AP771A - "Vaccines containing a saponin and a sterol. " - Google Patents

"Vaccines containing a saponin and a sterol. " Download PDF

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Publication number
AP771A
AP771A APAP/P/1997/001123A AP9701123A AP771A AP 771 A AP771 A AP 771A AP 9701123 A AP9701123 A AP 9701123A AP 771 A AP771 A AP 771A
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qs21
virus
vaccine composition
mpl
vaccine
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APAP/P/1997/001123A
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AP9701123A0 (en
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Nathalie Marie- Garcon-Johnson
Martin Friede
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Smithkline Beecham Biolog
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Priority to GBGB9508326.7A priority Critical patent/GB9508326D0/en
Priority to GBGB9513107.4A priority patent/GB9513107D0/en
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Priority to PCT/EP1996/001464 priority patent/WO1996033739A1/en
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/002Protozoa antigens
    • A61K39/015Hemosporidia antigens, e.g. Plasmodium antigens
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/12Viral antigens
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/12Viral antigens
    • A61K39/245Herpetoviridae, e.g. herpes simplex virus
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/12Viral antigens
    • A61K39/29Hepatitis virus
    • A61K39/292Serum hepatitis virus, hepatitis B virus, e.g. Australia antigen
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/39Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/54Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/555Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55505Inorganic adjuvants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/555Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511Organic adjuvants
    • A61K2039/55555Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/555Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511Organic adjuvants
    • A61K2039/55572Lipopolysaccharides; Lipid A; Monophosphoryl lipid A
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/555Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511Organic adjuvants
    • A61K2039/55577Saponins; Quil A; QS21; ISCOMS
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2710/00MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA Viruses
    • C12N2710/00011MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA Viruses dsDNA Viruses
    • C12N2710/16011Herpesviridae
    • C12N2710/16611Simplexvirus, e.g. human herpesvirus 1, 2
    • C12N2710/16634Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2730/00Reverse Transcribing DNA Viruses
    • C12N2730/00011Reverse Transcribing DNA Viruses
    • C12N2730/10011Hepadnaviridae
    • C12N2730/10111Orthohepadnavirus, e.g. hepatitis B virus
    • C12N2730/10134Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
    • Y02A50/38Medical treatment of vector-borne diseases characterised by the agent
    • Y02A50/408Medical treatment of vector-borne diseases characterised by the agent the vector-borne disease being caused by a protozoa
    • Y02A50/411Medical treatment of vector-borne diseases characterised by the agent the vector-borne disease being caused by a protozoa of the genus Plasmodium, i.e. Malaria
    • Y02A50/412Medical treatment of vector-borne diseases characterised by the agent the vector-borne disease being caused by a protozoa of the genus Plasmodium, i.e. Malaria the medicinal preparation containing antigens or antibodies, e.g. vaccines, antisera
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
    • Y02A50/46Medical treatment of waterborne diseases characterized by the agent
    • Y02A50/462The waterborne disease being caused by a virus
    • Y02A50/463The waterborne disease being caused by a virus the virus being the Hepatitis A virus [HAV]
    • Y02A50/464The waterborne disease being caused by a virus the virus being the Hepatitis A virus [HAV] the medicinal preparation containing antigens or antibodies, e.g. vaccines, antisera

Abstract

The invention relates to a vaccine composition comprising an antigen, an immunoiogically active saponin fraction and a sterol.

Description

Ap . Ο Ο 7 7 1

VACCINES CONTAINING A SAPONIN AND A STEROL

The present invention relates to novel vaccine formulations, to methods of theirproduction and to their use in medicine. In particular, the present invention relates to 5 vaccines containing an antigen, an immunologically active fraction derived from thebark of Quillaja Saponaria Molina such as QS21, and a sterol.

Immunologically active saponin fractions having adjuvant activity derived from thebark of the South American tree Quillaja Saponaria Molina are known in the art. For 10 example QS21, also known as QA21, an Hole purified fraction from the Quillaja

Saponaria Molina tree and it's method of its production is disclosed (as QA21) in USpatent No. 5,057,540. Quillaia saponin has also been disclosed as an adjuvant by Scottet al, InL Archs. Allergy Appl. Immun., 1985, 77, 409. However, the use of QS21 asan adjuvant is associated with certain disadvantages. For example when QS21 is 15 injected into a mammal as a free molecule it has been observed that necrosis, that is. tosay, localised tissue death, occurs at the injection site.

