EP1214053A1 - Adjuvant comprising a polyoxyethylene alkyl ether or ester and at least one nonionic surfactant - Google Patents

Adjuvant comprising a polyoxyethylene alkyl ether or ester and at least one nonionic surfactant

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Publication number
EP1214053A1
EP1214053A1 EP00964232A EP00964232A EP1214053A1 EP 1214053 A1 EP1214053 A1 EP 1214053A1 EP 00964232 A EP00964232 A EP 00964232A EP 00964232 A EP00964232 A EP 00964232A EP 1214053 A1 EP1214053 A1 EP 1214053A1
Authority
EP
European Patent Office
Prior art keywords
polyoxyethylene
vaccine
adjuvant
ester
ether
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP00964232A
Other languages
German (de)
English (en)
French (fr)
Inventor
Martin Smithkline Beecham Biologicals S.A. Friede
Philippe SmithKline Beecham Bio. s.a. HERMAND
Veronique Henderickx
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
GlaxoSmithKline Biologicals SA
Original Assignee
SmithKline Beecham Biologicals SA
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
Priority claimed from GBGB9922700.1A external-priority patent/GB9922700D0/en
Priority claimed from GB0016647A external-priority patent/GB0016647D0/en
Application filed by SmithKline Beecham Biologicals SA filed Critical SmithKline Beecham Biologicals SA
Publication of EP1214053A1 publication Critical patent/EP1214053A1/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61P37/08—Antiallergic agents
    • 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
    • A61K2039/55555—Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • Y—GENERAL 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
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a novel adjuvant system comprising a polyoxyethylene alkyl ether or ester surfactant in combination with at least one additional non-ionic surfactant.
  • said additional non-ionic surfactant is an Octoxynol.
  • the present invention provides said novel adjuvants, vaccines comprising them, and methods of their manufacture and their formulation into vaccines.
  • the use of the adjuvants or vaccines of the present invention in the prophylaxis or therapy of disease are also provided.
  • a method to enhance an immune response in a host using the adjuvant and vaccines of the present invention is also provided.
  • the adjuvants are particularly useful as a mucosal adjuvant, but are also effective systemically.
  • mucosal vaccination is attractive since it has been shown in animals that mucosal administration of antigens has a greater efficiency of inducing protective responses at mucosal surfaces, which is the route of entry of many pathogens.
  • mucosal vaccination such as intranasal vaccination, may induce 0 mucosal immunity not only in the nasal mucosa, but also in distant mucosal sites such as the genital mucosa (Mestecky, 1987, Journal of Clinical Immunology, 7, 265-276; McGhee and Kiyono, Infectious Agents and Disease, 1993, 2, 55-73).
  • safe and effective mucosal adjuvants which are suitable for use in humans, remains to be identified.
  • the present invention provides 5 a solution to this problem.
  • vaccine preparations comprising an admixture of either polyoxyethylene castor oil or caprylic/capric acid glycerides, with polyoxyethylene sorbitan monoesters, and an antigen, are capable of inducing systemic immune responses after topical administration to a mucosal membrane (WO 94/17827).
  • This patent application discloses the combination of the non-ionic surfactant TWEEN20TM (polyoxyethylene sorbitan monoester) and Imwitor742TM (caprylic/capric acid glycerides), or a combination of TWEEN20TM and polyoxyethylene castor oil are able to enhance the systemic immune response following intranasal immunisation. Details of the effect of this formulation on the enhancement of the immune response towards intranasally administered antigens have also been described in the literature (Gizurarson et al. 1996. Vaccine Research, 5, 69-75; Aggerbeck et al. 1997, Vaccine, 15, 307-316; Tebbey et al.,Viral Immunol 1999;12(l):41-5).
  • Non-ionic surfactants have also been formulated in such a way as to form non-ionic surfactant vesicles (commonly known as NISV, US 5,679,355). Such formulations of non-ionic surfactants, often in the presence of cholesterol, form lipid-bilayer vesicles which entrapp antigen within the inner aqueous phase or within the bilayer itself.
  • Surfactants are commonly used in the formulation of oil emulsion adjuvants for systemic administration, and function to stabilise the oil droplets.
  • polyoxyethylene sorbitan esters TWEENTM
  • SPANTM sorbitan fatty acid esters
  • TWEENTM polyoxyethylene sorbitan esters
  • SPANTM sorbitan fatty acid esters
  • the applicant presents here the surprising finding that polyoxyethylene alkyl ethers or esters, in combination with at least one additional non-ionic surfactant, together act as a potent adjuvants for vaccines.
  • such compositions may be administered systemically, but are also potent in the induction of systemic immune responses when the vaccine compositions are administered mucosally.
  • the immune responses induced by mucosal administration of vaccines of the present invention may be at least as high as those observed after a systemic injection of conventional vaccine.
  • the present invention provides safe and potent adjuvants which are easily manufactured, and comprise at least one polyoxyethylene alkyl ether or ester and at least one additional non-ionic surfactant.
  • the surfactants employed in the invention may be in aqueous solution or may form suspensions of particulate structures such as vesicles or micelles.
  • Preferably the surfactants are in the form of an aqueous solution or a micelle.
  • one embodiment of the present invention consists of a vaccine formulation comprising a polyoxyethylene alkyl ether of general formula (I), wherein n is between 1 and 50, preferably 4-24, more preferably 6-12, and most preferably 9; the R component is C,. 50 , preferably C 4 -C 20 alkyl and most preferably C 12 alkyl.
  • concentration of the polyoxyethylene ethers should be in the range 0.1-20% , preferably from 0.1-10% , and most preferably in the range 0.1-1 % .
  • Suitable polyoxyethylene ethers are selected from the following group: polyoxyethylene-9- lauryl ether, polyoxyethylene-9-stearyl ether, polyoxyethylene-8-stearyl ether, polyoxyethylene-4-lauryl ether, polyoxyethylene-35-lauryl ether, and polyoxyethylene-23-lauryl ether.
