WO1993018791A1 - Vaccin de prevention des maladies dues a l'infection par vih et son procede de production - Google Patents

Vaccin de prevention des maladies dues a l'infection par vih et son procede de production Download PDF

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Publication number
WO1993018791A1
WO1993018791A1 PCT/JP1993/000327 JP9300327W WO9318791A1 WO 1993018791 A1 WO1993018791 A1 WO 1993018791A1 JP 9300327 W JP9300327 W JP 9300327W WO 9318791 A1 WO9318791 A1 WO 9318791A1
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Prior art keywords
peptide
vaccine
peptides
protein
hiv
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PCT/JP1993/000327
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English (en)
Japanese (ja)
Inventor
Kenji Okuda
Original Assignee
Inmel Co., Ltd.
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
Application filed by Inmel Co., Ltd. filed Critical Inmel Co., Ltd.
Publication of WO1993018791A1 publication Critical patent/WO1993018791A1/fr

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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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • 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
    • C12N2740/16211—Human Immunodeficiency Virus, HIV concerning HIV gagpol
    • C12N2740/16222—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Definitions

  • the present invention relates to a vaccine for preventing human immunodeficiency virus (Human Immunodeficiency Virus, hereinafter referred to as "HIV”) infection, and more particularly to a vaccine for preventing HIV infection comprising a plurality of peptides as immunogens.
  • HIV Human Immunodeficiency virus
  • An object of the present invention is to provide a vaccine for preventing HIV infection which has high safety and high preventive and therapeutic effects.
  • the present inventor has conducted intensive studies and found that, unlike vaccines using synthetic peptides of As a vaccine license, a plurality of peptides containing at least a peptide corresponding to a specific region of the HIV envelope (env) protein gp120 and an invariant site of gp120 or the internal structure protein gag ⁇ tide are used as vaccine licenses. It is possible to efficiently produce antibodies without the need for ⁇ ⁇ ! Genetic manipulation, and it is highly safe, and the antibodies can affect each other. It has been found that it is extremely effective as an infectious disease preventive vaccine.
  • the vaccine for the prevention of HIV infection of the present invention is based on the above findings, and more specifically, the V3 region of the HIV (human immunodeficiency virus) envelope gp120 peptide (amino acid position 30 in the envelope protein). 3-322) and a plurality of peptides consisting of the constant site peptide of gpl20 or the constant site peptide of the internal structural protein gag.
  • the V3 region peptide of the HIV envelope gp120 (amino acid positions 303 to 322 in the envelope protein) and the constant site of gpl20 ⁇ the constant site of the peptide or the internal structural protein gag ⁇
  • the present invention provides a vaccine for preventing HIV infection, which comprises a complex comprising a peptide consisting of a peptide and a carrier protein.
  • the V3 region peptide of the HIV envelope gp120 (amino acid positions 303 to 322 in the envelope protein) and the invariant site of gpl20 peptide or the invariant site of the internal
  • a method for the manufacture of a vaccine to prevent HIV infection which includes a step of mixing an adjuvant with a peptide containing a peptide that can be withdrawn11.
  • the V3 region peptide of HIV envelope gp120 (amino acid positions 303 to 322 in the envelope protein) and the constant site peptide of gpl20 or the constant site peptide of internal structural protein gag
  • the present invention provides a method for producing a vaccine for preventing HIV infection, which comprises the step of binding a peptide consisting of the following to a carrier protein.
  • a vaccine for preventing HIV infection of the present invention will be described in detail with reference to the drawings as necessary.
  • amino acid sequence in the present specification, the sequence is described from (left) to C-terminal (right) (for example, in the following amino acid sequence (1), Asn is the N-terminal, Cys is the C-terminal).
