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
  • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical 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
  • 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
  • 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
  • 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
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/04—Immunostimulants
• • 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
• • 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
• • 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 invention relates to the field of vaccine adjuvants.
• the invention relates to the use of an amphipathic compound for the manufacture of a vaccine composition intended for non-responders.
• the object of the invention is therefore to propose an improved vaccine as regards the rate of seroconversion which it makes it possible to obtain.
• the invention proposes the use of an amphipathic compound for the preparation of a vaccine composition comprising at least one subunit antigen intended to be administered to target populations comprising individuals "Non-Responders" to said antigen .
• the amphipathic compounds are derivatives of cholesterol linked to a quaternary ammonium or to a protonable amine by a carbamoyl bond.
• These compounds, such as DC-chol can be found under basic form, in the form of salt, or, and this is the most frequent case, both under the 2 forms in equilibrium in a mixture, the shift of equilibrium towards one or the other dependent form the composition of the mixture and in particular its pH.
• DC-chol which is particularly advantageous for the purposes of the invention is DC-chol which can be obtained from cholesteryl chloroformate and from N, N-dimethylethylenediamine, according to the method described in US Pat. No.
• amphipathic compounds can be in the form of a dispersion in an aqueous or oily medium.
• the vaccine composition which should be modified in order to reduce the number of individuals who are non-responders therein is a composition comprising at least one highly purified subunit antigen.
• antigens are generally less immunogenic than less purified preparations obtained from whole germs, and can therefore lead to a higher proportion of Non-Responders.
• the number of non-Responders to the hepatitis B antigen is reduced. It can be any hepatitis B antigen, and in particular an antigen containing the S and pre-S 2 regions , such as the antigen described in patent EP 0 273 811.
• the vaccine composition according to the invention can be in liquid form or in lyophilized form.
• the vaccine composition according to the invention can be a monovalent (that is to say intended to protect only against one disease) or plurivalent (protecting against several diseases) composition.
• It can comprise, in addition to the adjuvant according to the invention, one or more other adjuvants intended, in a conventional manner, to increase the response of the immune system, whether it is a response of humoral type, of cellular type, or a mixture of the 2 types.
• the vaccine composition according to the invention can also comprise all the ingredients usually present in vaccines: stabilizer, preservative, cryoprotective, etc.
• This composition can be in liquid form or in the form of lyophilisate.
• FIG. 1 represents the reaction for obtaining DC-chol.
• Figures 2 and 3 and
• Example 3 illustrate the results obtained in Example 2.
• Example 1 Preparation of the immunization compositions.
• a hepatitis B antigen suspension is prepared, according to the method described in patent EP 0 273 811, with the exception of the addition of aluminum hydroxide. It is therefore a suspension at 4 mg / l of antigen in 1 mM phosphate buffer at pH 6.8. This suspension is called Suspension A.
• DC-chol powder obtained according to the mode of preparation described in Example 8 of patent application WO 96/40067 is available. This powder is suspended in 20 mM Tris / HCl buffer, 150 mM NaCl at Ph 6.8 under nitrogen at 4 ° C., maintaining stirring for 48 h. One then obtains a suspension at 2 g / l of DC-chol. By mixing volume to volume these 2 suspensions, a vaccine composition according to the invention is obtained which is distributed in doses of 0.5 ml each comprising 1 ⁇ g of antigen against hepatitis B and 0.5 mg of DC- chol.
• a new immunization composition is prepared from suspension A to which an adjuvant C of the prior art is added in order to obtain, per 0.5 ml dose, a quantity of antigen of 1 ⁇ g and a quantity of adjuvant 0.5mg.
• the nature and the dose of the adjuvant of the prior art were selected during comparative immunization tests against hepatitis B of BALB / C mice, by subcutaneous route.
• the adjuvant selected is that which, during these tests has shown a strong capacity to increase the humoral response to the antigen considered, the results obtained with this adjuvant being clearly superior to those obtained with aluminum hydroxide or with DC-chol.
• mice Each group of mice is immunized with a different vaccine composition:
• a second group is immunized with doses of 0.5 ml each comprising the hepatitis B antigen and aluminum hydroxide.
• a third group is immunized with doses of 0.5 ml each comprising the hepatitis B antigen and an adjuvant of the prior art.
• a fourth group is immunized with doses of 0.5 ml of the vaccine composition according to the invention.
• the immunization of the mice is carried out subcutaneously, one to two hours after the preparation of the immunizing compositions.
• blood is taken for dosing, and a second injection is carried out under the same conditions as the first.
• a second blood sample is taken three weeks after the second injection. All blood samples are coagulated, centrifuged; the collected serum is stored at -20 ° C until titration which is carried out by an ELISA technique.
• Non-Responders in the group of mice having received the vaccine composition according to the invention while the use of the adjuvant of the prior art, yet capable of greatly increasing the immune response of mice already "Responders”, does not does not allow, even after the booster injection, to make all subjects "Responders”.
• the immunization protocol is the same as that of Example 2.
• results obtained show the effectiveness of the subject of the invention which makes it possible to increase the rate of seroconversion and therefore to reduce the number of "non-responder" subjects during immunization against a highly purified antigen.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Virology (AREA)
• Immunology (AREA)
• Veterinary Medicine (AREA)
• Pharmacology & Pharmacy (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Mycology (AREA)
• Microbiology (AREA)
• Epidemiology (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Communicable Diseases (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Oncology (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Applications Claiming Priority (3)

Publications (1)

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• 1998
  • 1998-07-03 FR FR9808700A patent/FR2781160B1/fr not_active Expired - Lifetime
• 1999
  • 1999-07-02 EP EP99929389A patent/EP1093382A2/de not_active Withdrawn
  • 1999-07-02 US US09/720,863 patent/US6472159B1/en not_active Expired - Lifetime
  • 1999-07-02 CA CA 2337048 patent/CA2337048A1/en not_active Abandoned
  • 1999-07-02 AU AU46217/99A patent/AU4621799A/en not_active Abandoned
  • 1999-07-02 WO PCT/FR1999/001604 patent/WO2000001345A2/fr not_active Ceased

Non-Patent Citations (1)

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