  • said polyoxyethylene alkyl ether is polyoxyethylene-9-lauryl ether (laureth 9).
  • Alternative terms or names for polyoxyethylene lauryl ether are disclosed in the CAS registry.
  • the CAS registry number of polyoxyethylene-9 lauryl ether is: 9002-92-0.
  • Polyoxyethylene ethers such as polyoxyethylene lauryl ether are described in the Merck index (12 th ed: entry 7717, Merck & Co. Inc. , Whitehouse Station, N.J., USA; ISBN 0911910-12-3), where therapeutic uses are stated to include: topical anesthetic; anti-pruritic; and sclerosing agent activities.
  • polyoxyethylene ethers, or esters are non- ionic surfactants.
  • Laureth 9 is formed by reacting ethylene oxide with dodecyl alcohol, and has an average of nine ethylene oxide units.
  • n the average number of ethylene oxide units present in all of the surfactants in the mixture.
  • the ratio of the length of the polyoxyethylene section to the length of the alkyl chain in the surfactant affects the solubility of this class of detergent in an aqueous medium.
  • the adjuvants of the present invention may be in solution or may form paniculate structures such as micelles or vesicles.
  • the adjuvants of the present invention safe, easily sterilisable by for example passing through a 0.22 ⁇ m membrane, simple to administer, and may be manufactured in a simple fashion without the GMP and QC issues associated with the formation of uniform paniculate structures.
  • Some polyoxyethylene ethers, such as laureth 9, are capable of forming non-vesicular solutions.
  • polyoxyethylene-8 palmitoyl ether (C Ig E g ) is capable of forming vesicles. Accordingly, the use of vesicles of polyoxyethylene-8 palmitoyl ether in combination with at least one additional non-ionic surfactant, to form adjuvants of the present invention is specifically contemplated.
  • the polyoxyethylene alkyl ether element present in the adjuvant combinations of the present invention has haemolytic activity.
  • the haemolytic activity of a polyoxyethylene alkyl ether may be measured in vitro, with reference to the following assay, and is as expressed as the highest concentration of the detergent which fails to cause lysis of the red blood cells:
  • the polyoxyethylene alkyl ethers, or surfactants of general formula (I), of the present invention preferably have a haemolytic activity, of approximately between 0.5- 0.0001 % , more preferably between 0.05-0.0001 % , even more preferably between 0.005-0.0001 %, and most preferably between 0.003-0.0004% .
  • said polyoxyethylene ethers or esters should have a haemolytic activity similar (i.e. within a ten-fold difference) to that of either polyoxyethylene-9 lauryl ether or polyoxyethylene-8 stearyl ether.
  • At least one additional non-ionic surfactant which may be any detergent with suitable surface active properties.
  • Preferred non-ionic surfactants are not ones that fall within the general formula (I), e.g. Octoxynols and Polyoxyethylene sorbitan esters. Particularly preferred
  • Octoxynols include Triton X-45, t-octylphenoxy polyethoxyethanol (Triton X-100),
  • Triton X-100 is particularly preferred.
  • the Octoxynol series, including t-octylphenoxypolyethoxyethanol (TRITON XI 00TM) is described in Merck Index Entry 6858 (Page 1162, 12 th Edition, Merck & Co. Inc. , Whitehouse Station, N.J., USA; ISBN 0911910-12-3).
  • polyoxyethylene sorbitan esters are polyoxyethylene sorbitan esters.
  • the polyoxyethylene sorbitan esters including polyoxyethylene sorbitan monooleate (TWEEN80TM) are described in Merck Index Entry 7742 (Page 1308, 12 th Edition, Merck & Co. Inc., Whitehouse Station, N.J., USA; ISBN 0911910-12-3). Both Octoxynols and polyoxyethylene sorbitan esters may be purchased from Sigma Inc.
  • the preferred polyoxyethylene sorbitan ester is polyoxyethylene sorbitan monooleate (Tween 80TM).
  • the most prefered adjuvants of the present invention comprise a polyoxyethylene alkyl ether and an Octoxynol, such as t-octylphenoxypolyethoxyethanol (TRITON XI 00TM).
  • said combination may further comprise a polyoxyethylene sorbitan ester, such as polyoxyethylene sorbitan monooleate (TWEEN80TM).
  • said polyoxyethylene alkyl ether is polyoxyethylene-9-lauryl ether
  • said Octoxynol is t-octylphenoxypolyethoxyethanol (TRITON XI 00TM).
  • an ionic detergent may be added such as a bile salt or derivative of cholic acid.
  • the adjuvant formulation may comprise a polyoxyethylene alkyl ether or ester (formula I), an octoxynol, optionally comprising a polyoxyethylene sorbitan ester, and optionally comprising a bile salt or cholic acid derivative.
  • the preferred embodiment of this formulation comprises a combination of polyoxyethylene-9 lauryl ether, t-octylphenoxypolyethoxyethanol (TRITON XI 00TM), polyoxyethylene sorbitan monooleate and sodium deoxycholate.
  • the concentration of polyoxyethylene alkyl ether or ester, such as polyoxyethylene- 9 lauryl ether, in the adjuvants of the present invention will typically be in the range of 0.001 to 20 % , preferably 0.001 to 10 % and more preferably 0.001 to 1 % , and most preferably between 0.001 and 0.8% or about 0.5% (w/v).
  • the additional non-ionic surfactant which is not a polyoxyethylene ether or ester.
  • the or each of the additional non-ionic surfactants will typically be present in the final vaccine formulation at a concentration of between 0.001 to 20%, more preferably 0.01 to 10% , and most preferably up to about 2% (w/v).
  • additional non-ionic surfactants are present, these are preferably present in the final formulation at a concentration of up to about 2% each, typically at a concentration of up to about 0.6% each. If three or more additional non-ionic surfactants are present, they are generally present at up to a concentration of about 1 % each and typically in traces up to about 0.2% or 0.1 % each. Any mixture of surfactants may be present in the vaccine formulations according to the invention.
