
  • separate mucosal administration of the adjuvant of the invention may be used to enhance mucosal response to parentally-administered vaccines.
  • the present invention provides the use of a non-toxic mutant of CT or LT as a mucosal adjuvant in the preparation of a composition for mucosal administration.
  • the composition is a vaccine and is useful for the immunisation of a subject against a disease or the treatment of a subject suffering from a disease.
  • the mutant comprises one or more amino acid additions, substitutions or deletions in the amino acid sequence of the A subunit of CT or LT which is or are effective to abolish the toxicity of the toxin.
  • a method for the prevention or treatment of a disease in a subject comprising administering to the subject an immunologically effective dose of an antigen adjuvanted with a non-toxic CT or LT mutant by contacting a mucosal surface of the subject with said adjuvanted antigen.
  • the mucosal surface may be any suitable mucosal surface of the subject.
  • the administration may be carried out by inhalation, by means of a rectal or vaginal suppository, or a pessary, by feeding or other buccal administration, by means of an aerosol, by intranasal delivery or direct application to mucosal surfaces.
  • oral and intranasal administration are especially preferred.
  • the subject may be any organism susceptible to immunisation. Especially indicated are humans and other mammals such as livestock, pets and wildlife.
  • Diseases against which the subject may be immunised include all diseases capable of being treated or prevented by immunisation, including viral diseases, allergic manifestations, diseases caused by bacterial or other pathogens which enter through or colonise mucosal surfaces, AIDS, autoimmune diseases such as systemic Lupus Erythe-matosus, Alzheimer's disease and cancers.
  • viral infections which may be treated or prevented using the invention include infection by DNA viruses, such as EBV and VZV, and in particular herpesviridae, for example HSV and HCMV, adenoviridae, papovaviridae, such as HPV, hepadna -viridae, such as HBV, infection by RNA viruses, such as picorvaviridae, especially polivirus and HAV, rhinoviruses and FMDV, togaviridae, flaviviridae, coronaviridae, paramyxo -viridae, such as RSV, orthomyoxoviridae, such as influenza virus, and retroviridae, especially HIV.
  • DNA viruses such as EBV and VZV
  • herpesviridae for example HSV and HCMV
  • adenoviridae papovaviridae, such as HPV
  • hepadna -viridae such as HBV
  • RNA viruses such as picorvavirid
  • Examples of bacterial infections suitable for treatment or prophylaxis by the invention include infection with Helicobacter pylori , streptococci, meningococcus A, B, and C, bordetella pertussis and chlamydia and trachomatis.
  • Vaccine formulation suitable for delivery at mucosal surfaces may be prepared as set out hereinbelow, while further formulations will be apparent to those of skill in the art. Suitable administration regimes are, likewise, set out below while modifications of the exemplified values will be apparent to those of skill in the art.
  • the invention provides a mutant of CT or LT which is a non-toxic mucosal adjuvant and a second antigen for simultaneous separate or sequential administration. Simultaneous administration of the adjuvant and the second antigen when combined in a single vehicle, carrier or particle, as exemplified below, is particularly preferred.
  • the second antigen may be any antigen to which it is desired to raise an immune response in the subject.
  • Suitable antigens comprise bacterial, viral and protozoan antigens derived from pathogenic organisms, as well as allergens, allogens and antigens derived from tumours and self-antigens.
  • the antigen will be a protein, polypeptide or peptide antigen, but alternative antigenic structures, such as nucleic acid antigens, carbohydrate antigens, and whole or attenuated or inactivated organisms such as bacteria, viruses or protozoa are not excluded.
  • the invention further provides a method for the manufacture of an adjuvanted vaccine comprising the steps of:
  • antigens useful in the present invention include HSV gD, gB and other glycoproteins; HIV gp120 and other proteins; CMV gB or gH; HCV antigens; HDV delta antigen; HAV antigens; EBV and VZV antigens; B. pertussis antigens and H. pylori antigens.
  • the second antigen may be the immunogenic component of the vaccine intended for injection.
  • Such vaccines, and the immunogenic components thereof may be subunit vaccines, whole inactivated or attenuated organisms or polynucleotide vaccines.
  • the vaccines according to the invention may either be prophylactic (to prevent infection) or therapeutic (to treat disease after infection).
  • These vaccines may either be prophylactic (to prevent infection) or therapeutic (to treat disease after infection).
  • Such vaccines comprise antigen or antigens, usually in combination with “pharmaceutically acceptable carriers,” which include any carrier that does not itself induce the production of antibodies harmful to the individual receiving the composition.
  • Suitable carriers are typically large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, lipid aggregates (such as oil droplet emulsions or liposomes), and inactive virus particles.
  • these carriers are well known to those of ordinary skill in the art.
  • these carriers may function as immunostimulating agents (“adjuvants”).
  • the antigen may be conjugated to a bacterial toxoid, such as a toxoid from diphtheria, tetanus, cholera, H. pylori , etc. pathogens.
  • Preferred adjuvants to enhance effectiveness of the composition include, but are not limited to: (1) aluminum salts (alum), such as aluminum hydroxide, aluminum phosphate, aluminum sulfate, etc; (2) oil-in-water emulsion formulations (with or without other specific immunostimulating agents such as muramyl peptides (see below) or bacterial cell wall components), such as for example (a) MF59 (PCT Publ. No.
  • aluminum salts alum
  • oil-in-water emulsion formulations with or without other specific immunostimulating agents such as muramyl peptides (see below) or bacterial cell wall components
  • MF59 PCT Publ. No.
  • WO 90/14837 containing 5% Squalene, 0.5% Tween 80, and 0.5% Span 85 (optionally containing various amounts of MTP-PE (see below), although not required) formulated into submicron particles using a microfluidizer such as Model 110Y microfluidizer (Microfluidics, Newton, Mass.), (b) SAF, containing 10% Squalane, 0.4% Tween 80, 5% pluronic-blocked polymer L121, and thr-MDP (see below) either microfluidized into a submicron emulsion or vortexed to generate a larger particle size emulsion, and (c) RibiTM adjuvant system (RAS), (Ribi Immunochem, Hamilton, MT) containing 2% Squalene, 0.2% Tween 80, and one or more bacterial cell wall components from the group consisting of monophosphorylipid A (MPL), trehalose dimycolate (TDM), and cell wall skeleton (CWS),
  • muramyl peptides include, but are not limited to, N-acetyl-muramyl-L-threonyl-D-isoglutamine (thr-MDP),N-acetyl-normuramyl-1-alanyl-d-isoglutamine (nor-MDP),N-acetylmuramyl-1-alanyl-d-isoglutaminyl-1-alani ne-2-(1′-2′-dipalmitoyl-sn-glycero-3-huydroxyphosphoryloxy )-ethylamine (MTP-PE), etc.
  • the immunogenic compositions typically will contain diluents, such as water, saline, glycerol, ethanol, etc.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering substances, and the like, may be present in such vehicles.
  • the immunogenic compositions are prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection may also be prepared.
