+

WO2008100142A2 - Formulation vaccinale - Google Patents

Formulation vaccinale Download PDF

Info

Publication number
WO2008100142A2
WO2008100142A2 PCT/NL2008/050079 NL2008050079W WO2008100142A2 WO 2008100142 A2 WO2008100142 A2 WO 2008100142A2 NL 2008050079 W NL2008050079 W NL 2008050079W WO 2008100142 A2 WO2008100142 A2 WO 2008100142A2
Authority
WO
WIPO (PCT)
Prior art keywords
biodegradable hydrogel
antigen
entrapped
hydrogel
entrapped antigen
Prior art date
Application number
PCT/NL2008/050079
Other languages
English (en)
Other versions
WO2008100142A3 (fr
Inventor
Sebastianus Hermanus Adrianus Kremer
Rudolf Verrijk
Yvette Jacqueline Van Der Raad-Meijer
Original Assignee
Octoplus Sciences B.V.
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
Priority claimed from EP07008366A external-priority patent/EP1985284A1/fr
Application filed by Octoplus Sciences B.V. filed Critical Octoplus Sciences B.V.
Publication of WO2008100142A2 publication Critical patent/WO2008100142A2/fr
Publication of WO2008100142A3 publication Critical patent/WO2008100142A3/fr

Links

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
    • A61K39/12—Viral antigens
    • A61K39/29—Hepatitis virus
    • A61K39/292—Serum hepatitis virus, hepatitis B virus, e.g. Australia antigen
    • 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
    • A61K39/12—Viral antigens
    • 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
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55505—Inorganic adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55555—Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2730/00—Reverse transcribing DNA viruses
    • C12N2730/00011—Details
    • C12N2730/10011—Hepadnaviridae
    • C12N2730/10111—Orthohepadnavirus, e.g. hepatitis B virus
    • C12N2730/10134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • the present invention relates to biodegradable hydrogel-entrapped antigen, as well as a vaccine formulation comprising free antigen and such polymer-entrapped antigen.
  • the biodegradable polymers preferably comprise hydroxyethyl methacrylate- derivatized dextran.
  • the invention relates to such biodegradable hydrogel- entrapped antigen and/or vaccine formulation for use as a medicament, and the use of such biodegradable hydrogel-entrapped antigen and/or vaccine formulation in the preparation of a medicament for immunization of a subject.
  • the invention relates to a kit for immunization of a subject comprising such lyophilized biodegradable hydrogel-entrapped antigen and/or vaccine formulation, and to a method of immunizing a subject in need thereof comprising administering to said subject such biodegradable hydrogel-entrapped antigen and/or vaccine formulation.
  • the hydrophobic polymers polylacti- de(PLA), polyglycolide(PGA), and poly(lactide-co-glycolide)(PLGA) are generally known to be safe because they undergo in vivo hydrolysis to lactic acid and glycolic acid, which are physiologically acceptable monomers.
  • the degradation rates of these polymers vary with the glycolide/lactide ratio and molecular weight thereof, and, therefore, the release of the drug can be sustained over several months by adjusting the molecular weight and glycolide/lactide ratio of the polymer as well as the particle size.
  • the hepatitis B virus model represents a good model of a system where a single- shot vaccination would be highly advantageous.
  • Infection with hepatitis B virus (HBV) represents a global public health problem and is the 10 th leading cause of death worldwide.
  • HBV is classified as a member of the Hepadnaviridae family of viruses, which cause liver diseases in human and animals. HBV resides in the liver of infected humans, which it enters via the bloodstream. The virus replicates in hepatocytes and subsequently infects more liver cells.
  • HBV is transmitted by either skin puncture or mucous contact with infected body fluids.
  • the highest concentration of HBV is found in the blood; however, the virus is present in and can be transmitted through all body fluids, such as saliva, semen and perspiration.
  • HBV infection can also be aided through contaminated surfaces, such as needles and surgical tools, since the virus is resistant to breakdown and can survive and stay infectious outside the body for at least 7 days.
  • the main routes of HBV transmission are perinatal transmission, transmission from child to child, unsafe injections and blood transfusions and sexual intercourse.