  • Non-ionic surfactants such as those discussed above have preferred concentrations in the final vaccine composition as follows: octyl- or nonylphenoxy polyoxyethanols such as Triton X-100TM or other detergents in the Triton series: from 0.001 % to 20% , preferably 0.001 % to 10% , more preferably from 0.001 to 1 % , and most preferably 0.005 to 0.1 % (w/v); and if present polyoxyethylene sorbitan esters such as Tween 80TM: 0.01 to 1 %, most preferably about 0.1 % (w/v).
  • octyl- or nonylphenoxy polyoxyethanols such as Triton X-100TM or other detergents in the Triton series: from 0.001 % to 20% , preferably 0.001 % to 10% , more preferably from 0.001 to 1 % , and most preferably 0.005 to 0.1 % (w/v); and if present polyoxyethylene sorb
  • the total concentration of detergent in the vaccine or adjuvant formulations of the present invention is typically in the range of 0.001 to 40%, preferably between 0.001 and 20%, more preferably between 0.001 and 10%, more preferably still between 0.001 and 1 %, and most preferably between 0.001 to 0.-7%. (w/v).
  • the vaccine preparations of the present invention may be used to protect or treat a mammal susceptible to, or suffering from disease, by means of administering said vaccine via a mucosal route, such as the oral/bucal/intestinal/vaginal/rectal or nasal route. Such administration may be in a droplet, spray, or dry powdered form. Nebulised or aerosolised vaccine formulations also form part of this invention. Enteric formulations such as gastro resistant capsules and granules for oral administration, suppositories for rectal or vaginal administration also form part of this invention. The present invention may also be used to enhance the immunogenicity of antigens applied to the skin (transdermal or transcutaneous delivery). In addition, the adjuvants of the present invention may be parentally delivered, for example intramuscular, or subcutaneous administration. When used for intranasal vaccination, the vaccines of the present invention are preferably haemolytic in nature.
  • a variety of administration devices may be used.
  • a spray device such as the commercially available AccusprayTM (Becton Dickinson) may be used.
  • Preferred spray devices for intranasal use are devices for which the performance of the device is not dependent upon the pressure applied by the user. These devices are known as pressure threshold devices. Liquid is released from the nozzle only when a threshold pressure is attained. These devices make it easier to achieve a spray with a regular droplet size. Pressure threshold devices suitable for use with the present invention are known in the art and are described for example in WO 91/13281 and EP 311 863 B. Such devices are commercially available from Pfeiffer GmbH.
  • Preferred intranasal devices produce droplets (measured using water as the liquid) in the range 1 to 200 ⁇ m, preferably 10 to 120 ⁇ m. Below lO ⁇ m there is a risk of inhalation, therefore it is desirable to have no more than about 5 % of droplets below lO ⁇ m. Droplets above 120 ⁇ m do not spread as well as smaller droplets, so it is desirable to have no more than about 5% of droplets exceeding 120 ⁇ m.
  • Bi-dose delivery is a further preferred feature of an intranasal delivery device for use with the vaccines according to the invention.
  • Bi-dose devices contain two subdoses of a single vaccine dose, one sub-dose for administration to each nostril.
  • the invention provides in a further aspect a kit comprising an intranasal administration device as described herein containing a vaccine formulation according to the invention.
  • the adjuvant formulations of the present invention may also comprise a bile acid or derivative of cholic acid.
  • the derivative of cholic acid is a salt thereof, and more preferably a sodium salt thereof.
  • bile acids and derivatives thereof include cholic acid itself, deoxy cholic acid, taurodeoxycholate, chenodeoxy colic acid, lithocholic acid ursodeoxycholic acid, hyodeoxy cholic acid and derivatives like glyco-, tauro-, amidopropyl-1- propanesulfonic-, amidopropyl-2-hydroxy-l-propanesulfonic derivatives of the aforementioned bile acids, or N,N-bis (3DGluconoamidopropyl) deoxy cholamide.
  • NaDOC sodium deoxycholate
  • the adjuvant formulation of the present invention are advantageous when in the form of an aqueous solution or a suspension of non-vesicular forms.
  • Such formulations are easy to manufacture reproducibly, and also to sterilise (terminal filtration through a 450 or 220 nm pore membrane) and are also easy to administer to the nasal mucosa in the form of a spray without degradation of complex physical structure of the adjuvant.
  • Polyoxyethylene-9 lauryl ether in combination with TRITON-X 100TM forms an aqueous solution (small micelles may also be present).
  • a method of inducing or enhancing an immune response in a host comprising admixing the antigen and the adjuvants of the present invention, and administering said admixture to the host.
  • the route of administration to said host is via a mucosal surface, and more preferably via the nasal mucosa.
  • the admixture is preferably administered as a spray.
  • systemic immune response is induced by a nasal administration of the vaccines of the present invention.
  • the methods to enhance an immune response may be either a priming or boosting dose of the vaccine, and that the vaccine comprises an influenza antigen or antigenic preparation.
  • the prefered adjuvant formulation for administering to the nasal mucosa in these methods are combinations of polyoxyethylene alkyl ether and an octoxynol, such as a preferred combination of polyoxyethylene-9 lauryl ether and t- octylphenoxypolyethoxyethanol (TRITON XI 00TM), optionally said adjuvant combination additionally comprising a polyoxyethylene sorbitan ester (such as the monooleate, TWEEN 80TM) and/or a bile salt or cholic acid derivative such as sodium deoxycholate.
  • a polyoxyethylene sorbitan ester such as the monooleate, TWEEN 80TM
  • a bile salt or cholic acid derivative such as sodium deoxycholate.
  • compositions of the present invention will be used to formulate vaccines containing antigens derived from a wide variety of sources.
