WO2000000217A1 - Mucosal targeting immunisation - Google Patents
Mucosal targeting immunisation Download PDFInfo
- Publication number
- WO2000000217A1 WO2000000217A1 PCT/FR1999/001539 FR9901539W WO0000217A1 WO 2000000217 A1 WO2000000217 A1 WO 2000000217A1 FR 9901539 W FR9901539 W FR 9901539W WO 0000217 A1 WO0000217 A1 WO 0000217A1
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- WIPO (PCT)
- Prior art keywords
- iga
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- use according
- mucosa
- immunogenic composition
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
-
- 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
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
-
- 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
-
- 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
- C12N2740/00—Reverse transcribing RNA viruses
- C12N2740/00011—Details
- C12N2740/10011—Retroviridae
- C12N2740/16011—Human Immunodeficiency Virus, HIV
- C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
- C12N2740/16122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
Definitions
- the present invention relates to an immunization method for inducing a local immune response, in particular in the rectogenitourinary mucous region. It also relates to the use of immunogens for the production of vaccine compositions intended to be administered according to said method.
- the main route of transmission of the AIDS virus is through the mucous membranes, in particular the genital and rectal mucosa, or even the oral mucosa. From these mucous membranes, the virus quickly spreads to the draining nodes, before joining the peripheral blood.
- the targeting of local mucosal-type immunity can be demonstrated by the presence of specific antibodies contained in the mucous membranes or secretions (Thibodeau L. et al., Aids Research and Human Retrovirus, 1379, 1992; Russel MW et al. , Reviews of infectious diseases, 5440-5446, 1988).
- Gaffar A. et al. (US3931398) teach that an injection of a vaccine into the oral cavity would induce local immunity. No antibody measurements are reported. It therefore seems that the proximity of the injection site to the place of targeting of local immunity is essential, as also reported by Letchworth G.J. et al. above.
- the present invention aims at the use of specific immunogen of a pathogenic agent having an entry point at the level of a mucosa for the production of an immunogenic composition intended for administration to humans parenterally on the surface of a separate part of the body remote from said mucosa, so as to directly develop a local response in IgA, IgG and / or IgM antibodies and in B cells secreting said antibodies at the level of said mucosa and of the ganglia which drains it.
- a particular objective of the invention relates to the targeting of the rectal, genital and / or urinary mucosa by parenteral administration in the thigh. Faced with this observation, we can now search for multiple sites injections distinct from the mucous membranes which will directly allow the induction of a local response in these mucous membranes, in particular in antibodies and in B cells secreting antibodies found in the mucous membranes and the ganglia which drain them.
- Another particular objective of the invention is to provide such an immunization route for developing local immunity against the AIDS virus (HIV).
- HIV AIDS virus
- Another objective of the invention is to simultaneously induce systemic immunity, in particular humoral and / or cellular, detectable in the peripheral blood.
- the present invention thus relates to the development of a local response, in particular at the level of the recto-genito-urinary mucosa and of the ganglia which drain it by parenteral injection of an immunogenic composition into a part of the body distinct from the mucosa, such as the thigh.
- Parenteral administration in the thigh and in the surrounding upper regions, in particular the groin makes it possible to target the iliac and inguinal nodes.
- the intramuscular route is preferred in one or both of the lower limbs, particularly in the quadriceps, particularly in the anterior rectus muscle.
- Such an immunization pathway proves capable of locally inducing at the level of this mucosa on the one hand the production of immunoglobulins in the secretions and, on the other hand regionally, at the level of the ganglia draining this mucosa, the production of antibody secreting B cells, while inducing systemic immunity.
- This immunity is capable of inducing protection against the entry and spread of the pathogen considered from this recto-genito-urinary mucous region.
- the invention applies both to the field of prophylaxis (e.g. vaccines) and to the field of active immunotherapy.
- immunogenic composition therefore covers compositions for prophylactic purposes, in particular vaccines, and compositions for curative purposes in which the immunogen is of antigen type.
- a first particular object of the invention is therefore the use of an immunogen specific for a pathogenic agent having an entry point at the level of the recto-genito-urinary mucous region, for the production of an immunogenic composition.
- intended to be administered to man parenterally in the thigh preferably intramuscularly, especially in the quadriceps, in particular in the anterior rectus muscle (parenteral administration in a thigh muscle will preferably be in the muscle of each right and left lower limb), so as to develop a local response in IgA antibody, or even also in IgG and / or IgM antibody, and in B cells secreting IgG, IgM and / or IgA at the level of respectively on the one hand the recto-genitourinary mucous membranes and their secretions, and on the other hand the lymph nodes which drain this mucous membrane, in particular external and internal iliac nodes and inguinal nodes.