  • a person infected with HBV can carry the virus symptomatic (acute Hepatitis B) or asymptomatic. In both cases an infected person can either cure from the infection and develop lifelong immunity or become chronically infected, which, if untreated, lasts for life.
  • the current vaccination regimen against HBV consists of three injections; one prime injection and two booster injections that are routinely administered at 1 month and 4 to 6 months following the first (prime) injection.
  • Vaccine efficacy after a full series of injections is estimated at 95%, with a duration of immunity of 15 years or more.
  • compliance to this 3 doses regiment is relatively poor, especially in developing countries, mainly due to logistic reasons.
  • biodegradable hydrogel-entrapped antigen and vaccine formulation according to the present invention aim to improve overall compliance by providing the convenience of a one shot vaccination.
  • the present invention relates to a biodegradable hydrogel- entrapped antigen, wherein the biodegradable hydrogel comprises a network of polymer chains, which polymer chains are interconnected to one another through spacers, which spacers comprise a crosslinking unit and at least one bond which is hydrolysable under physiological conditions.
  • the present invention relates to a single-shot vaccine formulation comprising free antigen, as well as such biodegradable hydrogel-entrapped antigen.
  • the invention is directed to the use of such biodegradable hydrogel-entrapped antigen or vaccine formulation in the preparation of a medicament for immunization of a subject.
  • the invention also relates to a kit for immunization of a subject, said kit comprising a lyophilized biodegradable hydrogel-entrapped antigen or vaccine formulation as defined in the present invention and reconstitution fluid suitable to dissolve and/or disperse the lyophilized biodegradable hydrogel-entrapped antigen or vaccine formulation, to a method for immunizing a subject in need thereof comprising administering to said subject a biodegradable hydrogel-entrapped antigen or vaccine formulation according to the invention, and to a pharmaceutical composition comprising a biodegradable hydrogel-entrapped antigen or vaccine formulation of the invention and one or more pharmaceutically acceptable carriers and/or excipients.
  • the present invention relates to a biodegradable hydrogel-entrapped antigen, wherein the biodegradable hydrogel comprises a network of polymer chains, which polymer chains are interconnected to one another through spacers, which spacers comprise a crosslinking unit and at least one bond which is hydrolysable under physiological conditions.
  • hydrogel' refers to a water-swollen, three-dimensional network of crosslinked hydrophilic macromolecules. More specifically, the hydrogel used in the present invention consists of two interpenetrating networks interconnected to one another through hydrolysable spacers. Hydrogels generally contain at least 10% of the total weight (or volume) water.
  • a lactate ester bond can be introduced in the hydrogel by introducing e.g. lactic acid monomer, glycolic acid monomer, lactic acid dimer, glycolic acid dimer, oligoglycolic acid, o ⁇ golactic acid, polyglycolic acid residues and/or polylactic acid residues or any combination of these between the polymer chain and the crosslinkable unit.
  • a non-limiting example of such polymeric hydrogel is disclosed in European Patent EP 0910412 (Dex-lactate-HEMA).
  • One skilled in the art will be capable of introducing such lactate, glycolate and/or ⁇ -caprolactone ester bond and/or carbonate bond based on the disclosure of e.g. EP 0910412, which is herein incorporated by reference.
  • Hydrogels according to the present invention can suitably be prepared by first synthesizing spacers that contain at least one crosslink- able group and at least one hydrolytically labile group; coupling said spacers to a water- soluble polymer, and crosslinking the polymers obtained, preferably in the presence of the antigen to be entrapped within the hydrogel.
  • the biodegradable hydrogel comprises dextran derivatized with optionally hydroxylated alkyl methacrylate, preferably hydroxyethyl methacrylate- derivatized dextran. More preferably, the biodegradable hydrogel consists essentially of hydroxyethyl methacrylate-derivatized dextran (Dex-HEMA). In such hydroxyethyl methacrylate-derivatized dextran, a dextran backbone is substituted with HEMA side chains. The HEMA side chains are preferably coupled to the dextran backbone via a hydrolysable bond, preferably a carbonate bond.