  • antigens may include human, bacterial, or viral nucleic acid, pathogen derived antigen or antigenic preparations, tumour derived antigen or antigenic preparations, host-derived antigens, including GnRH and IgE peptides, recombinantiy produced protein or peptides, and chimeric fusion proteins.
  • the vaccine formulations of the present invention contain an antigen or antigenic composition capable of eliciting an immune response against a human pathogen, which antigen or antigenic composition is derived from HIV-1, (such as tat, nef, gpl 20 or gpl 60), human herpes viruses, such as gD or derivatives thereof or Immediate Early protein such as ICP27 from HSV1 or HSV2, cytomegalovirus ((esp Human)(such as gB or derivatives thereof), Rotavirus (including live- attenuated viruses), Epstein Barr virus (such as gp350 or derivatives thereof), Varicella Zoster Virus (such as gpl, II and IE63), or from a hepatitis virus such as hepatitis B virus (for example Hepatitis B Surface antigen or a derivative thereof), hepatitis A virus, hepatitis C virus and hepatitis E virus, or from other viral pathogens, such as paramyxo
  • Encephalitis Virus or Influenza virus (whole live or inactivated virus, split influenza virus, grown in eggs or MDCK cells, or Vero cells or whole flu virosomes (as described by R. Gluck, Vaccine, 1992, 10, 915-920) or purified or recombinant proteins thereof, such as HA, NP, NA, or M proteins, or combinations thereof), or derived from bacterial pathogens such as Neisseria spp, including N. gonorrhea and N. meningitidis (for example capsular polysaccharides and conjugates thereof, transferrin-binding proteins, lactoferrin binding proteins, PilC, adhesins); S.
  • Influenza virus whole live or inactivated virus, split influenza virus, grown in eggs or MDCK cells, or Vero cells or whole flu virosomes (as described by R. Gluck, Vaccine, 1992, 10, 915-920) or purified or recombinant proteins thereof, such as HA, NP,
  • M catarrhalis also known as Branhamella catarrhalis
  • Branhamella catarrhalis for example high and low molecular weight adhesins and invasinsj
  • Bordetella spp including B. pertussis (for example pertactin, pertussis toxin or derivatives thereof, filamente
  • Mycobacterium spp. including M. tuberculosis (for example ESAT6, Antigen 85 A, -B or -C), M. bovis, M. leprae, M. avium, M. paratuberculosis, M. smegmatis; Legionella spp, including L. pneumophila;
  • M. tuberculosis for example ESAT6, Antigen 85 A, -B or -C
  • M. bovis for example ESAT6, Antigen 85 A, -B or -C
  • M. bovis for example ESAT6, Antigen 85 A, -B or -C
  • M. bovis for example ESAT6, Antigen 85 A, -B or -C
  • M. bovis for example ESAT6, Antigen 85 A, -B or -C
  • M. bovis for example ESAT6, Antigen 85 A, -B or -C
  • M. bovis for example ESAT6, Antigen 85 A, -B or -C
  • Escherichia spp including enter otoxic E. coli (for example colonization factors, heat-labile toxin or derivatives thereof, heat-stable toxin or derivatives thereof), enterohemorragic E. coli, enteropathogenic E. coli (for example shiga toxin-like toxin or derivatives thereof); Vibrio spp, including V. cholera (for example cholera toxin or derivatives thereof j; Shigella spp, including S. sonnei, S. dysenteriae, S. flexnerii; Yersinia spp, including Y. enterocolitica (for example a Yop protein) , Y. pestis, Y.
  • enterotoxic E. coli for example colonization factors, heat-labile toxin or derivatives thereof, heat-stable toxin or derivatives thereof
  • enterohemorragic E. coli enteropathogenic E. coli (for example shiga toxin-like toxin or derivative
  • pseudotuberculosis Campy lobacter spp, including C. jejuni (for example toxins, adhesins and invasins) and C. coli; Salmonella spp, including S. typhi, S. paratyphi, S. choleraesuis, S. enteritidis; Listeria spp., including L. monocytogenes; Helicobacter spp, including H. pylori (for example urease, catalase, vacuolating toxin); Pseudomonas spp, including P. aeruginosa; Staphylococcus spp., including S. aureus, S.
  • C. jejuni for example toxins, adhesins and invasins
  • Salmonella spp including S. typhi, S. paratyphi, S. choleraesuis, S. enteritidis
  • Listeria spp. including L. monocytogenes
  • Clostridium spp. including C. tetani (for example tetanus toxin and derivative thereof), C. botulinum (for example botulinum toxin and derivative thereof), C. difficile (for example clostridium toxins A or B and derivatives thereof); Bacillus spp., including B. anthracis (for example botulinum toxin and derivatives thereof);
  • Corynebacterium spp. including C. diphtheriae (for example diphtheria toxin and derivatives thereof); Borrelia spp., including B. burgdorferi (for example OspA,
  • Chlamydia spp. including C. trachomatis (for example MOMP, heparin-binding proteins), C. pneumoniae (for example MOMP, heparin-binding proteins), C. psittaci; Leptospira spp., including L. interrogans; Treponema spp., including T. pallidum (for example the rare outer membrane proteins), T. denticola, T. hyodysenteriae; or derived from parasites such as Plasmodium spp., including P. falciparum; Toxoplasma spp . , including T. gondii (for example SAG2, SAG3, Tg34);
  • C. trachomatis for example MOMP, heparin-binding proteins
  • C. pneumoniae for example MOMP, heparin-binding proteins
  • C. psittaci Leptospira spp., including L. interrogans
  • Entamoeba spp. including E. histolytica
  • Babesia spp. including B. microti
  • Trypanosoma spp. including T. cruzi; Giardia spp., including G. lamblia;
  • Leshmania spp. including L. major; Pneumocystis spp., including P. carinii; Trichomonas spp., including T. vaginalis; Schisostoma spp., including S. mansoni, or derived from yeast such as Candida spp., including C. albicans; Cryptococcus spp., including C. neoformans.