- Parenteral and in particular intramuscular injection into the thigh indeed appears
- the HIV virus Herpes viruses, eg Herpes simplex, in particular type 2, Candida, Chlamydia, Human papillomavirus, Genital Mycoplasmas, Treponema pallidum, Papovaviruses, eg Condyloma accuminatum and gonococcal infections.
- Herpes viruses eg Herpes simplex, in particular type 2
- Candida Chlamydia
- Human papillomavirus Genital Mycoplasmas
- Treponema pallidum eg Condyloma accuminatum and gonococcal infections.
- Papovaviruses eg Condyloma accuminatum and gonococcal infections.
- this mode of administration is not limited to inducing a local response, and can also make it possible to induce at the same time a systemic response, the two actions combining, and complementing, or even reinforcing, so particularly advantageous. Consequently, the use in accordance with the invention also aims to develop, in addition to a local response according to the invention, a systemic response of the IgG and / or IgM type, and optionally IgA (antibodies and secretory B cells).
- Another object of the invention is the method of immunization against pathogenic agents as described above, consisting in administering by any means known per se, the appropriate immunogenic composition by parenteral route, in particular intramuscular, in the thigh, one or both lower limbs, preferably quadriceps, particularly the anterior rectus muscle.
- the immunization method can use each of the characteristics, alone or in combination, stated here in the context of use.
- the invention applies to all types of immunogenic composition and in particular known vaccines, whether they are of the conventional type or of the recombinant type.
- the compositions e.g. vaccines of the conventional type group together the compositions, e.g. whole live attenuated or inactivated vaccines, the subunits (proteins or peptides). They can be adjuvanted or non-adjuvanted and be presented in combined form bringing together different valences and / or different immunogenic forms of the same valence.
- compositions eg recombinant vaccines group together the live vectors expressing one or more immunogens of the pathogen considered as well as the polynucleotide plasmid vectors made up of DNA which can for example be naked or included in a liposome (see eg WO-A-90 11092, WO-A-93 19813, WO-A-94 21797, WO-A-95 20660) and which express one or more immunogens.
- vectors such as the vaccinia virus and especially the avian poxviruses (canarypox, fowlpox, pigeonpox, etc.), such as those described in Tartaglia et al. ., Virol. 1992, 188: 217, as well as adenoviruses.
- poxviruses such as the vaccinia virus and especially the avian poxviruses (canarypox, fowlpox, pigeonpox, etc.), such as those described in Tartaglia et al. ., Virol. 1992, 188: 217, as well as adenoviruses.
- compositions eg vaccines
- the invention cannot be limited to a particular type of composition, eg vaccines, but is intended to apply to all types of immunogenic compositions, eg vaccines, and to all the compositions, eg vaccines, available which can be used parenterally, in particular intramuscularly.
- the immunization protocol will depend on the type of composition or the composition used. It will include the number of administrations usually used for a given composition which, in general, will correspond to more than 1 administration, in particular from 2 to 4.
- anyone skilled in the art is in any case perfectly capable of routine to determine the optimum number of administrations (eg primary vaccination and booster). It should be noted, however, that injection into a site separate from the mucous membranes can alone target a local response, without the need for a reminder in the mucous membranes.
- This targeted immunization may also be associated with conventional systemic immunization with the same composition or another composition against the same pathogen.
- an immunization protocol targeting the oral mucosa comprising the administration of an immunogenic composition against the same pathogen, identical or different, in particular of the same composition, aimed at inducing a local IgG response.
- a sublingual injection is an appropriate means, other routes of administration in the oral cavity remaining possible.
- Such a combination is particularly useful for preventing or treating infection by a pathogen having both the oral and recto-genitourinary entry points. Mention may in particular be made of the HIV virus, Herpesvirus, etc.
- the invention also relates to the use of an immunogenic composition intended to be administered to a host parenterally in the thigh, in particular intramuscularly in the thigh, preferably in the quadriceps, in particular in the anterior rectus muscle, and on the other hand the use of another immunogenic composition, identical or different from the previous one, intended to be administered to the same host by sublingual injection in the floor of the mouth.
- the use and the immunization method in accordance with the invention find a preferred application in the context of vaccination against the HIV virus.
- a particular example is the use of a vaccine combining a vector expressing gp120 / gp160 of HIV and of the gp120 / gp160 glycoprotein subunit of this same virus.
- a particular example is described below.
- this anti-HIV vaccine for its administration by intramuscular route in the thigh, possibly combined with conventional sublingual and / or systemic administration, e.g. by intramuscular injection in the deltoid.
- the subject of the invention is also an immunogenic composition
- an immunogenic composition comprising at least one immunogen specific for a pathogen having an entry point at the level of the recto-genitourinary mucous region and a pharmaceutically acceptable vehicle or excipient, this vehicle or excipient, or this composition, leading, in conjunction with the immunogen, to a local response in IgG, IgM and / or IgA antibodies and in B cells secreting IgG, IgM and / or IgA in this mucous region, when the composition is administered parenterally to the thigh, in particular intramuscularly.