  • the preparation of Dex-HEMA is e.g. disclosed in EP 0910412.
  • the Dex-HEMA may have any degree of substitution (number of substitutes per 100 glucopyranose residues), i.e. the dextran backbone may contain any number of HEMA substitutes per 100 glucopyranose residues.
  • the controlled release characteristics may be tailored by varying the degree of subsitution.
  • Dex-HEMA having a degree of substitution of between 3-30 may for example be used.
  • the biodegradable hydrogel comprises hydroxyethyl methacrylate-derivatized dextran having degree of substitution in the range of 3-15, yet more preferably in the range of 5- 10, and most preferably in the range of 5-8. It was found by the present inventors that using such degree of substitution, suitable release profiles were obtained for antigens, e.g.
  • the biodegradable hydrogel-entrapped antigen is entrapped in microparticles having the capability to form a hydrogel.
  • Micropaiticle suspensions are easy to prepare and are easily used for injection.
  • Microparticles can e.g. be prepared by dissolving Dex-HEMA (and optionally the antigen) in water, adding this solution to a PEG phase, and emulsifying the resultant yielding a water-in- water emulsion (with the Dex-HEMA phase (optionally containing the antigen) being dispersed within the PEG phase).
  • the methacrylate or methacrylamide groups polymerize yielding stable microparticles.
  • Suitable initiator systems include a known initiator system of a tertiary amine and a persulphate, as disclosed in EP 0910 412 and in EP 1 371 364, both of which are herein incorporated by reference.
  • microparticles should be understood as solid or semisolid particles having a diameter in the region of about 0.1 to about 500 ⁇ m, regardless of their shape or internal structure.
  • microparticles would also encompass microspheres and microcapsules.
  • the microparticles have a diameter from about 0.1 to about 300 ⁇ m. Selecting such particle size will also ensure that a suspension of these microparticles is well-syringeable and can be easily and conveniently administered via intramuscular or subcutaneous injection.
  • the antigen is HBsAg antigen.
  • HBsAg' is well known in the art and refers to the Hepatitis B surface antigen. It is a part of the hepatitis B virus that, when in the blood, is one of the earliest markers of infection with hepatitis B virus, appearing even before symptoms. It is a complex macromolecular aggregate composed of protein, carbohydrates (in the form of glycoproteins) and lipids. Recombinant HBsAg can be produced with yeast cells (e.g. from Hansenula polymorpha) or mammalian cells (e.g. Chinese hamster ovary [CHO] cells). Depending on its source, the HBsAg particle may differ somewhat.
  • CHO-HBsAg contains 3 proteins, S, preSl, and preS2, each in two forms of glycosyla- tion, whereas the Hansenula-HBsAg contains only the non-glycosylated S peptide.
  • the term 'HBsAg' as used herein encompasses many variations of the HBsAg particle, including, but not limited to, HBsAg particles comprising as only protein S antigen (as mostly obtained from yeast), HBAg particles comprising S antigen, and preS 1 protein, HBsAg particles comprising S antigen, preS 1 protein, and preS2 protein, optionally glycosylated, and the like.
  • the term 'HBsAg' as used throughout the present application refers to a HBsAg particle comprising at least the S antigen, either glycosylated or non-glycosylated.
  • the HBsAg antigen is HBsAg antigen derived from Chinese Hamster Ovarian (CHO) cells. It was found that such CHO-derived HBsAg was considerably more immunopotent than yeast-derived HBsAg.
  • the present invention is directed to a single-shot vaccine formulation comprising free antigen, and biodegradable hydrogel-entrapped antigen as defined above.
  • the free antigen serves as a prime dose
  • the biodegradable hydrogel-entrapped antigen serves as boost dose.
  • the term 'free antigen' as used herein refers to antigen that is not entrapped within a polymer (micro)particle or network. It may be soluble, dispersible, or it may be complexed with an adjuvant such as aluminium or non-adjuvanted, as long as it is not entrapped in a polymer particle or network.