  • the preparation also may be emulsified or encapsulated in liposomes for enhanced adjuvant effect, as discussed above under pharmaceutically acceptable carriers.
  • Immunogenic compositions used as vaccines comprise an immunologically effective amount of the antigenic polypeptides, as well as any other of the above-mentioned components, as needed.
  • immunologically effective amount it is meant that the administration of that amount to an individual, either in a single dose or as part of a series, is effective for treatment or prevention. This amount varies depending upon the health and physical condition of the individual to be treated, the taxonomic group of individual to be treated (e.g., nonhuman primate, primate, etc.), the capacity of the individual's immune system to synthesize antibodies, the degree of protection desired, the formulation of the vaccine, the treating doctor's assessment of the medical situation, and other relevant factors. It is expected that the amount will fall in a relatively broad range that can be determined through routine trials.
  • the immunogenic compositions are conventionally administered parenterally, e.g., by injection, either subcutaneously or intramuscularly. Additional formulations suitable for other modes of administration include oral and pulmonary formulations, suppositories, and transdermal applications. Dosage treatment may be a single dose schedule or a multiple dose schedule. The vaccine may be administered in conjunction with other immunoregulatory agents.
  • suitable immunostimulatory agents include interleukins, such as interleukins 1,2, 4-7 and 12, and interferons, especially 7-interferon.
  • FIG. 1 a shows the titre of total ovalbumin specific antibody in BALB/c mice immunised i/n or s/c with either ovalbumin alone or ovalbumin together with toxin derivatives;
  • FIG. 1 b shows the titre of total toxin-specific antibody in the mice of FIG. 1 a;
  • FIG. 2 shows a measurement of ovalbumin-specific IgA in nasal and lung lavages of mice injected as in FIG. 1;
  • FIG. 3 shows the presence of tetanus toxoid-specific antibodies in the serum of BALB/c mice immunised i/n or s/c with tetanus toxin fragment C alone or together with toxin derivatives.
  • LTK7 Site-directed mutagenesis was used to replace the arginine residue at position seven of the A subunit of LT with lysine in order to construct a non-toxic LT mutant that could still assemble as a holotoxin with cell binding activity.
  • the mutant protein named LTK7
  • LTK7 was purified and tested for ADP-ribosyltransferase and toxic activity in several assays. LTK7 was still able to bind GM1 ganglioside receptor but showed a complete loss of enzymatic activity, in agreement with published data (Lobet et al., Infect. Immun. 1991; 59:2870-2879). Further, LTK7 was inactive in the mouse ileal loop assay and in vitro on Y1 cells, even when a dose equivalent to 10 7 toxic units of wild-type LT was tested (Table 1).
  • mice were separated into groups and immunised using ovalbumin as a reporter antigen. Animals were immunised intranasally (i/n) or subcutaneously (s/c) using 10 ⁇ g of ovalbumin alone or ovalbumin mixed with either 1 ⁇ g CT, LT or LTK7. Mice were split into four groups of six mice. Four mice from each group were lightly anaesthetised and immunised with either 10 ⁇ g of ovalbumin or 10 ⁇ g of ovalbumin with 1 ⁇ g of toxins, delivered in a total volume of 30 ⁇ l. The remaining two mice were immunised with the same amount of proteins s/c in a total volume of 100 ⁇ gl. Proteins given subcut were first adsorbed to 2% Al(OH) 3 .
  • Sera from each group were pooled from four and two mice respectively. Samples were prepared in duplicate from a dilution of 1:50. Absorbences were read at 450 nm using the kineticalc version 2.13 programme (Biotek instruments). This programme calculates the rate of change of substrate over thirty time points ten seconds apart.
  • ELISA titres of antibody were measured arbitrarily as the dilution of serum which gave half the maximal absorbence at 450 nm. Sera which failed to show absorbence at 450 nm 2.5 times greater than that observed with the equivalent pre-immune sera were considered negative. Results shown in FIGS. 1 a and 1 b represent the mean titre values from duplicate wells from one experiment. No significant levels of antibodies to ovalbumin above background were detected in the serum of mice immunised i/n with ovalbumin alone although mice immunised s/c efficiently sero-converted. Mice receiving ovalbumin along with either CT or LT i/n contained very high levels of anti-ovalbumin antibodies in their sera. These were equivalent to those observed when mice immunised s/c. Mice that received ovalbumin with LTK7 also showed very high levels of antibodies to ovalbumin.
  • mice The levels of anti-toxoid responses in these same groups are shown in FIG. 1 b . All mice, including those immunised with the mutant toxin, developed high levels of antibodies to these toxin in their sera.
  • Ovalbumin-specific IgA antibodies were measured by ELISA using an anti-mouse alpha-chain-specific conjugate antibody (Serotec). Samples were prepared from individual animals and columns in this figure represent the mean rate of change of substrate, using kineticalc, for four and two mice immunised i/n and s/c respectively. The figures are constructed using the raw absorbence data at a dilution of 1:3 with respect to lung washes. These correspond to titres of between 1:2 and 1:6 for nose washes and between 1:70 and 1:120 for lung washes. These titres were calculated using the method described above.
  • mice immunised s/c or i/n with ovalbumin alone contained no detectable ovalbumin-specific IgA in the washings sampled. All individual mice immunised with ovalbumin in combination with CT, LT or LTK7, showed detectable levels of anti-ovalbumin IgA. Thus both a local and systemic anti-ovalbumin response are detectable in these animals.
  • mice were immunised i/n with a) 10 ⁇ g of fragment C alone; b) 10 ⁇ g of fragment C +1 ⁇ g of LT; c) 10 ⁇ g of fragment C+1 ⁇ g of LTK7 and d) PBS only, all in a final volume of 30 ⁇ l.
  • Five mice were immunised i/n with a) 1 ⁇ g of LT and b) 1 ⁇ g of LTK7. The remaining two groups of mice were immunised s/c with either no protein or 10 ⁇ g of fragment C in a dose volume of 100 ⁇ l.
  • These vaccines were prepared as described in FIG. 1. Animals were immunised on day 1 and 22. Sample bleeds of 100 ⁇ l were collected on day 0, 21 and 35.
  • Fragment C-specific antibodies were measured by ELISA using tetanus toxid (10 ⁇ g/ml) as the coating antigen. Sera from each group were pooled. Samples were prepared in duplicate from a dilution of 1:50. ELISA titres were calculated as described above. Mice immunised s/c with Fragment C efficiently sero-converted producing high levels of anti-Fragment C antibodies (FIG. 3). Mice immunised i/n with Fragment C alone showed no significant sero-conversion. However mice immunised with Fragment C combined with LT or LTK7 showed high levels of anti Fragment C antibodies in their sera (FIG. 3).
  • mice that sero-convert to Fragment C can be protected against toxin challenge the groups were challenged with active tetanus toxin. All mice immunised s/c with Fragment C alone were protected whereas all mice immunised i/n were highly susceptible. All mice i/n immunised with Fragment C combined with either LT or LTK7 survived the challenge (Table 2). TABLE 2 Serum anti-Fragment C Deaths LT ⁇ 10/10 LTK7 ⁇ 10/10 LTK7 + Fragment C ++ 0/10 Lt + Fragment C ++++ 0/10 Fragment C +/ ⁇ 10/10