  • the “V3 region peptide” corresponds to (all or part of) the sequence of amino acid positions 303 to 322 of the glycoprotein gp120 having a molecular weight of 120,000 that constitutes the envelope protein (env) of HIV. Refers to a peptide (the amino acid number may be different depending on various strains).
  • the amino acid number may be different depending on various strains.
  • Rusche et al. Proc. Nat. Acad. Sci. USA, 85, 3198-320. 2 (1988)).
  • a peptide (24 amino acids) having the following amino acid sequence is preferably used.
  • V3 region peptides (1) to (6) as described above can be used alone as V3 region peptides.
  • a plurality of types of V3 region peptides are mixed. It is preferable to use it because it is effective against a number of mutations in HIV and enhances the preventive effect against multiple types of HIV (and corresponds to a high degree of HIV isomerism).
  • Such preferred combinations include, for example, the following two or three combinations.
  • each peptide having the largest number of moles among them is 1, the mole of the peptide having the smallest number of moles is used.
  • the number is preferably l / 3tU :, more preferably 1/2 or more (particularly 4/5 or more).
  • the “invariant site peptide” includes a peptide (Ho or a part thereof) corresponding to the sequence of amino acid positions 252 to 274 of gp120 constituting the envelope protein (env) of HIV ( ⁇ or part thereof). Et al., Science, J, 1021-1023, 1985); and a constant site peptide having a sequence similar to a part of a protein (pi 7) having a molecular weight of 17,000 that constitutes the internal structural protein gag of Z or HIV ( (About 30 amino acids) (Achour et al., Proc. Nat. Acad. Sci., USA, 87, 7045-704, 1990).
  • a peptide having a sequence similar to pi 7 of gag a peptide having a structure represented by the following formula (7) (a peptide similar to HGP-30) is preferably used.
  • the constant site corresponding to the sequence of gp120 is more specific. Specifically, for example, a peptide having an amino acid sequence as shown below (number of amino acids 2
  • helper T cell activation site peptide constitutes the envelope protein (env) of HIV.
  • a peptide corresponding to! 1 ( ⁇ or part of) amino acid positions 430 to 445 of gpl20 (Cease et al., Proc. Nat. Acad. Sci, USA, 84, 424-4253, 1987). More specifically, for example, in the present invention, a peptide having an amino acid sequence as shown below (15 to 16 ms of amino acids) is preferably used.
  • cysteine (Cys) in parentheses is a melamine that is suitable for binding to a peptide or carrier (carrier) protein having a relatively low cysteine content other than KLH or HSA. Is shown.
  • the above-mentioned various peptides may be obtained from the HIV virus itself, but from the viewpoint of safety and safety, it is preferable to use a synthesis method (particularly, a synthesis method using automatic peptide synthesis).
  • the above-mentioned plural kinds of peptides are usually It can also be used as a vaccine (usually with adjuvant) without using this carrier protein (see J. Immunol., ⁇ 8_, 914-920 (1992)).
  • the carrier protein used for binding to the habutene can be used without any particular limitation.
  • proteins containing a cysteine group are particularly preferably used.
  • Such a cysteine-containing protein is preferably a protein containing 10 or more, preferably 20 or more (more preferably 30 or more) cysteine groups in one molecule (on average).
  • the molecular weight of such a protein is preferably about 100,000 to 500,000 (more preferably, about 300,000 to 400,000).
  • albumin such as human serum albumin (HSA), horseshoe hemocyanin (KLH; molecular weight of about 360 ⁇ ), and the like are preferably used.
  • the method for preparing the complex by binding the carrier protein to a plurality of peptides is not particularly limited, but the binding can be carried out using a suitable acylating agent such as N-hydroxysuccinimide ester. It is.
  • a suitable acylating agent such as N-hydroxysuccinimide ester.
  • an N-hydroxysuccinimide ester such as m-maleimidobenzoyl N-hydroxysuccinimide ester (MBS) is preferably used as the acylating agent.
  • the carrier protein for example, KLH or HSA.
  • the plurality of peptides may be preliminarily mixed and then bound to the carrier protein, or each of the peptides may be bound after binding the carrier protein.
  • One carrier protein complex may be mixed, Further, these two methods may be used in an appropriate combination.
  • the present invention comprises a multifaceted peptide comprising at least the gp120 and / or gag invariant site peptide and at least a V3 region peptide (if necessary, a carrier protein).
  • the molar ratio of the V3 region peptide to the invariant site peptide is 1: 3 to 3: l®g, and even 2: 1
  • the mole number is the same as the mole number of the smallest mole peptide. It is preferable that the peptide having a large amount is 3 mol or less, more preferably 2 mol or less (especially 1.1 to 1.0 mol ⁇ S).
  • the vaccine of the present invention containing the above-mentioned plural kinds of peptides (and, if necessary, a carrier protein) is usually used together with an appropriate adjuvant.
  • adjuvant used with the vaccine of the present invention known ones can be used without particular limitation.
  • adjuvants include aluminum (aluminum sulphide or aluminum adjuvant), Iscom (ISCOM), MDP-PE (oil-containing muramyl tripeptide), and ribosome.
  • Iscom Iscom
  • MDP-PE oil-containing muramyl tripeptide
  • ribosome aluminum sulphide or aluminum adjuvant
  • an antibacterial agent in view of the regulation.
  • the adjuvant is preferably used in an amount of 1.5 to 5 times @g (more preferably 1.5 to 2 times mS.) Of the vaccine of the present invention.
  • the above-mentioned aram is preferably mixed at a rate of about 300 yag / ml.
  • the dose of the vaccine is preferably about 5 ⁇ g / kg per 1 kg of body weight.
  • the vaccine of the present invention As an immunization method using the vaccine of the present invention, it is preferable to administer the vaccine at least four times a day.
  • the interval between the administration days is not particularly limited, but it is preferable to administer the administration on, for example, 0 days, 30 days, 60 days, and 120 days.
  • the above dose is the first dose, and the dose after the second day may be reduced to about 1/3.
  • the vaccine of the present invention consisting of a complex of a plurality of peptides and a carrier protein is administered (with an adjuvant if necessary) at the first time
  • the vaccine of the present invention consisting of a plurality of secreted peptides is administered at the second and subsequent times.
  • the vaccine may be given (with an adjuvant if necessary).
  • Figure 1 is a copy of a photograph showing the results of western blotting of HIV «cells using ⁇ 3 ⁇ 4 & Qing.
  • the above three peptides were synthesized using an automatic peptide synthesizer (43 OA, manufactured by Applied Biosystems, USA). These three types of peptides were first used in a molar ratio of 10: 10: 10: 1 using MBS (m-maleimidobenzoyl-N-hydroxysuccinimidestere) and KLH (keyhole limpet hemocyanin) or HSA (human serum albumin). After conjugation with the product, purification was carried out using a Sephadex G25 column. The above individual peptides (1) to (3) are bound to KLH: ⁇ , the molar ratio was 30: 1.
  • the following peptides were used as gp120 constant site peptides for neutralizing antibody production.
  • the cysteine in the cocoon indicates a sequence synthesized when the cysteine is combined with another peptide or carrier carrier protein).
  • Equal amounts (equal weight) of the two components obtained above ie, the V3 peptide carrier conjugate and the invariant site peptide Z helper T cell-derived peptide-one carrier conjugate
  • the heron was immunized by administering 2 Ozg / kg of the carrier-conjugated vaccine, and the immunization was performed four times at one week intervals.
  • the measurement by the ELISA method was carried out by the method described in the report (AIDS,, 765-766 (1989) and AIDS, Mutual, 1140-1141 (1991)). That is, the peptide or that of the carrier-binding peptide was coated on a 96-well microplate. Here, a mixture of three peptides from different sites was used. Other antigens were used with each of the peptides. (The C 21 E peptide corresponds to the constant site of gp120, and the HGP-30 peptide corresponds to the protein at the central gag site of the virus).
  • HIV IIIB, III RF and IIIMN strains
  • CD4 + peripheral blood T cells (2X10 5 CELLz ⁇ E Le) along with the plate of 24-well 37, in the presence of Qingqing.
  • the cells were observed at C for 5 days, and the appearance of fused cells was observed.
  • Vn / Vo (number of cells fused in ⁇ ⁇ / ⁇ ) /
  • Neutmalizeing activity was determined by the number of reciprocal dilutions corresponding to the neutralizing activity. As a result, fusion inhibition of 70% or more was observed. At this time, the antibody ability was examined using the serum dilution number.
  • the inhibition of HIV replication by antisera was examined by another method, namely, the activity of inhibiting the ability to synthesize viral proteins. This examination was performed according to the method described in the literature (J. Virol, 6 ⁇ ., 2622-2628 (1988), Proc. Natl Acad. "Sic. USA, 88., 2249-2253 (1991)). .
  • the CEM cells were combined with the HIV-1 virus37. After incubating with C for 4 hours and washing well, the infected CEM drops were cultured in a medium containing a final mg of 2.5% serum. After 5 days incubation, the cell-free supernatant of the medium was collected and filtered through a 0.45 m filter. Virus concentration was determined using a commercially available p24 capture reagent (Coulter Co.).
  • IL-2 interleukin-12
  • peripheral blood lymphocytes were cultured in a 96-well microplate well with each of the final 2 ⁇ 10 lO zg / m 1 antigens.
  • Recombinant gp120 obtained from the virus ( ⁇ ⁇ ⁇ ) and the Ills virus gene (rgpl20, which was provided by San-Danisei Co., Ltd. of Yokohama) was used for heat-sterilized purified HIV-1. Represents the HIV envelope prepared by protein and fly)
  • HIV-infected Mo It-4 cells were solubilized with sodium dodecyl sulfate (SDS), and each solubilized sample was electrotransferred and transferred to nitrocellulose filter paper. Next, each filter paper was stained with a peroxynase-labeled anti-Peacock (or anti-human) IgG antibody.
  • SDS sodium dodecyl sulfate
  • Table 1 above shows the antibody titers of the vaccine immune sera obtained from the egrets against the respective synthetic peptides.
  • “KLH—mixed” indicates the multivalent actin of the present invention, and other licenses are KLH and its V3 region peptide (or C21E and HGP-30 peptide). This shows the conclusion. ⁇ " ⁇ " means not tested.
  • Peptides Mean reciprocal titer of antibody ( ⁇ ')
  • Table 2 above shows the antibody titers of JfiL purified from humans immunized with the vaccine. As shown in Table 2, a high antibody titer can be obtained with ELISA when immunized with the vaccine of the present invention.
  • Table 3 above shows the HIV neutralizing antibody titers using Pergum antiserum. ⁇
  • the sera obtained from the heron are the same as those shown in Table 1.
  • Table 4 above shows the HIV neutralizing antibody titers using human antisera. 3 ⁇ 43 ⁇ 4 & QI obtained from humans are the same as those shown in Table 2.
  • Virus growth inhibition was performed by detecting free ⁇ 24 protein in the culture supernatant. Also in this case, the results induced by the vaccine of the present invention (combination of multiple peptides) were observed (see Table 5 below).
  • IB # 5 shows the activity of inhibiting the production of HIV-1 p24 protein by rabbit heron serum. ⁇ Serum from herons is the same as in Table 1. "NTj stands for not tested.
  • Table 6 above shows the activity of HIV-1p24 protein production inhibition by human serum. Serum from humans is the same as in Table 2. “NT” means not tested.
  • the vaccine of the present invention It was found that the sera obtained by immunization had strong ability to suppress virus production. From the above results, it was found that the sera obtained by using the vaccine of the present invention certainly inhibited the growth of the virus.
  • Table 7 above shows the production of antigen-specific IL-12 by peripheral leukocytes from humans (individuals) who received the vaccine.
  • the values in the table are the average soil standard deviation (SD) of 4 to 6 samples.
  • FIG. 2 shows the results of Western blotting (copy of the photo).
  • FIG. 2 above shows Western blotting of HIV-infected cells using antiserum.
  • FIG. 2 shows the antibody produced in the egret, and the meaning of each lane is as follows.
  • FIG. 2 shows an antibody produced in humans, and the meaning of each sample (each lane) used here is the same as in (A) above.
  • the results of this western-producing show that the antibody against the gp120 constant site peptide bound to an antigen consisting of a molecule having a molecular weight of 120 K daltons. That is, it was confirmed that the antibody produced by the vaccine of the present invention reacts with the protein of HIV envelope.
  • H ⁇ As described above, according to the present invention, it is an effective vaccine not only for animals but also for humans. Since it does not use the HIV virus itself, it has high safety, high prevention efficiency, and humoral immunity. At the same time, a multivalent actin capable of activating cell-mediated immunity is produced.

Abstract

Vaccin pouvant faire face à une variation de l'antigénicité de divers VIH, et étant obtenu à partir de trois peptides bouclés V3, de deux peptides à région constante et d'un peptide auxiliaire activant l'immunité à médiation cellulaire, au moyen d'un procédé d'amélioration de l'immunogénicité. On peut préparer un vaccin en déterminant les peptides V3, par exemple, de la Thaïlande, du Japon et d'autres régions, au moyen du procédé d'amplification enzymatique du génome. L'emploi de ce vaccin permet à un anticorps dirigé contre la région V3, à un anticorps dirigé contre la région constante e^_n^_v^_, et à un anticorps dirigé contre la région g^_a^_g^_ de réguler la croissance du HIV dans une grande diversité d'aspects.
PCT/JP1993/000327 1992-03-26 1993-03-19 Vaccin de prevention des maladies dues a l'infection par vih et son procede de production WO1993018791A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
JP4/98602 1992-03-26
JP9860292 1992-03-26
JP4/237648 1992-08-14
JP23764892 1992-08-14
JP5/54239 1993-03-15
JP5054239A JPH0748276A (ja) 1992-03-26 1993-03-15 Ｈｉｖ感染症予防ワクチンおよびその製造法

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AU (1) AU3760593A (fr)
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4276106A3 (fr) * 2015-05-13 2024-01-24 The United States of America as represented by the Secretary of the Department of Health and Human Services Methodes et compositions pour eliciter des reponses immune a base des constructs contenant des elements conservatives

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63156729A (ja) * 1986-12-05 1988-06-29 エフ．ホフマン　―　ラ　ロシュ　アーゲー Ｅｎｖ／ｇａｇ−ポリペプチド
JPH01179687A (ja) * 1987-12-30 1989-07-17 Chemo Sero Therapeut Res Inst Ｈｉｖ融合蛋白質
JPH01502119A (ja) * 1987-01-16 1989-07-27 アンステイテユ・パストウール ヒト免疫不全レトロウイルス（ウイルスｈｉｖ）に対して誘導された抗体により認識できるペプチド、及び前記ウイルスの或る種に起因する感染の診断、場合によってはエイズに対するワクチン接種における該ペプチドの使用
JPH02160800A (ja) * 1988-04-26 1990-06-20 E I Du Pont De Nemours & Co ヒト免疫不全ウイルス（ＨＩＶ）ｅｎｖ‐コードペプチド
JPH03504556A (ja) * 1987-05-29 1991-10-09 タノツクス・バイオシステムズ・インコーポレーテツド Ｈｉｖ‐１を中和するモノクローナル抗体
EP0470980A1 (fr) * 1989-05-03 1992-02-19 Connaught Lab Peptides synthetiques pour vaccin contre l'hiv-1.

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1341285C (fr) * 1988-02-12 2001-08-14 Chang Yi Wang Peptides synthetiques servant a la detection d'anticorps de la proteine de surface gp120 du virus hiv, destines au diagnostic du sida, ainsi que d'etats pre-sidatiques, ou aux fins de vaccins

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63156729A (ja) * 1986-12-05 1988-06-29 エフ．ホフマン　―　ラ　ロシュ　アーゲー Ｅｎｖ／ｇａｇ−ポリペプチド
JPH01502119A (ja) * 1987-01-16 1989-07-27 アンステイテユ・パストウール ヒト免疫不全レトロウイルス（ウイルスｈｉｖ）に対して誘導された抗体により認識できるペプチド、及び前記ウイルスの或る種に起因する感染の診断、場合によってはエイズに対するワクチン接種における該ペプチドの使用
JPH03504556A (ja) * 1987-05-29 1991-10-09 タノツクス・バイオシステムズ・インコーポレーテツド Ｈｉｖ‐１を中和するモノクローナル抗体
JPH01179687A (ja) * 1987-12-30 1989-07-17 Chemo Sero Therapeut Res Inst Ｈｉｖ融合蛋白質
JPH02160800A (ja) * 1988-04-26 1990-06-20 E I Du Pont De Nemours & Co ヒト免疫不全ウイルス（ＨＩＶ）ｅｎｖ‐コードペプチド
EP0470980A1 (fr) * 1989-05-03 1992-02-19 Connaught Lab Peptides synthetiques pour vaccin contre l'hiv-1.

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4276106A3 (fr) * 2015-05-13 2024-01-24 The United States of America as represented by the Secretary of the Department of Health and Human Services Methodes et compositions pour eliciter des reponses immune a base des constructs contenant des elements conservatives

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JPH0748276A (ja) 1995-02-21

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