  • the free antigen is advantageously present in an amount sufficient to ensure priming of the immune response for vaccination.
  • the term 'aluminium' or 'alum' as used herein refers to any aluminium derivatives, e.g. aluminium salts and aluminium hydroxide.
  • the free antigen is free of aluminium adjuvant, i.e. is not complexed with aluminium.
  • aluminium adjuvant i.e. is not complexed with aluminium.
  • the use of adjuvanted free antigen improved immunization.
  • the invention relates to the use of a biodegradable hydrogel-entrapped antigen as herein defined or a vaccine formulation as herein defined in the preparation of a medicament for immunization of a subject.
  • a biodegradable hydrogel-entrapped antigen as herein defined or a vaccine formulation as herein defined in the preparation of a medicament for immunization of a subject.
  • Such medicament may be in any physical form known to the skilled person, such as liquid form or frozen form. It may also be lyophilized, spray-dried or solidified in any other way.
  • the present invention is directed to a kit for immunization of a subject, said kit comprising a lyophilized biodegradable hydrogel-entrapped antigen, such as HBsAg, as herein defined or vaccine formulation as herein defined and reconsti- tution fluid suitable to dissolve and/or disperse the lyophilized biodegradable hydrogel- entrapped antigen or vaccine formulation.
  • the reconstitution fluid may be any fluid capable of dissolving and/or dispersing the lyophilized biodegradable hydrogel- entrapped antigen or vaccine formulation.
  • suitable reconstitution fluids include physiological salt solution, water for injection, and isotonic sucrose solution.
  • the present invention relates to a method for immunizing a subject in need thereof comprising administering to said subject a biodegradable hydrogel-entrapped antigen as herein defined such as HBsAg or a vaccine formulation as defined herein.
  • a biodegradable hydrogel-entrapped antigen as herein defined such as HBsAg or a vaccine formulation as defined herein.
  • Subjects in need for immunization against Hepatitis B include without limitation children, travellers to endemic areas such as South East Asia, and inhabitants of e.g. Asia and South America. Administration may be via any route, but preferably takes place by means of injection, preferably intramuscular or subcutanous injection, more preferably by subcutanous injection.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a biodegradable hydrogel-entrapped antigen as herein defined or a vaccine formulation as defined herein, and one or more pharmaceutically acceptable carriers and/or excipients.
  • Suitable carriers and/or excipients are well known to the person skilled in the art and can e.g. be found in Remington's Pharmaceutical Sciences.
  • parenteral administration includes any invasive route of administration, such as subdermal, intradermal, subcutaneous, intramuscular, locoregional, intratumoral, intraperitoneal, interstitial, intralesional, with some less preference in the context of this invention also intravenous, intraarterial etc.
  • Highly preferred routes of administration of the composition are subcutaneous and intramuscular injection or implantation.
  • the pharmaceutical composition preferably is sterile and complies with the requirements of the cur- rent pharmacopoeias with regard to the content of endotoxins, osmolality, etc.
  • the ex- cipients are preferably selected to be safe and tolerable for parenteral administration.
  • the composition is formulated to be relatively isotonic (or isoosmotic), such as in the region of about 150 to 500 m ⁇ smol/kg, and preferably in the region of about 250 to 400 m ⁇ smol/kg.
  • the pH should be approximately in the physiological range in order to avoid pain and local intolerance upon injection.
  • the pH of the final composition is in the region of about 4 to 8.5, and more preferably in the region of about 5.0 to 7.5.
  • 'OctoVAX' and OctoVAX microspheres' refer to microparticles composed of Dex-HEMA, optionally comprising HBsAg antigen derived from either yeast or CHO cells.
  • Figure 1 shows the in vitro yeast-HBsAg release at pH 8.4 from OctoVAX microspheres having a water content of 50% and a HBsAg load of 0.61 mg.