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Immunology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Mycology (AREA)
  • Microbiology (AREA)
  • Epidemiology (AREA)
  • Neurology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Biomedical Technology (AREA)
  • Oncology (AREA)
  • Genetics & Genomics (AREA)
  • Neurosurgery (AREA)
  • Communicable Diseases (AREA)
  • Biophysics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Virology (AREA)
  • Pulmonology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Medicinal Preparation (AREA)
US10/163,448 1993-12-22 2002-06-04 Nontoxic mucosal adjuvant Abandoned US20020187154A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US10/163,448 US20020187154A1 (en) 1993-12-22 2002-06-04 Nontoxic mucosal adjuvant

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
GB939326174A GB9326174D0 (en) 1993-12-22 1993-12-22 Mucosal adjuvant
GB9326174.1 1993-12-22
IB9400068 1994-03-24
IBPCT/IB94/00068 1994-12-24
US64633396A 1996-06-05 1996-06-05
US4609898A 1998-03-23 1998-03-23
US10/163,448 US20020187154A1 (en) 1993-12-22 2002-06-04 Nontoxic mucosal adjuvant

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US4609898A Division 1993-12-22 1998-03-23

Publications (1)

Publication Number Publication Date
US20020187154A1 true US20020187154A1 (en) 2002-12-12

Family

ID=10747021

Family Applications (3)

Application Number Title Priority Date Filing Date
US10/163,448 Abandoned US20020187154A1 (en) 1993-12-22 2002-06-04 Nontoxic mucosal adjuvant
US10/351,075 Expired - Fee Related US7070781B2 (en) 1993-12-22 2003-01-24 Nontoxic mucosal adjuvant
US11/399,571 Expired - Fee Related US7485304B2 (en) 1993-12-22 2006-04-06 Non-toxic mucosal adjuvant

Family Applications After (2)

Application Number Title Priority Date Filing Date
US10/351,075 Expired - Fee Related US7070781B2 (en) 1993-12-22 2003-01-24 Nontoxic mucosal adjuvant
US11/399,571 Expired - Fee Related US7485304B2 (en) 1993-12-22 2006-04-06 Non-toxic mucosal adjuvant

Country Status (13)

Country Link
US (3) US20020187154A1 (enExample)
EP (1) EP0732937B2 (enExample)
JP (4) JP4283889B2 (enExample)
AT (1) ATE187078T1 (enExample)
AU (1) AU1278595A (enExample)
CA (1) CA2179771C (enExample)
DE (1) DE69421939T3 (enExample)
DK (1) DK0732937T4 (enExample)
ES (1) ES2139879T5 (enExample)
GB (1) GB9326174D0 (enExample)
GR (1) GR3032497T3 (enExample)
PT (1) PT732937E (enExample)
WO (1) WO1995017211A1 (enExample)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040028690A1 (en) * 1993-12-22 2004-02-12 Rino Rappuoli Nontoxic mucosal adjuvant
US20050031587A1 (en) * 2002-10-04 2005-02-10 Yamanouchi Pharmaceutical Co., Ltd. Immune response induction method
US20110280911A1 (en) * 2008-11-17 2011-11-17 The Regents Of The University Of Michigan Cancer vaccine compositions and methods of using the same
US8758766B2 (en) 2008-12-24 2014-06-24 The Kingdom of The Netherlands, Represented by The Mininster of Health, Welfare and Sport, on Behalf of The Minster The National Institute of Public Health and The Environment Modified Streptococcus pneumoniae pneumolysin (PLY) polypeptides

