Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/02—Bacterial antigens
  • A61K39/105—Delta proteobacteriales, e.g. Lawsonia; Epsilon proteobacteriales, e.g. campylobacter, helicobacter
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/12—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
  • A61K39/21—Retroviridae, e.g. equine infectious anemia virus
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/40—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against enzymes
• • 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

Definitions

• the present invention relates to the use of a vaccine adjuvant for the preparation of a vaccine for the administration of neonatal mammals, as well as to a method of immunizing newborns.
• the invention relates to the use of
• Vaccine development is always difficult, but it is particularly complicated when it comes to vaccines for newborns; Indeed, we noticed that when we proceeded to immunization during the 1st months of life, one obtained a smaller amount of antibody that when immunization was performed later; furthermore, the antibodies obtained were generally of shorter duration than when the immunization took place later.
• T-cell responses obtained at an early stage of life although being rapidly maturing responses, are both qualitatively and quantitatively different from those that are induced at an early stage. later life.
• newborns would need to be armed very early to be able to fight against a number of pathogens, to which they are likely to be exposed at a very young age, in particular the Human Immunodeficiency Virus, the Respiratory Syncytial Virus, the malaria agent Heicobacter pyori, Haemophilus influenza type B, the polio virus, the hepatitis B virus, the agents of whooping cough, tetanus, diphtheria, meningitis, pneumonia.
• the Human Immunodeficiency Virus the Respiratory Syncytial Virus
• the malaria agent Heicobacter pyori Haemophilus influenza type B
• the polio virus the hepatitis B virus
• the agents of whooping cough tetanus, diphtheria, meningitis, pneumonia.
• the present invention relates to the use of DCchol for the preparation of a vaccine composition for administration to newborns.
• the vaccine composition comprises at least one antigen against infections caused by Heicobacter pyori.
• the vaccine composition comprises at least the TAT antigen of the AIDS virus.
• the subject of the invention is also a method of immunizing neonates according to which neonates are administered at least one vaccine antigen, in which the Further improvement is to also administer at least one adjuvant comprising DCchol.
• newborns are defined as children up to one month old at the time of the first injection.
• an animal model has been developed. Indeed, although it is difficult to formally compare the immune maturation from one species to another, many experiments have nevertheless validated the hypothesis that whatever the species, the immune maturation always follows the same stages, the difference between the different species residing in the kinetics of passage from one stage to another.
• the vaccine formulations according to the present invention although intended essentially for administration to human neonates, have been developed on the basis of tests carried out on young mice, the stages of immune maturation from mouse to mouse adult having been demonstrated to be essentially the same as the stages of immune maturation from the human infant to the adult male. In this model, one-month-old human infants are represented by one-week-old mice.
• the immune response is meant obtaining in the newborn an immune response approximating that obtained in adults; it may especially be an antibody or T-cell response which would be quantitatively increased compared with that generally obtained with the vaccines of the prior art, or else a qualitative modification of the response obtained; the qualitative characteristics of the immune responses which can be expressed by the nature of the antibodies produced, as well as by the nature and the quantity of the cytokines induced, which makes it possible in particular to determine the Th1 or Th2 orientation of the response.
• the humoral response that is to say the immunoglobulins produced, considering that IgG2a reflect an orientation of the answer in the sense that the ThI 5 and IgG indicate a direction the answer to the type Th2.
• interferon ⁇ is a Indicator of an orientation ThI
• Interleukins 4 and 5 are indicators of an orientation Tn2.
• DCchol within the meaning of the present invention is meant 3 ⁇ -pST- (TSf ', N'-dimethylaminoethane) carbamoyl] cholesterol, which can be obtained from cholesteryl chloroformate and N, N-dimethylethylenediamine, according to the method described in USP 5,283,185 or according to the method described in Example 8 of USP Patent 5,753,262.
• the salt form of DCchol in particular chloride, is used.
• vaccine composition is meant a composition comprising at least one vaccine antigen of interest for the immunization of newborns. It may be a monovalent vaccine composition, that is to say comprising a single type of antigen, or a combination vaccine comprising several antigens for simultaneously immunizing against one or more diseases.
• Antigens susceptible to be adjuvanted by the present invention may be of various nature; they may be proteins, peptides, oligo- or polysaccharides (conjugated or otherwise), viruses or portions of viruses, etc., more generally any antigen of interest to be introduced into a vaccine composition. pediatric.
• the present invention does not relate to the use of DCchol for adjuvanting vaccine compositions which, instead of including the antigens themselves, would include antigens in the form of their "precursor" which is DNA.