- the characteristics set out here with regard to the other objects of the invention can be used alone or in combination.
- vCP205 is an ALVAC canarypox virus whose construction is described in Example 14 of WO-A-95 27507 to which a person skilled in the art may refer. It is capable of expressing the env, gag and pro genes of the HIV-1 virus. These genes are inserted into the C3 locus and are regulated by the H6 and I3L promoters of the vaccinia virus.
- These cassettes were inserted into the C3 locus, between the flanking sequences of ALVAC, in a 5'-5 'configuration, and linked to the H6 and I3L promoters.
- VCP205 was produced on fibroblasts from chicken embryos in DMEM-Ham F12 medium without serum, added with lactoglutamate and clarified by centrifugation.
- the mean titer was 10 8.0 TCID 5 o ml on QT35 cells.
- the vaccine solutions are prepared by dilution in PBS ("phosphate buffer saline") with Ca ++ and Mg ++ .
- the subunit produced is a hybrid gp160 subunit obtained from a pox vector.
- a WTG9150 vaccine vector is used to produce gp160.
- This vector codes for a soluble hybrid gp160 in which the gp120 part is derived from the HIV-1 MN strain and the gp41 part comes from the LAI isolate.
- the corresponding DNA sequences were fused using an SmaI artificial restriction site not modifying either of the two amino acid sequences of gp120 and gp41. The construction is briefly described below.
- sequence coding for gp120 MN was amplified from SupT1 cells infected with HIV-MN, by PCR technique with oligonucleotides introducing a SphI restriction site and a SmaI site respectively immediately downstream of the sequence coding for the leader peptide and upstream of the cleavage sites located between gp120 and gp41.
- the sequence coding for gp41 was thus produced: the complete coding sequence for env HIV-1 LAI was placed under the control of the vaccinia virus promoter PH5R.
- a SphI restriction site was created immediately downstream of the sequence coding for the leader peptide, without altering the amino acid sequence.
- a SmaI restriction site was also created immediately upstream of the sequence coding for the cleavage sites between gp120 and gp41, without altering the amino acid sequence.
- the two cleavage sites in position 507-516 (amino acid numbering according to Myers et al. In: Human retroviruses and AIDS (1994) Los Alamos National Lab. (USA)) were mutated (original sequence: KRR ...
- WTG9150 was then constructed by conventional homologous recombination and propagated to ensure the expression of gp160 according to the method usually used for vCP205 on BHK21 cells. Gp160 was then purified by immunoaffinity chromatography.
- One of the two monkeys received an additional injection of the same mixture (vCP205 + gp160 MN / LAI-2) in the floor of the mouth as well as the upper right thigh, three months after the last injection.
- Lymphocytes from peripheral blood and certain lymph nodes were analyzed in ELISPOT for the detection of B cells producing IgA and IgG antibodies specific for gp160 and CPpp.
- the vaccine is a mixture containing 10 6.3 DICC50 of vCP205 and 100 ⁇ g of gp160 subunit.
- An ALVAC vector comprising no HIV sequence was also used as a control.
- Group 1 4 monkeys (rhesus macaques) received 4 times, at 1 month in the interval, an injection of the vaccine mixture sublingually into the floor of the mouth; mixture at equal volume of vCP205 at 10 6 ' 9 DICC 50 / ml and gp160 at 400 ⁇ g / ml; 0.25 ml on the right and 0.25 ml on the left.
- - Group 2 4 monkeys (rhesus macaques) received 4 times, 1 month apart, an injection of the vaccine mixture intramuscularly into the thigh (perpendicular to, and into the anterior rectus muscle); mixture at equal volume from vCP205 to 10 6 ' 6 DICC 50 / ml and from gp160 to 200 ⁇ g / ml; 0.5 ml on the right and 0.5 ml on the left.
- controls 3 monkeys (rhesus macaques) received 4 times, 1 month apart, an injection of the ALVAC vector intramuscularly into the thigh; ALVAC (CPpp) at 10 6 ' 3 DICC 50 / ml; 0.5 ml on the right and 0.5 ml on the left.
- the right and left lymph nodes of each category were removed after sacrifice of the animal, crushed (the right and left submandibular lymph nodes were pooled), then subjected to the analysis of antibody-producing cells by the ELISPOT technique (adapted from Erikson K. et al., Journal of Immunological methods, 153: 107-113, 1992).