  • Preferred bacterial vaccines comprise antigens derived from Streptococcus spp, including S. pneumoniae (for example capsular polysaccharides and conjugates thereof, PsaA, PspA, streptolysin, choline-binding proteins)and the protein antigen
  • H. influenzae type B for example PRP and conjugates thereof
  • non typeable H. influenzae for example OMP26
  • high molecular weight adhesins P5, P6, protein D and lipoprotein D
  • fimbrin and fimbrin derived peptides US 5,843,464
  • Other preferred bacterial vaccines comprise antigens derived from Morexella Catarrhalis (including outer membrane vesicles thereof, and OMP106
  • the vaccine formulation of the invention comprises the HIV-1 antigen, gpl20, especially when expressed in CHO cells.
  • the vaccine formulation of the invention comprises gD2t as hereinabove defined.
  • vaccines containing the claimed adjuvant comprise antigen derived from the Human Papilloma Virus (HPV) considered to be responsible for genital warts, (HPV 6 or HPV 11 and others), and the HPV viruses responsible for cervical cancer (HPV 16, HPV 18 and others).
  • HPV Human Papilloma Virus
  • Particularly preferred forms of genital wart prophylactic, or therapeutic, vaccine comprise LI particles or capsomers, and fusion protein? comprising one or more antigens selected from the HPV 6 and HPV 11 proteins E6, E7, LI, and L2.
  • fusion protein L2E7 as disclosed in WO 96/26277, and proteinD(l/3)-E7 disclosed in GB 9717953.5 (PCT/EP98/05285).
  • a preferred HPV cervical infection or cancer, prophylaxis or therapeutic vaccine, composition may comprise HPV 16 or 18 antigens.
  • HPV 16 or 18 antigens For example, LI or L2 antigen monomers, or LI or L2 antigens presented together as a virus like particle (VLP) or the LI alone protein presented alone in a VLP or capsomer structure.
  • VLP virus like particle
  • antigens, virus like particles and capsomer are per se known. See for example WO94/00152, WO94/20137, WO94/05792, and WO93/02184.
  • Additional early proteins may be included alone or as fusion proteins such as preferably E7, E2 or E5 for example; particularly preferred embodiments of this includes a VLP comprising L1E7 fusion proteins (WO 96/11272) .
  • Particularly preferred HPV 16 antigens comprise the early proteins E6 or E7 in fusion with a protein D carrier to form Protein D - E6 or E7 fusions from HPV 16, or combinations thereof; or combinations of E6 or E7 with L2 (WO 96/26277).
  • HPV 16 or 18 early proteins E6 and E7 may be presented in a single molecule, preferably a Protein D- E6/E7 fusion.
  • Such vaccine may optionally contain either or both E6 and E7 proteins from HPV 18, preferably in the form of a Protein D - E6 or Protein D - E7 fusion protein or Protein D E6/E7 fusion protein.
  • the vaccine of the present invention may additionally comprise antigens from other HPV strains, preferably from strains HPV 6, 11, 31, 33, or 45.
  • Vaccines of the present invention further comprise antigens derived from parasites that cause Malaria.
  • preferred antigens from Plasmodia falciparum include RTS,S and TRAP.
  • RTS is a hybrid protein comprising substantially all the C-terminal portion of the circumsporozoite (CS) protein of P. falciparum linked via four amino acids of the preS2 portion of Hepatitis B surface antigen to the surface (S) antigen of hepatitis B virus. It's full structure is disclosed in the International Patent Application No. PCT/EP92/02591 , published under Number WO 93/ 10152 claiming priority from UK patent application No.9124390.7.
  • RTS When expressed in yeast RTS is produced as a lipoprotein particle, and when it is co-expressed with the S antigen from HBV it produces a mixed particle known as RTS,S.
  • TRAP antigens are described in the International Patent Application No. PCT/GB89/00895, published under WO 90/01496.
  • a preferred embodiment of the present invention is a Malaria vaccine wherein the antigenic preparation comprises a combination of the RTS,S and TRAP antigens.
  • Other plasmodia antigens that are likely candidates to be components of a multistage Malaria vaccine are P.
  • the formulations may also contain an anti-tumour antigen and be useful for the immunotherapeutic treatment cancers.
  • the adjuvant formulation finds utility with tumour rejection antigens such as those for prostrate, breast, colorectal, lung, pancreatic, renal or melanoma cancers.
  • Exemplary antigens include MAGE 1 and MAGE 3 or other MAGE antigens for the treatment of melanoma, PRAME, BAGE or GAGE (Robbins and Kawakami, 1996, Current Opinions in Immunology 8, pps 628-636; Van den Eynde et al., International Journal of Clinical & Laboratory Research (submitted 1997); Correale et al. (1997), Journal of the National Cancer Institute 89, p293. Indeed these antigens are expressed in a wide range of tumour types such as melanoma, lung carcinoma, sarcoma and bladder carcinoma.
  • Tumor-Specific antigens are suitable for use with adjuvant of the present invention and include, but are not restricted to Prostate specific antigen (PSA) or Her-2/neu, KSA (GA733), MUC-1 and carcinoembryonic antigen (CEA). Accordingly in one aspect of the present invention there is provided a vaccine comprising an adjuvant composition according to the invention and a tumour rejection antigen.
  • PSA Prostate specific antigen
  • KSA Her-2/neu
  • CEA carcinoembryonic antigen
  • said antigen may be a self peptide hormone such as whole length Gonadotrophin hormone releasing hormone (GnRH, WO 95/20600), a short 10 amino acid long peptide, in the treatment of many cancers, or in immunocastration.
  • GnRH Gonadotrophin hormone releasing hormone
  • a short 10 amino acid long peptide in the treatment of many cancers, or in immunocastration.
  • compositions of the present invention will be used to formulate vaccines containing antigens derived from Borrelia sp.