• the present invention is of particular interest in the case of certain diseases likely to affect a newborn from the first moments of his life; it is for example AIDS, malaria, ...
• the vaccine composition may be administered by any of the routes customarily used for the administration of vaccines, and in particular by the subcutaneous, intramuscular, transcutaneous and intradermal routes.
• the administration schedule is advantageously a scheme providing for at least 2 successive administrations: an era the administration followed by a booster after some time, the era the administration being carried out in the 1st month of life.
• the vaccine composition prepared according to the invention exhibits increased immunogenicity without, however, experiencing increased reactogenicity.
• the reactogenicity can be appreciated in different ways; in the mouse, the following observations are made: - local reactogenicity: at the injection site verification of the presence or absence of an inflammatory granuloma with or without a scar preventing hair growth, - systemic reactogenicity: weekly weighing to check if the weight gain is normal or not.
• the vaccine compositions according to the invention may also comprise all the elements sometimes present in the compositions according to the prior art, such as preservatives, stabilizers or others.
• Vaccine composition comprising the TAT protein.
• Vaccine compositions comprising as antigen a detoxified TAT III B protein are prepared.
• This detoxified protein and its method of preparation are described in detail in the application WO99 / 33346 where it is identified by the term carboxymethyl TAT.
• This recombinant TAT antigen is present in solution at 2 g / l.
• the vaccine compositions are prepared either with an adjuvant according to the prior art, that is to say aluminum oxyhydroxide or a squalene-based emulsion, or according to the invention with DCchol; in addition, in order to be able to demonstrate the adjuvant power of the various products tested, a composition comprising only the antigen in saline solution is also prepared.
• the composition comprising aluminum oxyhydroxide is prepared from a suspension of 8 g / l, supplied by Superfos Biosector.
• the emulsion is prepared by mixing with Trulaturrax for a few seconds 0.18 g of Tween TM 80 (supplied by Merck) 0.16 g of sorbitan trioleate (supplied by Seppic under the name Montane VG TM 85) and 1.29 g of g squalene (supplied by the company Fluka) in sufficient water for 30 ml.
• the liposomal composition of DCchol is prepared by dispersing 1.3 g of
• Anotop TM (Whatmann) with a porosity of 0.2 ⁇ m.
• compositions prepared is diluted in a saline solution which finally contains 50 mmol / l of Tris (hydroxymethyl) aminomethane and 100 mmol / l of sodium chloride, the pH being adjusted to 7.4.
• Vaccine doses having the following composition are then obtained:
• mice and 1-week old "newborn" mice are available in groups of 6 to 8 (groups of mice) or 5 to 6 (groups of adult mice). Experiments were performed with 2 subcutaneous injections of the same vaccine formulation at OJ and D21. Blood samples are taken after the booster injection. The immunoglobulins specific for TAT are assayed by ELISA technique. A total of 10 to 40 mice per formulation was tested in several independent experiments: for DC-Chol: 27 adults, 38 neonates, for aluminum oxyhydroxide: 18 adults, 22 neonates; for the emulsion: 10 adults and 16 neonates and in saline: 10 adults and 15 neonates. The results obtained are shown in FIG. 1 which indicates, for each of the formulations tested, the total amount of IgG antibody expressed in 10 g of arbitrary ELISA titers.
• Vaccine compositions having as antigen the recombinant urease of Heilobacter pylori are prepared.
• This urease has already been described as a potential candidate for the manufacture of a vaccine against stomach ulcers induced by the bacteria Heicobacter pylori.
• a process for its preparation is described in the following publication: Journal of
• the vaccinating compositions are prepared in the same manner as described in the preceding example, except to replace at the time of final mixing, the suspension comprising the Tat antigen, with a suspension comprising urease.
• Vaccine doses of 50 ⁇ l are obtained, each time comprising 10 ⁇ g of urease and either 200 ⁇ g of DCchol or 200 ⁇ g of AlOOH.
• mice Male Balb / c mice and 1 week old mice are available, divided into groups of
• mice 5-8 (groups of adult mice, or groups of suckling mice).
• Blood sampling is carried out after the injection ere, after 1 reminder and possibly after the 2 nd point (in the case of Experiments 3 and 4).
• the immunoglobulins specific for urease are assayed by ELISA technique.
• mice injected before the era can not be achieved without sacrificing the animals.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
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• General Health & Medical Sciences (AREA)
• Immunology (AREA)
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• Chemical Kinetics & Catalysis (AREA)
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• Engineering & Computer Science (AREA)
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• Biophysics (AREA)
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• Molecular Biology (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
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• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

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• 2005
  • 2005-01-25 FR FR0500743A patent/FR2881050B1/fr not_active Expired - Fee Related
• 2006
  • 2006-01-17 CA CA002593115A patent/CA2593115A1/en not_active Abandoned
  • 2006-01-17 EP EP06709107A patent/EP1843786A2/de not_active Withdrawn
  • 2006-01-17 WO PCT/FR2006/000100 patent/WO2006079701A2/fr not_active Ceased

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