Families Citing this family (154)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9513371D0 (en) * 1995-06-30 1995-09-06 Biocine Spa Immunogenic detoxified mutant toxins
DE69434000T3 (de) 1993-10-05 2008-11-06 UCB Pharma Ltd., Slough Impfstoffzusammensetzungen
JP2010184934A (ja) * 1993-12-22 2010-08-26 Chiron Srl 非毒性の粘膜アジュバント
US6019982A (en) * 1994-08-26 2000-02-01 The Administrators Of The Tulane Educational Fund Mutant enterotoxin effective as a non-toxic oral adjuvant
US6436407B1 (en) 1994-08-26 2002-08-20 The Administrators Of The Tulane Educational Fund Mutant enterotoxin effective as a non-toxic adjuvant
GB9603314D0 (en) * 1996-02-16 1996-04-17 Biocine Spa Immunogenic detoxified mutant toxins
US20070043215A1 (en) * 1996-08-27 2007-02-22 Heath David G Recombinant f1-v plague vaccine
GB9622660D0 (en) * 1996-10-31 1997-01-08 Biocine Spa Immunogenic detoxified mutant toxin
US5980898A (en) 1996-11-14 1999-11-09 The United States Of America As Represented By The U.S. Army Medical Research & Material Command Adjuvant for transcutaneous immunization
US6797276B1 (en) 1996-11-14 2004-09-28 The United States Of America As Represented By The Secretary Of The Army Use of penetration enhancers and barrier disruption agents to enhance the transcutaneous immune response
US20060002949A1 (en) 1996-11-14 2006-01-05 Army Govt. Of The Usa, As Rep. By Secretary Of The Office Of The Command Judge Advocate, Hq Usamrmc. Transcutaneous immunization without heterologous adjuvant
CN101002727A (zh) * 1996-11-14 2007-07-25 (由国防部长代表的)美利坚合众国政府 经皮免疫之佐剂
US6818222B1 (en) 1997-03-21 2004-11-16 Chiron Corporation Detoxified mutants of bacterial ADP-ribosylating toxins as parenteral adjuvants
US6824793B1 (en) 1998-06-01 2004-11-30 Chiron Corporation Use of hyaluronic acid polymers for mucosal delivery of vaccine antigens and adjuvants
JP4610735B2 (ja) * 1998-06-01 2011-01-12 ノバルティス バクシンズ アンド ダイアグノスティックス，インコーポレーテッド ワクチン抗原およびアジュバントの粘膜送達のためのヒアルロン酸ポリマーの使用
US6576244B1 (en) 1998-06-19 2003-06-10 Acambis, Inc. LT and CT in parenteral immunization methods against helicobacter infection
WO2000011181A1 (en) 1998-08-20 2000-03-02 Connaught Laboratories Limited NUCLEIC ACID MOLECULES ENCODING INCLUSION MEMBRANE PROTEIN C OF $i(CHLAMYDIA)
US6693087B1 (en) 1998-08-20 2004-02-17 Aventis Pasteur Limited Nucleic acid molecules encoding POMP91A protein of Chlamydia
US6686339B1 (en) 1998-08-20 2004-02-03 Aventis Pasteur Limited Nucleic acid molecules encoding inclusion membrane protein C of Chlamydia
DE69939943D1 (de) * 1998-10-21 2009-01-02 Kitasato Inst Attenuierte Toxine als Adjuvantien
WO2000050078A1 (en) * 1999-02-26 2000-08-31 Chiron Corporation Use of bioadhesives and adjuvants for the mucosal delivery of antigens
US7115730B1 (en) 1999-04-27 2006-10-03 Chiron Srl Immunogenic detoxified mutant E. coli LT-A-toxin
US7384640B1 (en) 1999-09-30 2008-06-10 Wyeth Holdings Corporation Mutant cholera holotoxin as an adjuvant
CA2388337C (en) 1999-10-22 2013-01-08 Aventis Pasteur Limited Method of inducing and/or enhancing an immune response to tumor antigens
JP2003171291A (ja) * 1999-10-29 2003-06-17 Takeda Schering-Plough Animal Health Kk 乳房炎用粘膜予防剤
WO2001049317A2 (en) * 2000-01-05 2001-07-12 Aventis Pasteur Limited Enhancing the immune response to an antigen by presensitizing with an inducing agent prior to immunizing with the inducing agent and the antigen
EP1792995A3 (en) 2000-05-08 2007-06-13 Sanofi Pasteur Limited Chlamydia secretory locus orf and uses thereof
DK1282702T3 (da) 2000-05-10 2007-04-02 Sanofi Pasteur Ltd Immunogene polypeptider, som er kodet af KAGE-minigener, og anvendelser deraf
AU2001271268A1 (en) 2000-05-19 2001-12-03 The Administrators Of The Tulane Educational Fund Hybrid lt-a/ct-b holotoxin for use as an adjuvant
ES2284681T3 (es) 2000-08-25 2007-11-16 Aventis Pasteur Limited Epitopos de oligosacaridos del nucleo de lipopolisacaridos de maemophilus influenzae como vacunas para la prevencion de infecciones por haemophilus influenzae.
CA2434546C (en) 2001-01-12 2012-09-11 Chiron Corporation Induction of immune response by a replication-defective venezuelan equine encephalitis-sindbis chimeric virus replicon particle encoding an antigen
DK1372708T3 (da) 2001-02-13 2008-10-20 Us Gov Sec Army Vaccine til transkutan immunisering mod rejsediarre
GB0108024D0 (en) 2001-03-30 2001-05-23 Chiron Spa Bacterial toxins
CA2966716C (en) 2001-05-22 2019-11-26 The Government Of The United States Of America, As Represented By The Cretary, Department Of Health And Human Services Development of mutations useful for attenuating dengue viruses and chimeric dengue viruses
US7332174B2 (en) 2001-06-07 2008-02-19 Wyeth Holdings Corporation Mutant forms of cholera holotoxin as an adjuvant
AU2002346249B2 (en) 2001-06-07 2007-03-15 The Regents Of The University Of Colorado Mutant Forms of Cholera Holotoxin as an Adjuvant
NZ536859A (en) * 2002-05-14 2007-11-30 Chiron Srl Mucosal combination vaccines for bacterial meningitis
GB0220205D0 (en) * 2002-08-30 2002-10-09 Chiron Spa Neisseria toxin
WO2004028561A1 (ja) * 2002-09-30 2004-04-08 Yamanouchi Pharmaceutical Co., Ltd. 免疫応答誘導方法
HUE031886T2 (en) 2002-10-11 2017-08-28 Glaxosmithkline Biologicals Sa Polypeptide vaccines for extensive protection against hypervirulent meningococcal lines
EP2172213B1 (en) 2003-01-30 2013-04-03 Novartis AG Injectable vaccines against multiple meningococcal serogroups
GB0308198D0 (en) 2003-04-09 2003-05-14 Chiron Srl ADP-ribosylating bacterial toxin
GB0323103D0 (en) 2003-10-02 2003-11-05 Chiron Srl De-acetylated saccharides
NZ546430A (en) 2003-10-02 2009-04-30 Novartis Vaccines & Diagnostic Liquid vaccines for multiple meningococcal serogroups
JP5600375B2 (ja) 2004-03-09 2014-10-01 ノバルティス バクシンズ アンド ダイアグノスティックス，インコーポレーテッド インフルエンザウイルスワクチン
GB0409745D0 (en) 2004-04-30 2004-06-09 Chiron Srl Compositions including unconjugated carrier proteins