It has now surprisingly been found that necrosis at the injection site can be avoided byuse of formulations containing a combination of QS21 and a sterol. Preferred sterols 20 include β-sitosterol, sdgmasterol, ergosteroL, ergocalciferol and cholesterol. Thesesterols are well known in the art, for example cholesterol is disclosed in the MerckIndex, 11th Edn., page 341, as a naturally occuring sterol found in animal fat.

In a first aspect the present invendon therefore provides a vaccine composition 25 - comprising an antigen, an immunologically active saponin fraction and a sterol.Preferably the composidons of the invention contain the immunologically activesaponin fraction in substantially pure form. Preferably the compositions of theinvention contain QS21 in substantially pure form, that is to say, the QS21 is at least90% pure, preferably at least 95% pure and most preferably at least 98% pure.

30 Other immunologically active saponin fractions useful in compositions of the inventioninclude QA17/QS17. Compositions of the invention comprising QS21 and cholesterolshow decreased reactogenicity when compared to compositions in which thecholesterol is absent, while the adjuvant effect is maintained. In addition it is knownthat QS21 degrades under basic conditions where the pH is about 7 or greater. A 35 further advantage of the present compositions is that the stability of QS21 to base-mediated hydrolysis is enhanced in formulations containing cholesterol. AP/P/ S 7 / 0 1 12 3

Preferred compositions of the invention are those forming a liposome structure.Compositions where the steroi/immunologically active saponin fraction forms anIS COM. structure also form an aspect of the invention.

The ratio of QS21 : sterol will typically be in the order of 1 : 100 to 1 : 1 weight toweight. Preferably excess sterol is present, the ratio of QS21 : sterol being at least1 : 2 w/w. Typically for human administration QS21 and sterol will be present in avaccine in the range of about 1 gg to about 100 gg, preferably about 10 to about50 pg per dose.

The liposomes preferably contain a neutral lipid, for example phosphatidylcholine,which is preferably non-crystalline at room temperature, for example eggyolkphosphatidylcholine, dioleoyl phosphatidylcholine or dilauryl phosphatidylcholine. Tneliposomes may also contain a charged lipid which increases the stability of the lipsome-QS21 structure for liposomes composed of saturated lipids. In these cases the amountof charged lipid is preferably 1-20% w/w, most preferably 5-10%. The ratio of sterolto phospholipid is 1-50% (mol/mol), most preferably 20-25%.

Preferably the compositions of the invention contain MPL (3-deacylated mono- ·phosphoryl lipid A, also known as 3D-MPL). 3D-MPL is known from GB 2 220 211(Ribi) as a mixture of 3 types of De-O-acylated monophosphoryl lipid A with 4,5 or 6acylated chains and is manufactured by Ribi Immunochem, Montana. A preferred formis disclosed in International Patent Application 92/116556.

Suitable compositions of the invention are those wherein liposomes are initiallyprepared without MPL, and MPL is then added, preferably as 100 nm particles. TheMPL is therefore not contained within the vesicle membrane (known as MPL out).Compositions where the MPL is contained within the vesicle membrane (known asMPL in) also form an aspect of the invention. The antigen can be contained within thevesicle membrane or contained outside the vesicle membrane. Preferably solubleantigens are outside and hydrophobic or lipidated antigens are either contained insideor outside the membrane.

Often the vaccines of the invention will not require any specific carrier and beformulated in an aqueous or other pharmaceutically acceptable buffer. In some cases itmay be advantageous that the vaccines of the present invention will further containalum or be presented in an oil in water emulsion, or other suitable vehicle, such as forexample, liposomes, microspheres or encapsulated antigen particles. 2 AP .00771