  • the OctoVAX microspheres were prepared from Dex-HEMA having various degrees of substitution (DS4, DS5, DS8, DS 12 and DS 16, respectively). The measurements were performed in duplicate for OctoVAX microspheres having DS5, DS8, DS 12 and DS 16, and a single experiment was performed for OctoVAX microspheres having DS4.
  • the time axis is based on conversion of the pH8.4 accelerated release data to real-time release data by factors obtained in direct comparison of accelerated vs. real-time release.
  • FIG. 2 shows the in vitro yeast-HBsAg release at pH 8.4 from OctoVAX microspheres having a water content of 70% and a HBsAg load of 0.366 mg.
  • the OctoVAX microspheres are prepared from Dex-HEMA having various degrees of substitution (DS4, DS5, DS8, DS 12 and DS 16, respectively). The measurements were performed in duplicate for OctoVAX microspheres having DS5, DS8, DS 12 and DS 16, and a single experiment was performed for OctoVAX microspheres having DS4.
  • the time axis is based on conversion of the pH8.4 accelerated release data to real-time release data by factors obtained in direct comparison of accelerated vs. real-time release.
  • Figure 4 demonstrates the immunopotency of increasing dose OctoVAX microsphere formulations containing either yeast-derived HBsAg or CHO-derived HBsAg. Mean titre values for each group are indicated for day 84. The error bars indicate the SEM.
  • Figure 5 demonstrates the immunopotency of different prime compositions in combination with a consistent OctoVAX microsphere-dose containing yeast-derived HBsAg. Geometric mean titre values are indicated for each group for day 84. The error bars indicate the SEM.
  • Yeast-derived HBsAg was obtained from the Serum Institute of India Ltd., India.
  • CHO- derived HBsAg was obtained from SciGen IL Ltd., Israel.
  • Dex-HEMA DS4 was obtained from Utrecht University, Utrecht, The Netherlands.
  • Dex-HEMA DS5, DS8, DS 12, DS 16, DS20 and DS30 were obtained from PSCG, Gro- ningen, The Netherlands.
  • Dextran 40.000 PH EUR was purchased from Pharmacia, Uppsala, Sweden.
  • PEG 10.000 was obtained from Chempri, Raamsdonkveer, The Netherlands.
  • Sodium hydroxide (NaOH), boric acid (H 3 BO 3 ), sodium dihydroxyphosphate monohyd- rate (NaH 2 PO 4 -H 2 O), and disodium hydroxyphosphate dihydrate (Na 2 HP ⁇ 4.2H 2 O) were obtained from Merck, Darmstadt, Germany.
  • Phosphate buffered saline (PBS, pH 7.4) was purchased from Invitrogen (Gibco), Paisly, Scotland, UK.
  • Methanol (MeOH) HPLC grade was obtained from Biosolve, Valkenswaard, The Netherlands. Tween 20 was obtained from Merck, Hohenbrunn, Germany.
  • TEMED N,N,N',N'- Tetramethylethylenediamine
  • NaPS Sodium peroxodisulphate
  • Glycine Glycine
  • Na 2 B 4 O 7 sodium borate
  • microspheres were washed 5-fold by centrifuging the tubes at 3500 rpm (1 st time 20 minutes, subsequent times 7 minutes). After each centrifugation cycle the supernatant was removed and replaced by 5.0 ml fresh buffer. The microspheres were resuspended. After the last centrifugation cycle the supernatant was replaced by 5.0 ml of the release buffer and the microspheres were resuspended.
  • a Perkin Elmer HPLC system was used for the automated IVR.
  • the HPSEC column used was a TSKgel G5000 PWXI column (300x7.8 mm) with a TSKgel PWH Guardco- lumn (75x7.5 mm) installed.
  • the column temperature was set to 24°C and the peltier tray was set to 37°C.
  • the needle was flushed with MeOH/H2O (50:50).
  • the flow used was 1.0 ml/min and the runtime was 22 minutes.
  • the injection volume was set to 20 ⁇ l. With every sample an additional 10 ⁇ l was taken up for preflushing the needle.
  • UV detection was performed at 210 nm using a UV detector.
  • a mobile phase of PBS (pH 7.0) with 1% Tween 20 was used (isocratic).
  • a Thermo Electron elemental nitrogen analyzer was used for determination of encapsulation efficiency and remaining content of HBsAg in the samples.
  • An injection volume of 500 ⁇ l was used.
  • a calibration curve of glycine was used to calculate the amount of nitrogen in the samples.
  • OctoVAX microspheres were prepared using Dex-HEMA having various degrees of substitution (DS; DS4-16) (hereinafter e.g. referred to as "OctoVAX DS 4-16").
  • the microspheres were loaded with either 0.61 mg or 0.366 mg yeast-derived HBsAg, and were prepared in such a way that the water content was either 50% or 70%. Subsequently, the release profiles at pH 8.4 of HBsAg from such microspheres were determined.
  • microspheres having a water content of 50% and a HBsAg load of 0.61 mg it was found that the microspheres obtained with Dex-HEMA having a DS of 4 or 5 were not completely round in shape, whereas those obtained with Dex-HEMA having a DS of 8, 12 or 16 were perfectly round in shape.
  • microspheres having a water content of 10% and an HBsAg load of 0.366 mg it was found that the microspheres obtained with OctoVAX DS 4 were not completely round in shape. From OctoVAX DS5 onwards, spherical particles were found.
  • the release profiles obtained from the microspheres are shown in Figure 2.
  • the profiles of OctoVAX DS4 and OctoVAX DS5 were similar; a more or less linear profile was obtained. Both types of microspheres released their complete contents within approximately 15 days.
  • OctoVAX DS8 microspheres released less HBsAg and the release rate was slower than for OctoVAX DS4 and DS5.
  • OctoVAX DS 16 microspheres released their content only slightly slower than OctoVAX DS8 microspheres.
  • the antigen source was either Chinese hamster ovarian cells (CHO), or HBsAg produced in yeast.
  • the CHO material In contrast to the yeast material that consist of a single non- glycosylated protein, the CHO material consists of HBsAg particles made up of 3 proteins that are glycosylated. The CHO material as such mimics the HBsAg particles that are naturally occurring in blood of HBV infected humans.
  • the release profiles for the yeast material formulations DS5, 50% water
  • CHO material formulations DS8, 70%
  • serum was collected with 28- day intervals until day 84. Additionally, in the study presented in Table 1 serum was also collected at day 170 to obtain an indication about effects on the duration of the response.
  • Antibody titers were determined with the commercially available BioRad Mono- lisa HBs3.0 kit, and presented as mlU/ml in reference to the international standards included in this kit. In Table 1 the number of animals with serum antibody levels above those regarded as seroprotection limits are indicated.
  • mice with antibody titers higher than 30 mIU/ml as compared to the total number of mice in the group
  • Figure 3 shows that the CHO-derived HBsAg is intrinsically more potent in inducing antibodies as can be seen by comparing the 30 ⁇ g MS-CHO with the 30 ⁇ g MS-yeast, as well as by comparing 3 ⁇ g prime CHO + 3 ⁇ g MS-CHO with 3 ⁇ g prime yeast + 3 ⁇ g MS-yeast.
  • the titers induced by the prime-boost combination with 3 ⁇ g each, are approximately 10 fold higher with the CHO HBsAg compared to yeast material.
  • HBsAg-OctoVAX formulation a second animal study was performed to determine the dose of single shot (prime-boost) HBsAg-OctoVAX formulation at which discrimination between variations in composition can be determined.
  • the free alum- HBsAg dose was reduced to 1 ⁇ g for yeast-derived HBsAg and to 0,3 ⁇ g for CHO- derived HBsAg.
  • Increasing doses of OctoVAX microspheres containing HBsAg were admixed with a constant amount of free alum-HBs Ag.
  • the importance of the composition of the prime dose was studied by comparing alum-HBsAg prime with non- adjuvanted prime.
  • Serum was collected at at 28-day intervals until day 84.
  • Antibody titers were determined with a commercially available EIA kit (BioRad Monolisa HBs3.0), and presented as mlU/ml in reference to the international standards included in this kit.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Communicable Diseases (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une nouvelle formulation vaccinale comprenant un antigène encapsulé dans un hydrogel. Ce type d'antigène encapsulé dans un hydrogel peut être avantageusement utilisé dans la préparation d'une formulation vaccinale qui peut remplacer les protocoles habituels de vaccination en plusieurs injections. Ce type de formulation vaccinale fournit avantageusement un protocole de primo-vaccination et de rappel en une seule injection. L'invention concerne également une méthode pour immuniser un sujet qui en a besoin comprenant l'administration audit sujet dudit antigène encapsulé dans de l'hydrogel ou ce type de formulation vaccinale comprenant l'antigène encapsulé dans un hydrogel.
PCT/NL2008/050079 2007-02-12 2008-02-12 Formulation vaccinale WO2008100142A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP07002907.9 2007-02-12
EP07002907 2007-02-12
EP07008366.2 2007-04-25
EP07008366A EP1985284A1 (fr) 2007-04-25 2007-04-25 Formule de vaccin

Publications (2)

Publication Number Publication Date
WO2008100142A2 true WO2008100142A2 (fr) 2008-08-21
WO2008100142A3 WO2008100142A3 (fr) 2008-10-30

Family

ID=39682665

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/NL2008/050079 WO2008100142A2 (fr) 2007-02-12 2008-02-12 Formulation vaccinale

Country Status (1)

Country Link
WO (1) WO2008100142A2 (fr)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1128953A (zh) * 1993-07-12 1996-08-14 病毒研究院 水凝胶微囊包封的疫苗
DE69721265T2 (de) * 1996-07-01 2004-05-06 Universiteit Utrecht Hydrolysierbare hydrogele zur gesteuerten freisetzung
US6589549B2 (en) * 2000-04-27 2003-07-08 Macromed, Incorporated Bioactive agent delivering system comprised of microparticles within a biodegradable to improve release profiles

Also Published As

Publication number Publication date
WO2008100142A3 (fr) 2008-10-30

Similar Documents

Publication Publication Date Title
JP4918188B2 (ja) サブミクロンの水中油型エマルジョンと合わせた微粒子の使用
McKee et al. Old and new adjuvants
Azmi et al. Recent progress in adjuvant discovery for peptide-based subunit vaccines
CA2631714C (fr) Nanoparticules destinees a etre utilisees dans des compositions immunogenes
JP5037747B2 (ja) 免疫応答を刺激するための吸着された抗原を有するマイクロパーティクルの使用
ES2260291T3 (es) Microparticulas para la administracion de acidos nucleicos heterologos.
JP6013400B2 (ja) 免疫応答を誘導するための組成物
CZ289476B6 (cs) Očkovací přípravek a způsob jeho výroby
JP2002537102A (ja) 吸着された高分子および微粒子を有するミクロエマルジョン
KR20130111648A (ko) 항말라리아 백신
CN1231613A (zh) 抵抗疟疾的疫苗组合物
Kelleci et al. Particulate and non-particle adjuvants in Leishmaniasis vaccine designs: A review
JP2005514326A (ja) ミクロスフェア中に封入されたタンパク質およびアジュバントを送達するための組成物および方法
Garcia et al. An updated review of ISCOMSTM and ISCOMATRIXTM vaccines
O’Hagan New generation vaccine adjuvants
CN109876140A (zh) 一种治疗慢性乙肝的疫苗及其制备方法和应用
US20100021546A1 (en) Controlled-release immunogenic formulations to modulate immune response
EP1985284A1 (fr) Formule de vaccin
WO2008100142A2 (fr) Formulation vaccinale
Ke et al. Immunogenicity of the LrrG protein encapsulated in PLGA microparticles in Nile tilapia (Oreochromis niloticus) vaccinated against Streptococcus agalactiae
US20130259948A1 (en) Spray dried powder formulation for vaccines entrapping alum and the antigen in biodegradable polymer particles
Peyre Characterisation of the immunological events induced by biodegradable polymer vaccines
KR20250042906A (ko) 온도민감성 나노파티클 전달체를 이용한 결핵 예방용 조성물
Monteiro Garrido Castro e Silva PLGA-based particulate vaccine delivery systems for immunotherapy of cancer
PT1585542E (pt) Composições imunogénicas contendo fosfolípido

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08712605

Country of ref document: EP

Kind code of ref document: A2

122 Ep: pct application non-entry in european phase

Ref document number: 08712605

Country of ref document: EP

Kind code of ref document: A2

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载