GB0500787D0 (en) 2005-01-14 2005-02-23 Chiron Srl Integration of meningococcal conjugate vaccination
NZ550533A (en) 2004-04-30 2010-02-26 Novartis Vaccines & Diagnostic Meningococcal conjugate vaccination comprising N. meningitidis and diphtheria toxin
GB0410866D0 (en) 2004-05-14 2004-06-16 Chiron Srl Haemophilius influenzae
EP2848692B1 (en) 2004-05-21 2017-08-16 Novartis Vaccines and Diagnostics, Inc. Alphavirus vectors for influenza virus vaccines
JP2008508320A (ja) 2004-07-29 2008-03-21 カイロン コーポレイション Ｓｔｒｅｐｔｏｃｏｃｃｕｓａｇａｌａｃｔｉａｅのようなグラム陽性細菌に対する免疫原性組成物
GB0424092D0 (en) 2004-10-29 2004-12-01 Chiron Srl Immunogenic bacterial vesicles with outer membrane proteins
GB0502095D0 (en) 2005-02-01 2005-03-09 Chiron Srl Conjugation of streptococcal capsular saccharides
JP2008530245A (ja) 2005-02-18 2008-08-07 ノバルティス ヴァクシンズ アンド ダイアグノスティクス， インコーポレイテッド 尿路病原性菌株由来の抗原
SI1858920T1 (sl) 2005-02-18 2016-07-29 Glaxosmithkline Biologicals S.A. Proteini in nukleinske kisline iz escherichia coli, povezane z meningitisom/sepso
CA2626253A1 (en) 2005-10-18 2007-04-26 Novartis Vaccines And Diagnostics, Inc. Mucosal and systemic immunizations with alphavirus replicon particles
CA2628152C (en) 2005-11-04 2016-02-02 Novartis Vaccines And Diagnostics S.R.L. Adjuvanted vaccines with non-virion antigens prepared from influenza viruses grown in cell culture
AU2006310338A1 (en) * 2005-11-04 2007-05-10 Novartis Vaccines And Diagnostics Srl Adminstration routes for priming/boosting with influenza vaccines
ES2514316T3 (es) 2005-11-22 2014-10-28 Novartis Vaccines And Diagnostics, Inc. Partículas similares a virus (VLPs) de Norovirus y Sapovirus
GB0524066D0 (en) 2005-11-25 2006-01-04 Chiron Srl 741 ii
US7977314B2 (en) 2005-12-02 2011-07-12 Amorfix Life Sciences Limited Methods and compositions to treat and detect misfolded-SOD1 mediated diseases
PL2478916T3 (pl) 2006-01-27 2020-11-16 Seqirus UK Limited Szczepionki przeciw grypie zawierające hemaglutyninę i białka macierzy
ES2536426T3 (es) 2006-03-23 2015-05-25 Novartis Ag Compuestos de imidazoquinoxalina como inmunomoduladores
CN101448523A (zh) 2006-03-24 2009-06-03 诺华疫苗和诊断有限两合公司 无需冷藏储存流感疫苗
EP2382988A1 (en) 2006-03-31 2011-11-02 Novartis AG Combined mucosal and parenteral immunization against HIV
PT2054431E (pt) 2006-06-09 2011-11-03 Novartis Ag Confórmeros de adesinas bacterianas
GB0614460D0 (en) 2006-07-20 2006-08-30 Novartis Ag Vaccines
EP2586790A3 (en) 2006-08-16 2013-08-14 Novartis AG Immunogens from uropathogenic Escherichia coli
EP4585610A3 (en) 2006-09-11 2025-09-24 Seqirus UK Limited Making influenza virus vaccines without using eggs
PT2121011E (pt) 2006-12-06 2014-07-31 Novartis Ag Vacinas compreendendo um antigénio a partir de quatro estirpes do vírus da gripe
GB0700562D0 (en) 2007-01-11 2007-02-21 Novartis Vaccines & Diagnostic Modified Saccharides
CN101688194B (zh) 2007-05-23 2013-09-11 Uab研究基金会 去毒的肺炎球菌神经氨酸酶及其用途
KR20100045437A (ko) 2007-06-27 2010-05-03 노파르티스 아게 첨가물이 적은 인플루엔자 백신
GB0713880D0 (en) 2007-07-17 2007-08-29 Novartis Ag Conjugate purification
GB0714963D0 (en) 2007-08-01 2007-09-12 Novartis Ag Compositions comprising antigens
ES2528648T3 (es) 2007-09-11 2015-02-11 University Of Guelph Inmunógenos polisacáridos de la Clostridium Difficile
KR101621837B1 (ko) 2007-09-12 2016-05-17 노파르티스 아게 Ｇａｓ57 돌연변이 항원 및 ｇａｓ57 항체
GB0810305D0 (en) 2008-06-05 2008-07-09 Novartis Ag Influenza vaccination
GB0818453D0 (en) 2008-10-08 2008-11-12 Novartis Ag Fermentation processes for cultivating streptococci and purification processes for obtaining cps therefrom
EP2537857B1 (en) 2007-12-21 2017-01-18 GlaxoSmithKline Biologicals SA Mutant forms of streptolysin O
CN102356089B (zh) 2008-02-21 2014-02-19 诺华股份有限公司 脑膜炎球菌fHBP多肽
JP5518041B2 (ja) 2008-03-18 2014-06-11 ノバルティス アーゲー インフルエンザウイルスワクチン抗原の調製における改良
US8425922B2 (en) 2009-01-05 2013-04-23 EpitoGenesis, Inc. Adjuvant compositions and methods of use
CN103897045A (zh) 2009-01-12 2014-07-02 诺华股份有限公司 抗革兰氏阳性细菌疫苗中的Cna_B结构域
US8568732B2 (en) 2009-03-06 2013-10-29 Novartis Ag Chlamydia antigens
EP3263128A3 (en) 2009-04-14 2018-01-24 GlaxoSmithKline Biologicals S.A. Compositions for immunising against staphylococcus aureus
DK2442826T3 (en) 2009-06-15 2015-09-21 Univ Singapore Influenza vaccine, composition and methods of using
US10988511B2 (en) 2009-07-07 2021-04-27 Glaxosmithkline Biologicals Sa Conserved Escherichia bacterial IG-like domain (group 1) protein (ORF405) immunogens
CA2768186A1 (en) 2009-07-15 2011-01-20 Novartis Ag Rsv f protein compositions and methods for making same
AU2010272243A1 (en) 2009-07-16 2012-03-08 Novartis Ag Detoxified Escherichia coli immunogens
CN102596240B (zh) 2009-08-27 2015-02-04 诺华股份有限公司 包括脑膜炎球菌fHBP序列的杂交多肽
US20120237536A1 (en) 2009-09-10 2012-09-20 Novartis Combination vaccines against respiratory tract diseases
GB0917002D0 (en) 2009-09-28 2009-11-11 Novartis Vaccines Inst For Global Health Srl Improved shigella blebs
GB0917003D0 (en) 2009-09-28 2009-11-11 Novartis Vaccines Inst For Global Health Srl Purification of bacterial vesicles
BR112012009014B8 (pt) 2009-09-30 2022-10-04 Novartis Ag Processo para preparar conjugado de polissacarídeo capsular de s. aureus tipo 5 ou tipo 8 e molécula de transporte crm197, conjugado e composição imunogênica
CN102724988B (zh) 2009-09-30 2014-09-10 诺华股份有限公司 脑膜炎球菌fHBP多肽的表达
GB0918392D0 (en) 2009-10-20 2009-12-02 Novartis Ag Diagnostic and therapeutic methods
CA2779816A1 (en) 2009-10-27 2011-05-05 Novartis Ag Modified meningococcal fhbp polypeptides
GB0919690D0 (en) 2009-11-10 2009-12-23 Guy S And St Thomas S Nhs Foun compositions for immunising against staphylococcus aureus
WO2011080595A2 (en) 2009-12-30 2011-07-07 Novartis Ag Polysaccharide immunogens conjugated to e. coli carrier proteins
GB201003333D0 (en) 2010-02-26 2010-04-14 Novartis Ag Immunogenic proteins and compositions