Preferably the vaccine formulations will contain an antigen or antigenic compositioncapable of eliciting an immune response against a human or animal pathogen. Antigenor antigenic compositions known in the art can be used in the compositions of the 5 invention, including polysaccharide antigens, anrigen or antigenic compositions derivedfrom HIV-1, (such as gpl 20 or gpl 60), any of Feline Immunodeficiency virus, humanor animal herpes viruses, such as gD or derivatives thereof or Immediate Early proteinsuch as ICP27 from HSV1 orHSV2, cytomegalovirus (especially human) (such as gBor derivatives thereof), Varicella Zoster Virus (such as gpl, Π or ΠΙ), or from a 10 hepatitis virus such as hepatitis B virus for example Hepatitis B Surface antigen or aderivative thereof, hepatitis A virus, hepatitis C virus and hepatitis E virus, or fromother viral pathogens, such as Respiratory Syncytial virus (for example HSRV F and Gproteins or immunogenic fragments thereof disclosed in US Patent 5,149,650 orchimeric polypeptides containing immunogenic fragments from HSRV proteins F and. 15 G, eg FG glycoprotein disclosed in US Patent 5,194,595), antigens derived from meningitis strains such as meningitis A, B and C, Streptoccoccus Pneumonia, humanpapilloma virus, Influenza virus, Haemophilus Influenza B (Hib), Epstein Bair Virus .(EBV), or derived from bacterial pathogens such as Salmonella, Neisseria, Borrelia(for example OspA or OspB or derivatives thereof), or Chlamydia, or Bordetella for 20 example P.69, PT and FHA, or derived from parasites such as plasmodium ortoxoplasma. HSV Glycoprotein D (gD) or derivatives thereof is a preferred vaccine antigen. It islocated on the viral membrane, and is also found in the cytoplasm of infected cells 25 (Eisenberg R.J. et al; J of Virol 1980 35 428-435). It comprises 393 amino acids including a signal peptide and has a molecular weight of approximately 60 kD. Of allthe HSV envelope glycoproteins this is probably the best characterised (Cohen et al TVirology 60 157-166). In vivo it is known to play a central role in viral attachment tocell membranes. Moreover, glycoprotein D has been shown to be. able to elicit 30 neutralising antibodies in vivo and protect animals from lethal challenge.A truncatedform of the gD molecule is devoid of the C terminal anchor region and can beproduced in mammalian cells as a soluble protein which is exported into the cell culturesupernatant. Such soluble forms of gD are preferred. The production of truncatedforms of gD is described in EP 0 139 417. Preferably the gD is derived from HSV-2. 35 An embodiment of the invention is a truncated HSV-2 glycoprotein D of 308 aminoacids which comprises amino acids 1 through 306 naturally occuring glycoprotein withthe addition Asparagine and Glutamine at the C terminal end of the truncated proteindevoid of its membrane anchor region. This form of the protein includes the signal AP/P/ 9 7/01 123 3 peptide which is cleaved to allow for the mature soluble 283 amino acid protein to besecreted from a host cell.

In another aspect of the invention, Hepatitis B surface antigen is a preferred vaccine antigen. (

As used herein the expression Hepatitis B surface antigen' or HBsAg' includes any HBsAg antigen or fragment thereof displaying the antigenicity of HBV surface antigen.

It will be understood that in addition to the 226 amino acid sequence of the HBsAgantigen (see Tiollais et al, Nature. 317, 489 (1985) and references therein) HBsAg asherein described may, if desired, contain all or part of a pre-S sequence as described inthe above references and in. EP-A- 0 278 940. In particular the HBsAg may comprisea polypeptide comprising an amino acid sequence comprising residues 12-52 followedby residues 133-145 followed by residues 175-400 of the L-protein of HBsAg relative·to the open reading frame on a Hepatitis B virus of ad serotype (this polypeptide is .referred to as L*; see EP 0 414 374). HBsAg within the scope of the invention mayalso include the pre-S l-preS2-S polypeptide described in EP 0 198 474 (Endotronics)or close analogues thereof such as those described in EP 0 304 578 (Me Cormick andJones). HBsAg as herein described can also refer to mutants, for example the 'escapemutant' described in WO 91/14703 or European Patent Application Number 0 511855A1, especially HBsAg wherein the amino acid substitution at position 145 is toarginine from glycine.

Normally the HBsAg will be in particle form. The particles may comprise for exampleS protein alone or may be composite particles, for example (L*,S) where L* is asdefined above and S denotes tie S-protein of HBsAg. The said particle isadvantageously in tie form in which it is expressed in yeast.

The preparation of hepatitis B surface antigen S-protein is well documented. See for example, Harford et al (1983) in Develop· Biol. Standard 54, page 125, Gregg et al (1987) in Biotechnology. 5, page 479, EP 0 226 846, EP 0 299 108 and references therein.

The formulations within the scope of tie invention may also contain an anti-tumour antigen and be useful for immunotherapeutically treating cancers.

Vaccine preparation is generally described in New Trends and Developments in

Vaccines, edited by Voller et al., University Park Press, Baltimore, Maryland, U.S.A. 4 AP. Ο Ο 7 7 1 1978. Encapsulation within liposomes is described, for example, by Fullerton, U.S.Patent 4,235,877. Conjugation of proteins to macromolecules is disclosed, for'example, by Likhite, U.S. Patent 4,372,945 and by Armor et at, U.S. Patent4,474,757. 5

The amount of protein in each vaccine dose is selected as an amount which induces animmunoprotective response without significant, adverse side effects in typicalvaccinees. Such amount will vary depending upon which specific immunogen isemployed and how it is presented. Generally, it is expected that each dose will 10 comprise 1-1000 meg of protein, preferably 2-100 meg, most preferably 4-40 meg. Anoptimal amount for a particular vaccine can be ascertained by standard studiesinvolving observation of appropriate immune responses in subjects. Following aninitial vaccination, subjects may receive one or several booster immunisationadequately spaced. 15

The formulations of the present invention maybe used for both prophylatic andtherapeutic purposes.

Accordingly in a further aspect, the invention therefore provides use of a vaccine of the 20 invention for the treatment of human patients. The invention provides a method oftreatment comprising administering ah effective amount of a vaccine of the presentinvention to a patient. In particular, the invention provides a method of treating viral,bacterial, parasitic infections or cancer which comprises administering an effectiveamount of a vaccine of the present invention to a patient. 25

The following examples and data illustrates the invention. AP/P/ 9 7/01123 5

Examples 1.1 Method of preparation of liposomes: A mixture of lipid (such as phosphatidylcholine either from egg-yolk or synthetic) andcholesterol in organic solvent, is dried down under vacuum (or alternatively under astream of inert gas). An aqueous solution (such as phosphate buffered saline) is thenadded, and the vessel agitated until all the lipid is in suspension. This suspension is thenmicrofluidised until the liposome size is reduced to 100 nm, and then sterile filteredthrough a 0.2 pm filter. Extrusion or sonication could replace this step.

Typically the cholesterohphosphaddylcholine ratio is 1:4 (w/w), and the aqueoussolution is added to give a final cholesterol concentration of 5 to 50 mg/ml. If MPL inorganic solution is added to the lipid in organic solution ±e final liposomes containMPL in .the membrane (referred to as MPL in).

The liposomes have a defined size of 100 nm and are referred to as SUV (for smallunilamelar vesicles). If this solution is repeatedly frozen and thawed the vesicles fuseto form large multilamellar structures (MLV) of size ranging from 500nm to 15 pm.The liposomes by themselves are stable over time and have no fusogenic capacity. 1.2 Formulation procedure: QS21 in aqueous solution is added to the liposomes. This mixture is then added to theantigen solution which may if desired contain MPL in the form of lOOnm particles. 1.3 The lytic activity of QS21 is inhibited by liposomes containingcholesterol.

When QS21 is added to erythrocytes, they lyse them releasing hemoglobin. This lyticactivity can also be measured using liposomes which contain cholesterol in theirmembrane and an entrapped fluorescent dye, carboxyfluorescein - as the liposomes arelysed the dye is released which can be monitored by fluorescence spectroscopy. If thefluorescent liposomes do not contain cholesterol in their membrane no lysis of theliposomes is observed

If the QS21 is incubated with liposomes containing cholesterol prior to adding it toerythrocytes, the lysis of the erythrocytes is diminished depending on the ratio ofcholesterol to QS21. If a 1:1 ratio is used no lytic activity is detected. If the 6 AP. Ο Ο 7 7 1 liposomes do not contain cholesterol, inhibition of lysis requires a one thousand foldexcess of phospholipid over QS21.

The same holds true using fluorescent liposomes to measure the lytic activity. 5 In the graph below, the lvtic activity of 4 pg of QS21 treated with liposomes lacking cholesterol (1 mg eggyolk lecithin per ml) or containing cholesterol (1 mg lecithin, 500pg cholesterol per ml) was measured by fluorescence.

10

The data shows that QS21 associates in a specific manner with cholesterol in amembrane, thus causing lysis (of cells or fluorescent liposomes).

If the QS21 first associates with cholesterol in liposomes it is no longer lytic towardscells or other liposomes. This requires a minimum ratio of 0.5:1 chol:QS21(w/w). 15

Cholesterol is insoluble in aqueous solutions and does not form a stable suspension. Inthe presence of phospholipids the cholesterol resides within the phospholipid bilayerwhich can form a stable suspension of vesicles called liposomes. To avoid therequirement to add phospholipids a soluble derivative was tried. Polyoxyethanyl- 20 cholesterol sebacate is soluble in water at 60 mg/ml however even at a 2000 foldexcess (w/w) over QS21 no reduction in the lytic activity of QS21 was detected. AP/P/ 9 7/01 123 7 1.4 Increased stability of QS21 by liposomes containing cholesterol. QS21 is very susceptible to hydrolysis at a pH above 7. This hydrolysis can bemonitored by measuring the decrease in the peak corresponding to QS21 on reverse-phase HPLC. For example, the graph below shows that at pH 9 and at a temperatureof 37°C, 90% of-QS21 is hydrolysed within 16 hours. If liposomes containingcholesterol are added to the QS21 at a ratio of 2:1 (chol:QS21 w/w) no hydrolysis ofthe QS21 is detected under the same conditions. If the ratio is 1:1 10% of the QS21 isdegraded.

Incubation ot 20 pg QS21 In pr*jenc· of SUV containing cholesterol at pH ? for 16 hra atarc

It is concluded that when QS21 associates with liposomes containing cholesterol itbecomes much less susceptible to base-mediated hydrolysis. The hydrolysis product isdescribed as having no adjuvant activity when given parenterally, hence vaccinescontaining QS21 have to be formulated at acidic pH and kept at 4°C to maintainadjuvant composition. The use of liposomes may overcome this requirement 1.5 Reactogenicity studies:

Mice injected in tibialis muscle with 5 pg QS21 (or digitonin) added to increasingquantities of liposomes (expressed in terms of pg cholesterol). Lytic activity isexpressed as pg QS21 equivalent, which means that quantity of QS21 required toachieve the same hemolysis as the sample. 8 AP. Ο Ο 7 7 1

Redness, necrosis and toxicity in the muscle at the site of injection were scoredvisually after sacrificing the mice. formulation lytic activity pg redness . necrosis toxicity QS21 -PBS 5 -r-~- QS21 +1 pg chol (SUV) 4 •i- QS21 +5 pg chol (SUV) 0 . - QS21+25 pg chol (SUV 0 - -r SUV alone 0 - - - digitonin 5 - - PBS 0 - - - 5 The data shows that when the lytic activity is abolished by the addition of liposomescontaining cholesterol the toxicity due to the QS21 is also abolished. 1.6 Reactogenicity intra-muscularly in rabbits io

Values in U.I./L

Experiment Formulation DayO hemolysis Dayl hemolysis Day 3 hemolysis Rabbit n°lRabbit n°2Rabbit n°3Rabbit n°4Rabbit n°5 QS21 50pg 1078 1116 660 592 3400 8650 4648 4819 5662 7528 1523 1435 684 684 1736 Mean SD 1369 1160 6261 1757 1212 495 AP/P/ 9 7/01123 9 SUBSTITUTE SHEET (RULE 26)

Experiment Formuiati on DayO hemolysis Dayl hemolysis Day 3 hemolysis Rabbit n°6Rabbit n°7Rabbit n°8Rabbit n°9 Rabbit n°10 QS21 50pgChoi inSUV 50pg(i-.i) 596 540 611 521 1092 1670 602 1873 507 787 460 594 803 616 555 Mean SD 672 238 1088 636 606 125

Experiment Formuiati on DayO hemolysis Dayl hemolysis Day3 hemolysis Rabbit n° 11 332 344 387 Rabbit n°12 831 662 694 Rabbit n°13 QS21 50pg 464 356 519 Rabbit n°14 Choi in 528 720 614 e SUV 150pg Rabbit n°15 .(1:3) 1027 568 849 Mean 637 530 613 SD 285 173 175

Experiment Formulation DayO hemolysis Dayl hemolysis Day3 hemolysis Rabbit n°16Rabbit n°17Rabbit n°l 8Rabbit n°19 Rabbit n°20 QS21 50pgChoi in SUV250pg(1:5) 540 498 442 822 3182 4- 769 404 717 801 2410 745 471 (4535) 925 960 Mean 1 SD 1097 1175 1020 793 775 224 (1527) (1692) 10 SUBSTITUTE SHEET (RULE 26) AP. ο Ο 7 7 1

Experiment Formulation DayO hemolysis Dayl hemolysis Day3 hemolysis Rabbit n°21Rabbit n°22 ·Rabbit n°23Rabbit n°24Rabbit n°25 PBS . 3216606501395 429 290 535 603 (3545) 323 378 755 473 (5749) 263 Mean SD 691 419 438 155 (1059) (1396) 467 210 (1523) (2369)

The data shows that the addition of cholesterol-containing liposomes to theformulation significantly reduces the elevation in CPK (creatine phospho kinase) 5 caused by the QS21. Since the CPK increase is a measure of muscle damage thisindicates decreased muscle damage and is confirmed by the histopathology. 1.7 Binding of the liposome-QS21 complex to alum. 10 QS21 was incubated with neutral liposomes containing excess cholesterol as well asradioactive cholesterol and then incubated with alum (A1(OH)3) in PBS. Alone,neither neutral liposomes nor QS21 bind to alum in PBS, yet negatively chargedliposomes do. When together however, QS21 and neutral liposomes bind to alum. 15 The supernatant contained neither QS21 (assayed by orcinol test) nor radioactivecholesterol.

This indicates that the QS21 has bound to the liposomes and permits the liposome-QS21 combination to bind to the alum. This may arise from a negative charge beingimposed on the liposomes by the QS21, or to an exposure of hydrophobic regions on 20 the liposomes. The results also imply that QS21 does not extract cholesterol from themembrane.

This indicates that compositions of the invention can be used in alum based vaccines. 25 1.8 Comparison of liposomal QS21/MPL and free QS21+MPL for antibody arid CMI induction AP/P/ 9 7./ 0 1 1 2 3 SUV were prepared by extrusion (EYPC:chol:MPL 20:5:1). 11 SUBSTITUTE SHEET (RULE 26)

For MPL out, liposomes were prepared without MPL and MPL added as 100 nm.particles QS21 was added prior to antigen. Chol:QS21 = 5:1 (w/w) MLV were made by freeze-thawing SUV 3x prior to antigen addition. 5 To have theantigen entrapped, the antigen was added to SUV prior to freeze-thawingand QS21 added after freeze-thaw. Antigen encapsulation = 5% in, 95% out-mice (balb/c for gD, B10BR for RTSs) were injected twice in the footpad.gD is the glycoprotein D from Herpes Simplex virus. RTSs is the Hepatitis B surfaceantigen (HBsAg) genetically modified to contain an epitope from the Plasmodiium 10 falciparum sporozoit ag = 10 pg RTSs anti HBsAg Titres 15days post boost formulation IgGl IgG2a IgG2b SUV/QS + MPL(out) + Ag 1175 10114 71753 MLV/QS + MPL(oui) + Ag 2247 11170 41755 MLV/QS/MPL(m) + Ag 969 7073 18827 MLV/QS/MPL(in)/Ag(m) + Ag 1812 2853 9393 QS + MPL + Ag 372 9294 44457 Ag <100 <100 <100 SUV/QS + MPL(out) <100 <100 <100 MLV/QS/MPL(in) <100 <100 <100 ag = 20pg gD anti- gD CMI formulation IgG IFN-y96 hr(pg/ml) IL2 48hr pg/ml SUV/QS + MPL(out) + Ag 2347 1572 960 SUV/QS/MPL(in) + Ag 2036 1113 15 MLV/QS + MPLfout) + Ag 1578 863 15 MLV/QS/MPLcm) + A g 676 373 15 MLV/QS/MPL(in)/Aa(in) + Ag 1064 715 15 QS + MPL + Ag 1177 764 15 Ag <100 567 44 SUV/QS + MPL(out) <100 181 15 MLV/QS/MPLcin) <100 814 105 12 AP. Ο Ο 7 7 1

The data shows that SUV/QS-MPLiout) induces high antibody titres at least as good5 as QS21+MPL, as well as inducing IL2 a marker of cell mediated immunity, while quenching QS21 reactogenicity.

Additional results from a second experiment comparing QS21 and QS21 in thepresence of cholesterol (SUV) in balb/c mice with HSV gD as antigen are shown 10 below:

Isotypes 7days post II

Formulation antigen IgG 7 postII (GMT) IgG 14postII (GMT) IgGl pg/ml % IgG2a pg/ml % IgG2b pg/ml % SUV/QS21 + MPL out gD (5gg) 20290 16343 331 26 716 56 222 17 SUV/QS2i/MPLin gD (5gg) 12566 10731 418 44 412 44 111 12 QS21+MPL gD (5gg) 10504 10168 200 34 285 48 107 18 SUV/QS21 +MPL out none 0 0 0 0 0 0 0 0 QS21 gD(5gg) 3468 4132 156 66 67 28 14 6 SUV/QS21 gD (5pg) 11253 11589 484 57 304 36 65 8 1.9 Comparison of gpl20 plus liposomal MPL/QS21 with free MPL/QS21 15 Liposomes = SUV containing MPL in the membrane

Chol:QS21 = 6:1

£ g i I 0 / L 6 /d/dV

Response was tested two weeks after one immunisation formulation proliftn IFN-g ng/ml IL2 pg/ml ILS pg/ml SUV/MPL/QS21 + Ag 12606 16.6 59 476 MPL+QS21+Ag 16726 15.8 60 404 20

After second immunisation: formulation proliftn IFN-g ng/ml IL4 pg/ml ILS pg/ml SUV/MPL/QS21 + Ag 12606 135 0 250 MPL+QS21+Ag 16726 60 0 500 13 SUBSTITUTE SHEET (RULE 26)

The data shows that QS21 associated with cholesterol-containing liposomes and MPLinduces Thl/ThO response equal to MPL+QS21.

At this ratio of cholesterol to QS21, QS21 is non-toxic in rabbits (by CPK).

In a second experiment balb/c mice were immunised intra-footpad with gpl20 in thepresence of QS21 or QS21 + SUV containing cholesterol. The cytotoxic T-lymphocyteactivity in spleen cells was measured.

This demonstrates that QS21 alone induces CTL activity, and that QS21 in the • _____ presence of liposomes containing cholesterol induces CTL activity at least as good as,or better than, QS21 alone. 2. Vaccines 2.1 Formulation of HBsAg L*,S particles. HBsAg L*,S particles may be formulated as follows: 10pg of HBsAg L*,S particles/dose are incubated lh. at room temperature underagitation. The volume is adjusted using water for injection and a PBS solution andcompleted to a final volume of 70μ1/ dose with an aqueous solution of QS21 (10μg/dose). pH is kept at 7 ± 0.5.

Similar formulations may be prepared using 1 and 50pg of HBsAg L*,S and also usingthe HBsAg S antigen.

These formulations may be tested in the Woodchuck surrogate therapeutic model usingWoodchuck HB V antigens as a model. 14 AP.00771

Woodchuck model DQ QS21 (i.e. QS21/cholesterol or quenched QS21) may be tested in the woodchucktherapeutic model where animals are chronically infected with the virus. Specific 5 woodchuck hepatitis virus vaccine may be add mixed wi± QS21 as such or DQ andwith or without MPL and administered to the animals every months for 6 months.Effectiveness of the vaccine may be assess through viral DNA clearance. 2.2 Guinea Pig Model (HSV) 10 2.2.1 Prophylactic model

Groups of 12 female Hartley guinea pigs were either injected intramuscularly on day0 and day 28 with the following formulations: 15 1st experiment: gD 5 pg + QS21 50 pg + SUV containing 50 pg cholesterolgD 5 pg + QS21 100 pg + SUV containing 100 pg cholesterolgD 5 pg + QS21 50 pg + SUV containing 250 pg cholesterol 20 gD 5 pg + QS21 50 pg2nd experiment: gD 5pg + MPL 12.5 pg + QS21 12.5pg + SUV containing 62.5 pg cholesterol, or leftuntreated. 25

The animals were bled at 14 and 28 days after the second immunisation, and the seratested for their gD-specific ELISA antibody titres.

Animals were then challenged intravaginally with 105 pfu HSV-2 MS strain. They30 were scored daily from day 4 to 12 for evaluation of primary herpetic lesions. Scoring was as follows:

Vaginal lesions: - bleeding = 0.5 - redness for one or 2 days without bleeding = 0.5 35 - redness and bleeding for a day = 1 - redness without bleeding lasting at least 3 days = 1External herpetic vesicles: - < 4 small vesicles = 2 - >= 4 small vesicles or one big vesicle 4 >= 4 large lesions 8 fusing large lesions = 40 16 - fusing large lesions on all external genital area = 32. AP/P/ 9 7/01123

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The table and graph show that in the prophylactic model, a very high level ofprotection against primary disease was induced upon immunisation with gD / MPL /QS21 / SUV. Both the incidence of external lesions and the lesion severity appearedhighly reduced in the group of animals immunised with gD / MPL / QS21 /SUV. 2.2.2 Therapeutic Model

In the therapeutic model, female Hartley guinea pigs were first challenged with 10^pfu HSV-2 MS strain. Animals with herpetic lesions were then randomly allotted togroups of 16.

On day 21 and day 42, they were either immunised with one of the followingformulations: - gD + MPL 50pg + QS21 50pg + SUV containing 250 ug cholesterol, - gD + A1(OH)3 + MPL 50pg + QS21 50ug, + SUV containing 250 pg cholesterolor left untreated.

They were monitored daily from day 22 to 75 for evaluation of recurrent disease.Scoring was as described for the prophylactic model. The results are shown in thetable and graph below: 18 (_Λ MPL/ QS21/SUV with or without Alum had a marked effect on the median severity of recurrent disease. It also slightly reduced episodenumber and duration (see Table). ο *-ι

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Claims (15)

  1. AP Claims for National Phase 0 0 7 7 1 * ing now jx'siicuj.’.riy lioscwiHot! ,ιηι’,.:··οοί'ΐaiuccl ηi·,/our said inv.;u.i·;m<! it, 'Y.l·:;:·. ·nuiuicr :)ie same is to he pei'iormet'/i.w.e dee lure that what I/\ve claim is —
    1. A vaccine composition comprising an antigen, an immunologically activesaponin fraction, and a sterol, characterised in that the ratio of saponin:sterol is from 1:1to l:100(w/w).
  2. 2. A vaccine composition according to claim 1 wherein the ratio ofsaponimsterol is in the range from 1:1 to 1:5 (w/w).
  3. 3. A vaccine composition according to claim 1 wherein the ratio ofsaponimsterol is 1:2 (w/w).
  4. 4. A vaccine composition according to any of claims 1 to 3, wherein theimmunologically active saponin fraction is QS21.
  5. 5., A vaccine composition according to any of claims 1 to 3, wherein the sterol is cholesterol.
  6. 6- A vaccine composition according to any of claims 1 to 5 which further contains 3D-MPL. AP/P/ 9 7/01 123
  7. 7. A vaccine composition as claimed in any of claims 1 to 6 which furthercomprises a carrier.
  8. 8. A vaccine composition as claimed in claim 7, wherein the carrier is selectedfrom the group comprising: oil in water emulsions, alum, microspheres and encapsulatedantigen particles.
  9. 9. A vaccine composition as claimed in any of the claims 1 to 8, furthercomprising an antigen or antigenic composition derived from any of HumanImmunodeficiency Virus, Feline Immunodeficiency Virus, Varicella Zoster virus, Herpes AP .0 0 7 7 1 Simplex Virus type 1, Herpes Simplex virus type 2, Human cytomegalovirus, Hepatitis A,B, C or E, Respiratory Syncytial virus, human papilloma virus, Influenza virus, Hib,Meningitis virus, Salmonella, Neisseria, Borrelia, Chlamydia, Bordetella, Plasmodium orToxoplasma.'
  10. 10. A vaccine as claimed in any of the claims 1 to 8, further comprising an antigen derived from a tumour. 1 1. A composition as claimed in any of the preceding claims for use in medicine.
  11. 12. Use of composition as defined in any of the claims 1 to 9, for the manufactureof a vaccine for the prophylatic treatment of viral, bacterial or parasitic infections.
  12. 13. Use of composition as defined in any of the claims 1 to 10, for the manufacture of a /accine for the immunotherapeutic treatment of viral, bacterial, parasiticinfections or cancer.
  13. 14. A method of treating a mammal suffering from or susceptible to a pathogenicinfection comprising the administration of a safe and effective amount of a compositionaccording to any of claims 1 to 9.
  14. 15. A method of treating a mammal suffering from or susceptible to cancercomprising the administration of a safe and effective amount of a composition as claimedin claim 10.
  15. 16. A process for making a vaccine composition as claimed in any of claims 1 to10, comprising admixing an immunologically active saponin fraction and cholesterol withan antigen or antigenic composition.
    THE ΛΡΡ'λΙΕΑΝΤ AP/P/ 9 7/01 123
APAP/P/1997/001123A 1995-04-25 1996-04-01 "Vaccines containing a saponin and a sterol. " AP771A (en)

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PCT/EP1996/001464 WO1996033739A1 (en) 1995-04-25 1996-04-01 Vaccines containing a saponin and a sterol

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