- the vaccine consists of two products injected separately, first of all vCP20) 55 to 1100 6655 DDIICCC50, then of the gp160 MN / LAI subunit at 50 ⁇ g adjuvanted by a conventional adjuvant
- the number of B lymphocytes secreting IgG and IgA specific for gp160 was measured for 10 6 mononuclear cells, in each sample (lymph nodes and blood) of the two macaques. The mean and standard deviation of triplicate counts for each sample are shown.
- the right and left nodes of each category (submaxillary, axillary, inguinal, internal iliac, external iliac) were removed after sacrifice of the animal, crushed, the right and left lymph nodes of each category were pooled, then subjected to the analysis of antibody-producing cells by the ELISPOT technique (adapted from Eriksson K. et al., Journal of Immunological Methods, 153: 107-113, 1992).
- the anti-gp160 antibodies IgA and IgG antibodies were also assayed by the ELISA technique in the serum and mucous secretions (urine, vaginal and rectal washings) of the two macaques.
- the samples were taken before the two late boosters (S99), then after immunization just before the animal was sacrificed (S104 or S105).
- the results are expressed, for each secretion, as the ratio of the specific anti-gp160 IgA or IgG activity measured at the time of sacrifice. compared to that evaluated before the two late recalls (S99).
- a secretion was considered to be significantly positive in specific IgA or IgG if this ratio was greater than 3 (the specific activity of a secretion corresponds to the specific IgA or IgG titer (here of gp160) divided by the titer in IgA or total IgG).
- IgA has also been detected in some urinary, vaginal and rectal secretions.
- Vaccines against Herpes simplex, Candida, Chiamydia, Human Papillomavirus, Genital Mycoplasma or Treponema pallidum have been injected into the thigh muscles in order to stimulate and target a local IgA antibody response at least in rectal, genital and / or urinary mucosa.
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Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
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AU43754/99A AU751970B2 (en) | 1998-06-26 | 1999-06-25 | Mucosal targeting immunisation |
EP99926545A EP1089758A1 (en) | 1998-06-26 | 1999-06-25 | Mucosal targeting immunisation |
CA002335506A CA2335506A1 (en) | 1998-06-26 | 1999-06-25 | Mucosal targeting immunisation |
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FR9808353 | 1998-06-26 | ||
FR98/08353 | 1998-06-26 |
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WO2000000217A1 true WO2000000217A1 (en) | 2000-01-06 |
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PCT/FR1999/001539 WO2000000217A1 (en) | 1998-06-26 | 1999-06-25 | Mucosal targeting immunisation |
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EP (1) | EP1089758A1 (en) |
AU (1) | AU751970B2 (en) |
CA (1) | CA2335506A1 (en) |
WO (1) | WO2000000217A1 (en) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3931398A (en) * | 1973-06-20 | 1976-01-06 | Colgate-Palmolive Company | Method for local immunization against dental caries |
US4368191A (en) * | 1978-06-07 | 1983-01-11 | Sarkisov Arutjun K | Vaccine and method prophylaxis and treatment of trichophytosis caused by pathogenic organism trichophyton mentagrophtyes and method for preparing same |
US5462734A (en) * | 1990-11-02 | 1995-10-31 | Wisconsin Alumni Research Foundation | Bovine herpesvirus vaccine and method of using same |
FR2751879A1 (en) * | 1996-07-30 | 1998-02-06 | Transgene Sa | PHARMACEUTICAL COMPOSITION AGAINST TUMORS AND PAPILLOMAVIRUS INFECTIONS |
-
1999
- 1999-06-25 AU AU43754/99A patent/AU751970B2/en not_active Ceased
- 1999-06-25 CA CA002335506A patent/CA2335506A1/en not_active Abandoned
- 1999-06-25 EP EP99926545A patent/EP1089758A1/en not_active Withdrawn
- 1999-06-25 WO PCT/FR1999/001539 patent/WO2000000217A1/en not_active Application Discontinuation
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3931398A (en) * | 1973-06-20 | 1976-01-06 | Colgate-Palmolive Company | Method for local immunization against dental caries |
US4368191A (en) * | 1978-06-07 | 1983-01-11 | Sarkisov Arutjun K | Vaccine and method prophylaxis and treatment of trichophytosis caused by pathogenic organism trichophyton mentagrophtyes and method for preparing same |
US5462734A (en) * | 1990-11-02 | 1995-10-31 | Wisconsin Alumni Research Foundation | Bovine herpesvirus vaccine and method of using same |
FR2751879A1 (en) * | 1996-07-30 | 1998-02-06 | Transgene Sa | PHARMACEUTICAL COMPOSITION AGAINST TUMORS AND PAPILLOMAVIRUS INFECTIONS |
Non-Patent Citations (7)
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AU751970B2 (en) | 2002-09-05 |
CA2335506A1 (en) | 2000-01-06 |
AU4375499A (en) | 2000-01-17 |
EP1089758A1 (en) | 2001-04-11 |
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