AU2011230619C1 (en) 2010-03-25 2016-06-23 Oregon Health & Science University CMV glycoproteins and recombinant vectors
GB201005625D0 (en) 2010-04-01 2010-05-19 Novartis Ag Immunogenic proteins and compositions
US9744228B2 (en) 2010-04-07 2017-08-29 Norvartis Ag Method for generating a parvovirus B19 virus-like particle
EP2558069A1 (en) 2010-04-13 2013-02-20 Novartis AG Benzonapthyridine compositions and uses thereof
KR20130121699A (ko) 2010-05-28 2013-11-06 테트리스 온라인, 인코포레이티드 상호작용 혼성 비동기 컴퓨터 게임 기반구조
GB201009861D0 (en) 2010-06-11 2010-07-21 Novartis Ag OMV vaccines
US9192661B2 (en) 2010-07-06 2015-11-24 Novartis Ag Delivery of self-replicating RNA using biodegradable polymer particles
AU2011276328C1 (en) 2010-07-06 2016-01-21 Novartis Ag Norovirus derived immunogenic compositions and methods
GB201101665D0 (en) 2011-01-31 2011-03-16 Novartis Ag Immunogenic compositions
GB201017519D0 (en) 2010-10-15 2010-12-01 Novartis Vaccines Inst For Global Health S R L Vaccines
WO2012072769A1 (en) 2010-12-01 2012-06-07 Novartis Ag Pneumococcal rrgb epitopes and clade combinations
CA2860331A1 (en) 2010-12-24 2012-06-28 Novartis Ag Compounds
WO2012103361A1 (en) 2011-01-26 2012-08-02 Novartis Ag Rsv immunization regimen
US20140093556A1 (en) 2011-01-28 2014-04-03 Sanofi Pasteur Sa Immunological Compositions Against HIV
CA2835644C (en) 2011-05-13 2021-06-15 Novartis Ag Pre-fusion rsv f antigens
HUE037408T2 (hu) 2011-06-10 2018-08-28 Univ Oregon Health & Science CMV glikoproteinek és rekombináns vektorok
US10561720B2 (en) 2011-06-24 2020-02-18 EpitoGenesis, Inc. Pharmaceutical compositions, comprising a combination of select carriers, vitamins, tannins and flavonoids as antigen-specific immuno-modulators
CA2841047A1 (en) 2011-07-06 2013-01-10 Novartis Ag Immunogenic compositions and uses thereof
EP2729165B1 (en) 2011-07-06 2017-11-08 GlaxoSmithKline Biologicals SA Immunogenic combination compositions and uses thereof
EP2729178A1 (en) 2011-07-08 2014-05-14 Novartis AG Tyrosine ligation process
ES2687129T3 (es) 2011-07-25 2018-10-23 Glaxosmithkline Biologicals Sa Composiciones y métodos para evaluar la inmunogenicidad funcional de vacunas contra parvovirus
CA2789539A1 (en) 2011-09-12 2013-03-12 International Aids Vaccine Initiative Immunoselection of recombinant vesicular stomatitis virus expressing hiv-1 proteins by broadly neutralizing antibodies
US9358284B2 (en) 2011-09-14 2016-06-07 Glaxosmithkline Biologicals Sa Methods for making saccharide-protein glycoconjugates
EP2755994A2 (en) 2011-09-14 2014-07-23 Novartis AG Escherichia coli vaccine combination
US9402894B2 (en) 2011-10-27 2016-08-02 International Aids Vaccine Initiative Viral particles derived from an enveloped virus
RU2636350C2 (ru) 2011-11-07 2017-11-22 Новартис Аг МОЛЕКУЛА, СОДЕРЖАЩАЯ SPR0096 и SPR2021
WO2013108272A2 (en) 2012-01-20 2013-07-25 International Centre For Genetic Engineering And Biotechnology Blood stage malaria vaccine
RU2014151567A (ru) 2012-05-22 2016-07-10 Новартис Аг Конъюгат менингококка серогруппы х
ES2631608T3 (es) 2012-06-27 2017-09-01 International Aids Vaccine Initiative Variante de la glicoproteína Env del VIH-1
US20150140068A1 (en) 2012-07-06 2015-05-21 Novartis Ag Immunogenic compositions and uses thereof
JP6283674B2 (ja) 2012-09-18 2018-02-21 グラクソスミスクライン バイオロジカルズ ソシエテ アノニム 外膜小胞
TR201808684T4 (tr) 2012-10-02 2018-07-23 Glaxosmithkline Biologicals Sa Lineer olmayan sakarit konjügatları.
RU2015106791A (ru) 2012-10-03 2016-11-20 Глэксосмитиклайн Байолоджикалз Са Иммуногенные композиции
CN111249455A (zh) 2012-11-30 2020-06-09 葛兰素史密丝克莱恩生物有限公司 假单胞菌抗原和抗原组合
BR112015018014A2 (pt) 2013-02-01 2017-07-11 Glaxosmithkline Biologicals Sa liberação intradérmica de composições imunológicas compreendendo agonistas do receptor do tipo toll
WO2014140938A2 (en) 2013-03-14 2014-09-18 Centre Hospitalier Universitaire Vaudois Immunological methods
EP2848937A1 (en) 2013-09-05 2015-03-18 International Aids Vaccine Initiative Methods of identifying novel HIV-1 immunogens
US10058604B2 (en) 2013-10-07 2018-08-28 International Aids Vaccine Initiative Soluble HIV-1 envelope glycoprotein trimers
EP2870974A1 (en) 2013-11-08 2015-05-13 Novartis AG Salmonella conjugate vaccines
CN106103469B (zh) 2014-03-26 2020-11-27 葛兰素史密丝克莱恩生物有限公司 突变型葡萄球菌抗原
EP3185896B1 (en) 2014-06-20 2025-04-02 University of Saskatchewan Exotoxin/thermolysin compositions and methods and uses for treating or preventing laminitis
EP3069730A3 (en) 2015-03-20 2017-03-15 International Aids Vaccine Initiative Soluble hiv-1 envelope glycoprotein trimers
US9931394B2 (en) 2015-03-23 2018-04-03 International Aids Vaccine Initiative Soluble HIV-1 envelope glycoprotein trimers
AU2016353553B2 (en) 2015-11-09 2022-01-20 The University Of British Columbia Amyloid beta epitopes and antibodies thereto
KR102776187B1 (ko) 2015-11-09 2025-03-07 더 유니버시티 오브 브리티쉬 콜롬비아 아밀로이드 베타에서의 n-말단 에피토프 및 이에 형태적으로-선택적인 항체
EP3374381A4 (en) 2015-11-09 2019-05-15 The University Of British Columbia EPITOPES IN THE AMYLOID-BETA MEDIUM REGION AND CONFORMITY-SELECTIVE ANTIBODIES THEREOF
CN109476729A (zh) 2016-07-18 2019-03-15 英属哥伦比亚大学 淀粉样蛋白β的抗体
US20180125920A1 (en) 2016-11-09 2018-05-10 The University Of British Columbia Methods for preventing and treating A-beta oligomer-associated and/or -induced diseases and conditions
US12286469B2 (en) 2017-07-18 2025-04-29 The University Of British Columbia Humanized antibodies binding to amyloid-beta (A-beta)
WO2020097923A1 (en) 2018-11-16 2020-05-22 The University Of Hong Kong Live attenuated influenza b virus compositions methods of making and using thereof
IT201900007060A1 (it) 2019-05-21 2020-11-21 St Superiore Di Sanita Cellule tumorali ingegnerizzate e loro usi
IT201900012540A1 (it) 2019-07-22 2021-01-22 Humanitas Mirasole Spa Inibitori di CHI3L1 e loro usi
WO2021169673A1 (en) 2020-02-26 2021-09-02 Versitech Limited Pd-1-based vaccines against coronavirus infection