  • antigens may include nucleic acid, pathogen derived antigen or antigenic preparations, recombinantiy produced protein or peptides, and chimeric fusion proteins.
  • the antigen is OspA.
  • the OspA may be a full mature protein in a lipidated form virtue of the host cell (E.Coli) termed (Lipo-OspA) or a non-lipidated derivative.
  • non-lipidated derivatives include the non-lipidated NSl -OspA fusion protein which has the first 81 N-terminal amino acids of the non-structural protein (NSl) of the influenza virus, and the complete OspA protein, and another, MDP-OspA is a non-lipidated form of OspA carrying 3 additional N-terminal amino acids.
  • Vaccines of the present invention may be used for the prophylaxis or therapy of allergy.
  • Such vaccines would comprise allergen specific (for example Der pi) and allergen non-specific antigens (for example peptides derived from human IgE, including but not restricted to the stanworth decapeptide (EP 0 477 231 Bl)).
  • Non-live influenza virus preparations may be derived from the conventional embryonated egg method, or they may be derived from any of the new generation methods using tissue culture to grow the virus.
  • Suitable cell substrates for growing the virus include for example dog kidney cells such as MDCK or cells from a clone of MDCK, MDCK-like cells, monkey kidney cells such as AGMK cells including Vero cells, or any other cell type suitable for the production of influenza virus for vaccine purposes.
  • Suitable cell substrates include human cells e.g. MRC-5 cells. Suitable cell substrates are not limited to cell lines; for example primary cells such as chicken embryo fibroblasts are also included.
  • the influenza virus antigen preparation may be produced by any of a number of commercially applicable processes, for example the split flu process described in patent no. DD 300 833.
  • Commercially available split influenza includes FluarixTM which is sold by SmithKline Beecham, as such Fluarix in combination with the adjuvant of the present invention constitute a preferred vaccine of the present invention.
  • the influenza vaccine according to the invention is preferably a multivalent influenza vaccine comprising two or more strains of influenza. Most preferably it is a trivalent vaccine comprising three strains.
  • Conventional influenza vaccine generally comprise three strains of influenza, two A strains and one B strain.
  • monovalent vaccines which may be useful for example in a pandemic situation, are not excluded from the invention.
  • a monovalent, pandemic flu vaccine will most likely contain influenza antigen from a single A strain.
  • a preferred vaccine formulation comprises egg or tissue culture influenza antigen, preferably split influenza antigen, a polyoxyethylene alkyl ether and at least one additional non-ionic surfactant, optionally comprising a bile salt or derivative of cholic acid.
  • this vaccine comprises split influenza virus antigen, polyoxyethylene-9 lauryl ether and TRITON-X 100TM.
  • this most preferred vaccine may further comprise a polyoxyethylene sorbitan ester, such as TWEEN80TM, and/or sodium deoxy cholate.
  • each vaccine dose is selected as an amount which induces an immunoprotective response without significant, adverse side effects in typical vaccinees. Such amount will vary depending upon which specific immunogen is employed and how it is presented. Generally, it is expected that each dose will comprise 1-1000 ⁇ g of protein, preferably 1-500 ⁇ g, preferably l-100 ⁇ g, most preferably 1 to 50 ⁇ g. An optimal amount for a particular vaccine can be ascertained by standard studies involving observation of appropriate immune responses in subjects. Following an initial vaccination, subjects may receive one or several booster immunisation adequately spaced.
  • the adjuvant affect of the polyoxyethylene alkyl ether is enhanced synergistically by the additional non-ionic surfactant.
  • the synergy may be observed in the magnitude of the immune response from the combined adjuvant formulation being greater than the sum of the immune responses generated by each individual component when used alone.
  • synergism may also be observed when low doses of polyoxyethylene ether and additional non-ionic surfactant generate significant immune responses, even when one or each component may not generate significant or detectable immune responses when used alone.
  • One aspect of the present invention is adjuvant and vaccine formulations comprising a polyoxyethylene alkyl ether or ester and at least one additional non-ionic surfactant, wherein the antigen present in the vaccine is not entrapped within a non- ionic surfactant vesicle.
  • the vaccines of the present invention may also be administered via the oral route.
  • the pharmaceutically acceptible excipient may also include alkaline buffers, or enteric capsules or microgranules.
  • the vaccines of the present invention may also be administered by the vaginal route.
  • the pharmaceutically acceptable excipients may also include emulsifiers, polymers such as CARBOPOL ® , and other known stablilisers of vaginal creams and suppositories.
  • the vaccines of the present invention may also be administered by the rectal route.
  • the excipients may also include waxes and polymers known in the art for forming rectal suppositories.
  • the formulations of the present invention may be used for both prophylactic and therapeutic purposes. Accordingly, the present invention provides for a method of treating a mammal susceptible to or suffering from an infectious disease or cancer, or allergy, or auto-immune disease. In a further aspect of the present invention there is provided an adjuvant combination and a vaccine as herein described for use in medicine. 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. 1978.
  • One embodiment of the present invention relates to the use of non-ionic surfactants such as a polyoxyethylene alkyl ether or ester of general formula (I), and an octoxynol, in the manufacture of an adjuvant formulation.
  • non-ionic surfactants such as a polyoxyethylene alkyl ether or ester of general formula (I), and an octoxynol
  • the present invention also relates to the use of a polyoxyethylene alkyl ether or ester of general formula (I), an octoxynol, and an antigen, in the manufacture of vaccine formulations.
  • said adjuvant and vaccines manufactured as described may further comprise an polyoxyethylene sorbitan ester.
  • the preferred polyoxyethylene alkyl ether is polyoxyethylene-9 lauryl ether
  • the preferred Octoxynol is t-octylphenoxy polyethoxyethanol (Triton X- 100TM).
  • the adjuvants of the present invention may further be combined with other adjuvants including Cholera toxin and its B subunit, E.Coli heat labile enterotoxin LT, its B subunit LTB and detoxified versions thereof such as mLT; Monophosphoryl Lipid A and its non-toxic derivative 3-O-deacylated monophosphoryl lipid A (3D-MPL, as described in UK patent no.
  • immunologically active saponin fractions e.g. Quil A derived from the bark of the South American tree Quillaja Saponaria Molina and derivatives thereof (for example QS21, US Patent No.5, 057, 540), and the oligonucleotide adjuvant system CpG (as described in WO 96/02555), especially 5 TCG TCG TTT TGT CGT TTT GTC GTT 3' (SEQ ID NO. 1).
  • an adjuvant combination of a polyoxyethylene alkyl ether such as polyoxyethylene-9 lauryl ether
  • additional non-ionic surfactant such as t- octylphenoxy polyethoxyethanol (Triton X-100TM)
  • 3-O-deacylated monophosphoryl lipid A (3D-MPL)
  • This preferred embodiment may optionally further comprise a polyoxyethylene sorbitan ester such as TWEEN80TM, and/or a bile salt or cholic acid derivative such as sodium deoxy cholate.
  • Vaccines comprising this adjuvant formulation and influenza antigens, especially split influenza antigens are particularly preferred.
  • ELISA for the measurement of influenza-specific serum Ig Abs in monkeys Maxisorp Nunc immunoplates are coated overnight at 4°C with 50 ⁇ l/well of 1 ⁇ g/ml HA of ⁇ -propiolactone (BPL) inactivated influenza virus (supplied by SSD GmBH manufacturer, Dresden, Germany) diluted in PBS. Free sites on the plates are blocked (1 hour, 37°C) using saturation buffer : PBS containing 1 %BSA, 0.1 % polyoxyethylene sorbitan monolaurate (TWEEN 20).
  • saturation buffer PBS containing 1 %BSA, 0.1 % polyoxyethylene sorbitan monolaurate (TWEEN 20).
  • serial 2-fold dilutions in saturation buffer, 50 ⁇ l per well
  • a reference serum added as a standard curve (serum having a mid-point titer expressed as ELISA Unit/ml, and put in row A ) and serum samples (starting at a 1/100 dilution and put in rows B to H) are incubated for lhr 30mins at 37°C.
  • the plates are then washed ( ⁇ 3) with washing buffer (PBS, 0.1 % polyoxyethylene sorbitan monolaurate (TWEEN 20)).
  • biotinylated goat anti-human Ig (Amersham) diluted 1/3000 in saturation buffer are incubated (50 ⁇ l/well) for lhr 30mins, at 37°C. After 3 washings, and subsequent addition of streptavidin-horseradish peroxidase conjugate (Amersham), plates are washed 5 times and incubated for 20 min at room temperature with 50 ⁇ l/well of revelation buffer (OPDA 0.4 mg/ml (Sigma) and H 2 O 2 0.03 % in 50mM pH 4.5 citrate buffer). Revelation is stopped by adding 50 ⁇ l/well H 2 SO 4 2N. Optical densities are read at 492 and 630 nm by using Biorad 3550 immunoreader. Antibody titre are calculated by the 4 parameter mathematical method using Sof MaxPro software.
  • HAL Hemagglutination Inhibition
  • BPL inactivated whole virus is added (25 ⁇ l / well) at a concentration of 4 Hemagglutination Units (i.e. at a dilution which is 4-fold lower than the last one provoking an agglutination of red blood cells) for 30 minutes at room temperature (RT) under agitation.
  • Chicken red blood cells are then added (25 ⁇ l / well) for 1 hour at RT. Plates are finally kept overnight at 4°C before to be read.
  • the HAI titer corresponds to the inverse of the last serum dilution inhibiting the virus-induced hemagglutination.
  • TT tetanus toxoid
  • mice Maxisorp Nunc immunoplates were coated overnight at 4°C with 50 ⁇ l/well of 1 ⁇ g/ml antigen (TT provided by Behring) diluted in PBS (in rows B to H of plate), or with 50 ⁇ l of 5 ⁇ g/ml purified goat anti-mouse Ig (Boerhinger), in PBS (row A). Free sites on the plates were blocked (1 hour, 37°C) using saturation buffer : PBS containing 1%BSA, 0.1% polyoxyethylene sorbitan monolaurate (TWEEN 20), and 4% Normal Bovine Serum (NBS).
  • saturation buffer PBS containing 1%BSA, 0.1% polyoxyethylene sorbitan monolaurate (TWEEN 20), and 4% Normal Bovine Serum (NBS).
  • IgG isotype mixture added as a standard curve (mixture of mouse monoclonal antibodies IgGl, IgG2a and IgG2b from Sigma, starting at 200 ng ml and put in row A) and serum samples (starting at a 1/100 dilution and put in rows B to H) were incubated for lhr 30mins at 37°C. The plates were then washed ( ⁇ 3) with washing buffer (PBS, 0.1 % polyoxyethylene sorbitan monolaurate (TWEEN 20)).
  • PBS washing buffer
  • TWEEN 20 polyoxyethylene sorbitan monolaurate
  • biotinylated goat anti-mouse IgG (Amersham) diluted 1/5000 in saturation buffer were incubated (50 ⁇ l/well) for lhr 30mins, at 37°C. After 3 washings, and subsequent addition of strep tavidin-horseradish peroxidase conjugate (Amersham), plates were washed 5 times and incubated for 20 min at room temperature with 50 ⁇ l well of revelation buffer (OPDA 0.4 mg/ml (Sigma) and H 2 O 2 0.03% in 50mM pH 4.5 citrate buffer). Revelation was stopped by adding 50 ⁇ l/well H 2 SO 4 2N. Optical densities were read at 492 and 630 nm by using Biorad 3550 immunoreader. Antibody titre were calculated by the 4 parameter mathematical method using SoftMaxPro software.
  • Example 2 Effect of Laureth 9 together with a combination ofTWEEN80 and TritonXlOO on the immunogenicity of an intranasal influenza vaccine in primed Rhesus monkeys
  • the priming was done in Rhesus monkeys by administering with a spray device (under anesthesia) in each nostril 25 ⁇ g HA per strain of ⁇ -propiolactone-inactivated A/Beijing/262/95 and B/Harbin 7/94 influenza virus contained in 100 ⁇ l PBS.
  • monkeys (4 or 5 animals/group) were boosted intranasally (under anesthesia) with 200 ⁇ l of solution (100 ⁇ l per nostril, delivered with a spray device) containing 30 ⁇ g HA strain of BPL-inactivated A/Beijing/262/95 and B/Harbin/7/94 influenza virus in either A: polyoxyethylene-9-lauryl ether 0.5% (L9); B: polyoxyethylene-9- lauryl ether 0.5% + TWEEN80 (0.11%) + triton-X-100 (0.074%); or by C: intramuscular injection of 15 ⁇ g HA strain of an influenza vaccine containing the same strains as in A and B. Viral antigens were grown in eggs from seed stocks by the supplier (SSD GmBH, Dresden, Germany). HAI and Ig Ab responses were measured in sera as described in example 1. Results are expressed as percentages of animals having experienced a 4-fold Ab rise upon boosting.
  • polyoxyethylene-9-lauryl ether is added to the induction of anti-influenza systemic immune responses.
  • this level of adjuvanticity is significantly improved by the addition of additional non-ionic surfactants.
  • polyoxyethylene-9-lauryl ether is supplemented with TWEEN80 and triton-X-100, this formulation is capable of boosting pre-established systemic Ig Ab responses as efficiently as the classical parenteral influenza vaccine.
  • HAI haemagluttination inhibition
  • Example 3 A comparison of the immunogenicity of an intranasal split influenza vaccine formulated with laureth 9 with TWEEN80 and triton-X-100, with the immunogenicity of a licensed conventional parenteral vaccine (FluarixTM) in healthy adult subjects.
  • FluarixTM a licensed conventional parenteral vaccine
  • the formulations contained three inactivated split virion antigens prepared from the WHO recommended strains of the 1998/1999 season.
  • the device used for administration of the vaccines was the AccusprayTM intranasal syringe from Becton Dickinson. The device works on a similar basis to a conventional syringe, but has a special tip containing spiral channels which result in the production of a spray when even pressure is exerted on the plunger. lOO ⁇ l of the formulation was sprayed in each nostril.
  • composition of the formulation contained the following inactivated split virions:
  • the volume of one dose was 200 ⁇ l (lOO ⁇ l sub-doses for each nostril).
  • Formulation A was adjuvanted with laureth 9 to obtain a final concentration of 0.5 % (w/v).
  • the comparator FluarixTM/ ⁇ -Rix® (B) is SmithKlineBeecham Biologicals' commercial inactivated trivalent split influenza vaccine, which is administered intramuscularly in a dose of 500 ⁇ l.
  • TWEEN80 and triton-X-100 compared to the conventional parenteral vaccine i.e.
  • the immunogenicity of the vaccines was examined by assessing the serum haemagglutination inhibition (HI) titres to determine seroconversion rate (defined as the percentage of vaccinees who have at least a 4-fold increase in serum HI titres on day 21 compared to day 0, for each vaccine strain), conversion factor (defined as the fold increase in serum HI Geometric Mean Titres (GMTs) on day 21 compared to day 0, for each vaccine strain) and seroprotection rate (defined as the percentage of vaccinees with a serum HI titre >40 after vaccination (for each vaccine strain) that is accepted as indicating protection ).
  • HI serum haemagglutination inhibition
  • ELISA Enzyme Linked Immunosorbent Assay
  • HI seropositivity, serconversion and seroprotection rates twenty-one days after one dose of FluarixTM or the intranasal formulation can be seen in Table 3.
  • Table 3 HI seropositivity, serconversion and seroprotection rates at 21 days post dose 1 :
  • Seroprotection (n,%) number and percentage of subjects with titer > 40 Seroconversion (n,%) : number and percentage of subjects with at least a 4-fold increase in titres from day 0 to day 21
  • Table 4 Percentages of subjects with a two-fold or a four-fold increase in the specific/total IgA ratio between day 21 and day 0 (1 dose).
  • the immunogenicity results tabulated above show that the intranasal formulation produced similar levels of seropositivity, seroconversion and seroprotection to the conventional parenteral vaccine (FluarixTM) twenty-one days after one dose.
  • the intranasal formulation generally produced a better mucosal IgA response after one dose than the conventional parenteral vaccine (FluarixTM).
  • Example 4 Effect of Laureth-9 together with Triton X100 on the immunogenicity of an intranasal tetanus toxoid vaccine in primed mice
  • mice Tetanus, acellular Pertussis vaccine: ⁇ SIPANRIXTM SmithKline Beecham, Belgium).
  • mice were boosted intranasally (5 ⁇ l in each nostril, under anesthesia) with 5 ⁇ g TT in A: PBS; B: 0.5% polyoxyethylene-9 lauryl ether; C: 0.1% polyoxyethylene-9 lauryl ether; D: 0.1 % polyoxyethylene-9 lauryl ether + 0.02% Triton X100 or; E: by intramuscular injection of the DTPa vaccine (2x50 ⁇ l).
  • D 0.1 % polyoxyethylene-9 lauryl ether + 0.02% Triton X100 or
  • E by intramuscular injection of the DTPa vaccine (2x50 ⁇ l).
  • Two weeks after the boosting the sera were analyzed for their TT-specific IgG.
  • Laureth-9 low dose (0.1 %>) was ineffective in enhancing the boosting response to TT, contrary to the 0.5% dose.
  • the adjuvanticity of that formulation was strongly improved by supplementing it with Triton XI 00 (pO.OOOl).
  • the antibody response elicited was similar to the one induced by the commercial DTPa vaccine.

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