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6350612B1 (en) * 1986-01-28 2002-02-26 Chiron S.P.A. Isolation and expression of DNA sequence encoding the five subunits of Bordetella pertussis toxin
US20020044939A1 (en) * 1991-12-31 2002-04-18 Chiron S.P.A. Immunogenic detoxified mutants of cholera toxin
US6436407B1 (en) * 1994-08-26 2002-08-20 The Administrators Of The Tulane Educational Fund Mutant enterotoxin effective as a non-toxic adjuvant
US6440423B1 (en) * 1994-08-26 2002-08-27 The Administrators Of The Tulane Educational Fund Mutant enterotoxin effective as a non-toxic oral adjuvant
US20030113338A1 (en) * 1996-10-31 2003-06-19 Mariagrazia Pizza Immunogenic detoxified mutant e. coli lt-a toxin

Family Cites Families (59)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4328209A (en) 1979-04-11 1982-05-04 Board Of Regents, The University Of Texas System Cholera vaccine
US4428931A (en) 1982-03-15 1984-01-31 Merck & Co., Inc. Bacterial toxoids and gram-negative immune globulin therefrom
US4666837A (en) 1982-05-24 1987-05-19 Smithkline-Rit DNA sequences, recombinant DNA molecules and processes for producing the A and B subunits of cholera toxin and preparations containing so-obtained subunit or subunits
CH660375A5 (it) 1983-02-08 1987-04-15 Sclavo Spa Procedimento per la produzione di proteine correlate alla tossina difterica.
US5882653A (en) 1983-03-04 1999-03-16 The University Of Maryland System Vibrio cholerae 01 (CVD111) and non-01 (CVD112 and CVD112RM) serogroup vaccine strains, methods of making same and products thereof
US5668255A (en) 1984-06-07 1997-09-16 Seragen, Inc. Hybrid molecules having translocation region and cell-binding region
US5032398A (en) * 1986-08-01 1991-07-16 Kaslow Harvey R Selective modification of the catalytic subunit of pertussis toxin
US4892827A (en) 1986-09-24 1990-01-09 The United States Of America As Represented By The Department Of Health And Human Services Recombinant pseudomonas exotoxins: construction of an active immunotoxin with low side effects
KR0168039B1 (ko) 1987-09-04 1999-01-15 로버트 디. 웨스트 재조합 dna에서 유도한 보르데텔라 외독소 소단위체의 유사체 및 그를 포함하는 백신
US6713072B1 (en) 1987-11-02 2004-03-30 Chiron S.R.L. Immunologically active polypeptides with altered toxicity useful for the preparation of an antipertussis vaccine
US5925546A (en) 1987-11-02 1999-07-20 Chiron S.P.A. Immunologically active polypeptides with altered toxicity useful for the preparation of an antipertussis vaccine
US5358868A (en) 1987-11-24 1994-10-25 Connaught Laboratories Limited Genetic detoxification of pertussis toxin
US5221618A (en) 1987-11-24 1993-06-22 Connaught Laboratories Limited Genetic detoxification of pertussis toxin
US5332583A (en) 1987-11-24 1994-07-26 Connaught Laboratories Limited Vaccine containing genetically-detoxified pertussis holotoxin
US5244657A (en) 1987-11-24 1993-09-14 Connaught Laboratories Limited Genetic detoxification of pertussis toxin
GB8727489D0 (en) 1987-11-24 1987-12-23 Connaught Lab Detoxification of pertussis toxin
JP2849632B2 (ja) 1988-04-08 1999-01-20 社団法人北里研究所 ワクチン製剤
US5211657A (en) * 1988-11-07 1993-05-18 The United States Government As Represented By The Secretary Of The Department Of Health And Human Services Laminin a chain deduced amino acid sequence, expression vectors and active synthetic peptides
PT92511A (pt) * 1988-12-07 1990-06-29 Univ Leicester Processo de preparacao de um hospedeiro transformado e de proteinas de fusao da subunidade b de toxina labil ao calor
ATE127347T1 (de) * 1989-04-28 1995-09-15 Sclavo Spa Pertussistoxin-mutanten, dieselbe produzierende bordetella-stämme und ihre verwendung als vakzin gegen pertussis.
US5786189A (en) 1989-11-29 1998-07-28 Smithkline Beecham Biologicals (S.A.) Vaccine
IT1248735B (it) * 1990-06-21 1995-01-26 Sclavo Spa Vaccini acellulari contro la pertosse
US5241053A (en) * 1990-09-05 1993-08-31 Takeda Chemical Industries, Ltd. Fused proteins comprising glycoprotein gD of HSV-1 and LTB
IL101715A (en) 1991-05-02 2005-06-19 Amgen Inc Recombinant dna-derived cholera toxin subunit analogs
IT1253009B (it) 1991-12-31 1995-07-10 Sclavo Ricerca S R L Mutanti immunogenici detossificati della tossina colerica e della tossina lt, loro preparazione ed uso per la preparazione di vaccini
GB9513371D0 (en) * 1995-06-30 1995-09-06 Biocine Spa Immunogenic detoxified mutant toxins
US5874088A (en) 1992-07-06 1999-02-23 President And Fellows Of Harvard College Deletion mutants of cholera vaccines expressing heterologous antigens
CA2156191A1 (en) 1993-02-22 1994-09-01 Stephen B. Calderwood Heterologous antigens in live cell vaccine strains
US5871749A (en) 1993-07-27 1999-02-16 Csl Limited Therapeutic treatment of H. pylori associated gastroduodenal disease
US5856122A (en) 1993-08-24 1999-01-05 University Of Alberta Modification of pertussis toxin
DE69434000T3 (de) * 1993-10-05 2008-11-06 UCB Pharma Ltd., Slough Impfstoffzusammensetzungen
US5961970A (en) 1993-10-29 1999-10-05 Pharmos Corporation Submicron emulsions as vaccine adjuvants
GB9326174D0 (en) * 1993-12-22 1994-02-23 Biocine Sclavo Mucosal adjuvant
US20030072774A1 (en) * 1994-06-10 2003-04-17 Diane M. Gajewczyk Proteinaceous adjuvants
US5932714A (en) 1995-02-23 1999-08-03 Connaught Laboratories Limited Expression of gene products from genetically manipulated strains of Bordetella
GB9513733D0 (en) * 1995-07-05 1995-09-06 Univ Bristol Therapeutic agents
US6030624A (en) 1996-08-16 2000-02-29 Uab Research Foundation Mucosal immunogens for novel vaccines
US5908825A (en) 1997-01-09 1999-06-01 University Of Maryland At Baltimore Dosage composition for nasal delivery and method of use of the same
US6818222B1 (en) * 1997-03-21 2004-11-16 Chiron Corporation Detoxified mutants of bacterial ADP-ribosylating toxins as parenteral adjuvants
EP0919243A1 (en) * 1997-11-25 1999-06-02 Duphar International Research B.V Vaccine containing B subunits of heat-labile enterotoxin (LTB) of Escherichia coli as an adjuvant
WO1999036088A1 (en) * 1998-01-16 1999-07-22 Maxim Pharmaceuticals, Inc. RECOMBINANT CtB-BASED VACCINES
US6033673A (en) 1998-03-18 2000-03-07 The Administrators Of Tulane Educational Fund Double mutant enterotoxin for use as an adjuvant
GB9808932D0 (en) * 1998-04-27 1998-06-24 Chiron Spa Polyepitope carrier protein
ATE283920T1 (de) * 1998-04-30 2004-12-15 Chiron Srl Verfahren zur immunisierung und behandlung von h. pylori infektion
EA004794B1 (ru) * 1998-05-08 2004-08-26 Юниверсити Оф Бристоль Вакцина
PT1117435E (pt) * 1998-09-30 2008-02-21 Us Gov Univ Health Sciences Holotoxina da cólera mutante como adjuvante
WO2000037609A2 (en) * 1998-12-22 2000-06-29 Boyce Thompson Institute For Plant Research At Cornell Orally immunogenic bacterial enterotoxins expressed in transgenic plants
US7115730B1 (en) * 1999-04-27 2006-10-03 Chiron Srl Immunogenic detoxified mutant E. coli LT-A-toxin
NZ515322A (en) * 1999-05-13 2004-03-26 Wyeth Corp Adjuvant combination formulations
GB9923060D0 (en) * 1999-09-29 1999-12-01 Chiron Spa Vaccine
US7384640B1 (en) * 1999-09-30 2008-06-10 Wyeth Holdings Corporation Mutant cholera holotoxin as an adjuvant
US20040109874A1 (en) * 1999-11-10 2004-06-10 Powderject Vaccines, Inc. Induction of mucosal immunity by vaccination via the skin route
IL155690A0 (en) * 2000-11-10 2003-11-23 Wyeth Corp Adjuvant combination formulations
GB0108024D0 (en) * 2001-03-30 2001-05-23 Chiron Spa Bacterial toxins
CA2439111A1 (en) * 2001-04-05 2002-10-17 Chiron Corporation Mucosal boosting following parenteral priming
CA2514667C (en) * 2003-01-30 2013-01-08 Chiron Corporation Adjuvanted influenza vaccine
CA2542777C (en) * 2003-10-23 2016-02-02 Chiron Corporation Stabilised compositions
WO2006128296A1 (en) * 2005-06-01 2006-12-07 Sanofi Pasteur Limited Pal-based chlamydia vaccine
JP2010184634A (ja) * 2009-02-13 2010-08-26 Hitachi Automotive Systems Ltd 操舵制御装置

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6350612B1 (en) * 1986-01-28 2002-02-26 Chiron S.P.A. Isolation and expression of DNA sequence encoding the five subunits of Bordetella pertussis toxin
US20020044939A1 (en) * 1991-12-31 2002-04-18 Chiron S.P.A. Immunogenic detoxified mutants of cholera toxin
US6436407B1 (en) * 1994-08-26 2002-08-20 The Administrators Of The Tulane Educational Fund Mutant enterotoxin effective as a non-toxic adjuvant
US6440423B1 (en) * 1994-08-26 2002-08-27 The Administrators Of The Tulane Educational Fund Mutant enterotoxin effective as a non-toxic oral adjuvant
US20030113338A1 (en) * 1996-10-31 2003-06-19 Mariagrazia Pizza Immunogenic detoxified mutant e. coli lt-a toxin
US20030170262A1 (en) * 1996-10-31 2003-09-11 Chiron Corporation Immunogenic detoxified mutant E. coli LT-A toxin

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040028690A1 (en) * 1993-12-22 2004-02-12 Rino Rappuoli Nontoxic mucosal adjuvant
US7070781B2 (en) * 1993-12-22 2006-07-04 Chiron Srl Nontoxic mucosal adjuvant
US20060177469A1 (en) * 1993-12-22 2006-08-10 Chiron S.P.A. Non-toxic mucosal adjuvant
US7485304B2 (en) 1993-12-22 2009-02-03 Novartis Vaccines And Diagnostics Srl Non-toxic mucosal adjuvant
US20050031587A1 (en) * 2002-10-04 2005-02-10 Yamanouchi Pharmaceutical Co., Ltd. Immune response induction method
US20110280911A1 (en) * 2008-11-17 2011-11-17 The Regents Of The University Of Michigan Cancer vaccine compositions and methods of using the same
US9974844B2 (en) * 2008-11-17 2018-05-22 The Regents Of The University Of Michigan Cancer vaccine compositions and methods of using the same
US11116825B2 (en) 2008-11-17 2021-09-14 The Regents Of The University Of Michigan Cancer vaccine compositions and methods of using the same
US8758766B2 (en) 2008-12-24 2014-06-24 The Kingdom of The Netherlands, Represented by The Mininster of Health, Welfare and Sport, on Behalf of The Minster The National Institute of Public Health and The Environment Modified Streptococcus pneumoniae pneumolysin (PLY) polypeptides

Also Published As

Publication number Publication date
EP0732937A1 (en) 1996-09-25
JP2009298812A (ja) 2009-12-24
DK0732937T4 (da) 2009-06-08
JPH10500099A (ja) 1998-01-06
ATE187078T1 (de) 1999-12-15
ES2139879T5 (es) 2009-06-10
ES2139879T3 (es) 2000-02-16
PT732937E (pt) 2000-05-31
JP4283889B2 (ja) 2009-06-24
WO1995017211A1 (en) 1995-06-29
CA2179771A1 (en) 1995-06-29
DE69421939T3 (de) 2009-11-05
JP2006143729A (ja) 2006-06-08
EP0732937B1 (en) 1999-12-01
GR3032497T3 (en) 2000-05-31
DK0732937T3 (da) 2000-05-01
DE69421939T2 (de) 2000-06-15
JP5148577B2 (ja) 2013-02-20
AU1278595A (en) 1995-07-10
GB9326174D0 (en) 1994-02-23
US20040028690A1 (en) 2004-02-12
JP2012246326A (ja) 2012-12-13
EP0732937B2 (en) 2009-03-18
US20060177469A1 (en) 2006-08-10
US7485304B2 (en) 2009-02-03
DE69421939D1 (de) 2000-01-05
US7070781B2 (en) 2006-07-04
CA2179771C (en) 2001-02-20

Similar Documents

Publication Publication Date Title
US7070781B2 (en) Nontoxic mucosal adjuvant
KR100399258B1 (ko) 비독성경구용어쥬번트로써효과적인장독소돌연변이체
CA2284541C (en) Detoxified mutants of bacterial adp-ribosylating toxins as parenteral adjuvants
US20100255033A1 (en) Non-toxic double mutant forms of pertussis toxin as adjuvants
JP2004159660A (ja) コレラワクチンとしての欠失変異体
de Haan et al. Mutational analysis of the role of ADP‐ribosylation activity and GM1‐binding activity in the adjuvant properties of the Escherichia coli heat‐labile enterotoxin towards intranasally administered keyhole limpet hemocyanin
US7063852B2 (en) Hybrid LT-A/CT-B holotoxin for use as an adjuvant
JP2010184934A (ja) 非毒性の粘膜アジュバント
WO1998032461A1 (en) Mutant enterotoxin effective as a non-toxic adjuvant for hiv
AU771286B2 (en) Detoxified mutants of bacterial ADP-ribosylating toxins as parenteral adjuvants
EP1486215A2 (en) Detoxified mutants of bacterial ADP-ribosylating toxins as parenteral adjuvants
VERWEIJ et al. The role of ADP-ribosylation and G [sub M1]-binding activity in the mucosal immunogenicity and....

Legal Events

Date Code Title Description
AS Assignment

Owner name: CHIRON S.P.A., ITALY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:RAPPUOLI, RINO;REEL/FRAME:012860/0739

Effective date: 20020611

AS Assignment

Owner name: CHIRON S.R.L., ITALY

Free format text: CHANGE OF NAME;ASSIGNOR:CHIRON S.P.A.;REEL/FRAME:014699/0226

Effective date: 20021212

Owner name: CHIRON S.R.L.,ITALY

Free format text: CHANGE OF NAME;ASSIGNOR:CHIRON S.P.A.;REEL/FRAME:014699/0226

Effective date: 20021212

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION