WO2000025814A2 - Constituant pour un vaccin - Google Patents

Constituant pour un vaccin Download PDF

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Publication number
WO2000025814A2
WO2000025814A2 PCT/GB1999/003559 GB9903559W WO0025814A2 WO 2000025814 A2 WO2000025814 A2 WO 2000025814A2 GB 9903559 W GB9903559 W GB 9903559W WO 0025814 A2 WO0025814 A2 WO 0025814A2
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WIPO (PCT)
Prior art keywords
component according
peptide
mimotope
heptapeptide
phage
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PCT/GB1999/003559
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English (en)
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WO2000025814A3 (fr
Inventor
Bambos Michael Charalambous
Ian Michael Feavers
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University College London
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Priority to EP99951011A priority Critical patent/EP1124574A2/fr
Priority to JP2000579253A priority patent/JP2002528517A/ja
Publication of WO2000025814A2 publication Critical patent/WO2000025814A2/fr
Publication of WO2000025814A3 publication Critical patent/WO2000025814A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/02—Bacterial antigens
    • A61K39/095—Neisseria
    • 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
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • C07K14/22—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Neisseriaceae (F)
    • 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
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide

Definitions

  • the present invention relates to a component for a vaccine against meningococci and to a vaccine comprising such a component .
  • Meningococcal meningitis is a serious illness having a mortality rate of approximately 10%. Survivors of meningococcal meningitis may be left with various degrees of permanent neurological damage. In England and Wales alone there are around 1300 to 1500 meningococcal infection cases reported each year. Meningococci are the bacteria responsible for the disease and are divided into a number of different serogroups according to their immunological activity. Of these, serogroups A, B and C are responsible for about 90% meningococcal cases worldwide, whilst serogroup B accounts for more than 50% of the cases in the UK and many other European countries.
  • meningococci each have polysaccharide- containing coats and it has been found in serogroups A and C that such polysaccharides chemically conjugated to T-dependent protein antigens give rise to promising immunogenicity data from clinical trials in infants.
  • serogroups A and C that such polysaccharides chemically conjugated to T-dependent protein antigens give rise to promising immunogenicity data from clinical trials in infants.
  • B polysaccharide which is thought chemically to resemble human cell surface carbohydrates and may therefore be tolerated by the human immune system.
  • meningococci contain a lipooligosaccharide (LOS) component which is a surface glycolipid that forms a major outer membrane component and possesses a terminal galactose acceptor site for sialic acid. It is thought that sialylation of the LOS in immunotype B meningococci enhances the ability of the organism to evade the human immune response. Accordingly, researchers are investigating alternative target antigens on the surface of serogroup B meningococci, especially various protein antigens more likely to elicit an immune response in humans.
  • LOS lipooligosaccharide
  • the present invention aims to overcome the disadvantages of the prior art and provide a component for a vaccine against serogroup B meningococci.
  • the present invention provides a component for a vaccine against serogroup B meningococci, which comprises a mimotope of a surface lipooligosaccharide of a serogroup B meningococcus .
  • a mimotope (conformational homologue) of LOS is capable of eliciting an immune response in vivo .
  • the mimotope is preferable antigenically cross-reactive with a monoclonal antibody of high affinity to the surface lipooligosaccharide.
  • a monoclonal antibody of high affinity to the surface lipooligosaccharide.
  • high affinity is meant having an affinity constant of 10 5 M _1 , preferably at least 10 6 M _1 .
  • Such monoclonal antibodies include the following:
  • Monoclonal antibodies of high affinity to LOS may be prepared using outer membrane complexes as immunizing and detecting antigens according to established protocols (6) (7) .
  • the mimotope preferably comprises a peptide epitope which may be identified by screening a peptide library with the monoclonal antibody.
  • a peptide library such as a heptapeptide library preferably -containing all possible amino acid sequences should be used to give the greatest diversity of potential epitopes against which antigenic cross-reactivity with the monoclonal antibody can be assessed.
  • a random peptide library of this nature is used.
  • the heptapeptide sequence is SMYGSYN or APARQLP.
  • the peptide epitope may comprise a subsequence of any one of the heptapeptide sequences or may be present in a longer peptide incorporating any one of the above heptapeptides or sub-sequences therefrom.
  • the mimotope may comprise an oligopeptide which is structurally more constrained than a linear form of the oligopeptide.
  • An unsubstituted linear oligopeptide such as present free in solution would normally be able to assume a large number of different conformations.
  • an oligopeptide which is structurally constrained, perhaps by having one or usually two or more substituents which reduce in number the possible conformations which it can assume is preferred as the mimotope of the present invention. It is thought that peptides which assume fewer conformations or which have their conformations locked are more likely to elicit an immune response because they present to the binding portion of antibodies a structurally constrained epitope.
  • the oligopeptide may form part of the primary structure of a larger polypeptide containing the amino acid sequence of the oligopeptide.
  • the oligopeptide comprises a cyclic peptide, as discussed in further detail below.
  • substituents include covalent linkages to other moieties such as macromolecular structures including biological and non- biological structures.
  • biological structures include carrier proteins such as those described below for enhancing the immunogenicity of the mimotope.
  • non-biological structures include lipid vesicles such as micelles and the like.
  • the oligopeptide comprises a cyclic peptide. Use of a cyclic peptide is thought to be superior to a linear peptide because the cyclic peptide is able to assume fewer conformations that the linear peptide and is therefore structurally more constrained.
  • the cyclic peptide comprises a cyclised portion, which cyclised portion preferably comprises an amino acid sequence, the terminal amino acids of which are linked together by a covalent bond.
  • the covalent bond is conveniently a disulphide bridge, such as found between cysteine residues.
  • the cyclised portion typically comprises a heptapeptide and this heptapeptide can conveniently form part of the amino acid sequence which is flanked by the " amino acids which are linked by the covalent bond to form the cyclised portion.
  • the N terminal of the cyclic peptide preferably comprises an A residue.
  • the oligopeptide may be generated from a peptide library in the same way as described above.
  • a typical oligopeptide is shown in Figure 6 of the drawings.
  • the heptapeptide of the cyclised portion has the sequence SWXHXPY, wherein each X is the same or different and is an amino acid, preferably a naturally-occurring amino acid.
  • Particularly useful sequences are SWLHMPY, SWMHMPY, SWDHMPY and NTIGGYE.
  • SWLHQPY is a particularly preferred heptapeptide sequence which may be flanked by cysteine residues and is preferably terminated at the N terminal by an A residue. It is preferred that the N terminal A residue is unacetylated and preferably does not carry a charge as this may interfere with the immunogenicity of the oligopeptide. It is thought that at least a part of the peptide epitope i present in the heptapeptide.
  • a carrier is conjugated to th mimotope to enhance the immunogenicity thereof.
  • a number o carriers are known for this purpose, including variou immunogenic protein-based carriers such as diptheria toxoid (d CRM ⁇ g 7 )or tetanus toxoid and T-cell peptide.
  • the component for the vaccine may incorporate a plurality o mimotopes of the surface lipooligosaccharide in which eac mimotope is the same or different. By having more than on mimotope, the immunogenicity of the component may be enhanced.
  • the plurality of mimotopes may be conjugated together, fo example using a polylysine to which each mimotope is conjugated.
  • the serogroup B meningococcus is Neisseri meningitidis .
  • the present invention provides a vaccin comprising a component according to any one of the precedin claims optionally together with an adjuvant so as to increas the immune response thereto.
  • the present invention provides a method for producing a component for a vaccine against serogroup B meningococci, which method comprises screening with a monoclonal antibody a mimotope library comprising candidate mimotopes, and selecting at least one candidate mimotope with high affinity to the monoclonal antibody, wherein the monoclonal antibody has high affinity to a surface lipooligosaccharide of a sergroup B meningococcus .
  • the monoclonal antibody is preferably as described above and the mimotope preferably comprises a peptide epitope as discussed above.
  • the mimot-ope library preferably comprises a peptide library comprising candidate peptides, such as those described above.
  • the peptide library comprises a peptide phage-display library.
  • FIGURE 1 shows a graph of real time interaction kinetics of a monoclonal antibody with a peptide vaccine component according to the present invention
  • FIGURE 2 shows a graph of real time binding interaction of the monoclonal antibody with immobilised LOS protein of Neiseria meningi tidis;
  • FIGURE 3 shows an immunological response of mice sera to LOS 3
  • FIGURE 4 shows a further immunological response of mice sera to
  • FIGURE 5 shows the immunological responses of individual mice sera against LOS 3, 7, 9;
  • FIGURE 6 shows a schematic representation of a cyclic heptapeptide at the free N-terminus of the M13 phage membrane protein PHI;
  • FIGURE 7 shows initial rate constant for binding of peptides of the present invention to monoclonal antibody 9-2-L379;
  • FIGURE 8 shows a bar graph of phage particles recovered after each round of bio-panning with the monoclonal antibody.
  • FIGURE 9 shows a bar graph of phage particles bound in phage binding assays using various cyclic heptapeptides .
  • Serogroup B meningococcus immunotype LOS3,7,9 is the immunotope responsible for >50% of cases of bacterial meningitis seen in Europe.
  • An aim of this study is to determine whether linear peptides, selected by binding to LOS3,7,9 immunotyping antibodies, will elicit protective antibodies that cross-react with LOS3,7,9, when used to immunise animals. Initially, the binding characteristics of two LOS3,7,9 immunotyping antibodies were studied by resonant mirror analysis. The antibody with the greatest affinity for the LOS antigen was then chosen to "biopan" a heptapeptide phage-display library.
  • Monoclonal immunotyping antibodies The two immunotyping monoclonal antibodies to be studied, 9-2-L379 and 4A8-B2, (kind gifts from Drs . Zollinger and Poolman, respectively) were purified from ascitic fluid by standard Protein G affinity chromatography, and made up to a stock concentration of 1 ⁇ M.
  • Heptapeptide phage display library An M13 peptide phage display library (Ph.D.7) from New England Biolabs was used. The DNA sequences encoding random heptapeptides were inserted in to gene III, which encodes a surface protein expressed at one tip of the phage. The 21 nucleotide insertions were 3' to the sequence coding for the leader sequence so that the peptide is free at its N-terminus and attached to Protein III via its C- terminus .
  • the LOS coated biosensor surface was treated with 20mM HC1 to remove any weakly bound substances before interaction kinetics were performed, and also to regenerate the LOS surface after each antibody interaction.
  • the kinetic data for both the antibodies were all determined from the same LOS-coated biosensor cuvette.
  • Immobilisation of the consensus peptide to the biosensor cuvette surface The peptide was biotinylated by Chiron Technologies, Ltd to permit immobilisation to a biotin-coated biosensor cuvette via a streptavidin bridge.
  • Resonant mirror biosensor analysis The binding kinetics of the monoclonal antibodies were determined to the immobilized nLOS3,7,9 with an IAsys resonant mirror biosensor (Affinity Sensors, Saxon Way, Bar Hill, Cambridge) . Real-time kinetic analyses were performed in PBS / 0.05 % (v/v) Tween-20 at 25°C, according to the methods described by the manufacturer.
  • K 0FF Dissociation (K 0FF ) rates were determined by dilution to zero concentration of unbound antibody in the biosensor cuvette at high concentrations of interacting antibody. K 0FF and K Ass rates were calculated from the arc second response per second over various periods of time, and averaged. K Ass rates were plotted as a function of antibody concentration, and the slope of the linear regression gave the K 0N rate.
  • K A The Affinity constant
  • K D Dissociation equilibrium constant
  • the binding kinetics of 9-2-L379 used to biopan the heptapeptide library were determined to the immobilised consensus peptide.
  • the concentration of Tween-20 was 0.5% (v/v) in the PBS, identical to the biopanning buffer.
  • Biopanning a heptamer peptide phage-display library The immunotyping monoclonal antibody 9-2-L379 was immobilised to a carboxymethylated dextran coated biosensor cuvette surface by WO 00/25814 _ l ⁇ PCT/GB99/03559
  • the buffer was carefully pipetted into a sterile Eppendorf tube, and neutralised with 1 M Tris .
  • the harvested phage particles were amplified by infection of Escherichia coli and titrated. 2 x 10 11 phage particles from this 1 st biopan were then reacted with the immobilised antibody as before.
  • the phage from the second biopanning were then amplified and titrated, and 2 x 10 11 phage particles biopanned for a third time.
  • Phage from all three biopannings were isolated, and the region of the DNA insertion expressing the heptapeptide was sequenced.
  • Peptide synthesis The consensus peptide sequences were identified, and one peptide (#12) was synthesised with a cysteine bridge in the C-terminal position, the same site as its attachment to the M13 phage Protein III (Chiron Technologies, Ltd) . This enabled attachment to a sulfhydryl-coated ELISA plate for immunoassays, or the conjugation to the carrier protein, diptheria toxoid CRM ⁇ 97 for immunising animals, or to biotin for immobilisation to the resonant mirror biosensor cuvette surface.
  • mice 2 independent groups of 10 BALB/c mice were immunised subcutaneously (and boosted at 4 weeks) with : 20 ⁇ g of the consensus peptide #12; the peptide conjugated to CRM 19 7 carrier; the whole M13 phage displaying the consensus peptide; suitable buffer +/- CRM 197 as controls. Immunisations were performed with or without adjuvant. When adjuvant was included Freund' s complete adjuvant (CFA) was used in the initial immunisation, and Freund' s incomplete adjuvant in the booster. Serum samples were obtained at 4 weeks by exsanguinating 5 out of the 10 mice immunised; the remaining 5 mice were boosted and exsanguinated at 6 weeks.
  • CFA complete adjuvant
  • Antibody assays Cross-reactive anti-NmLOS3 , 7 , 9 antibody activity in pooled (5 mice) or individual serum samples was determined by a solid phase immunoassay with microtiter plates ( ⁇ unc, Roskilde, Denmark) coated with purified nLOS 3,7,9 (2) overnight at 37°C, according to Verheul, . et al (4) .
  • the secondary antibody (diluted 1 : 2000) was a rabbit anti-mouse IgG conjugated to peroxidase.
  • the magnitude of the cross- reactive serum antibody response to LOS3,7,9 was calculated from the geometric means obtained from double logio plots of OD4 5 0 and the reciprocal of the serum dilution.
  • the ratio of the anti- logio reciprocal serum dilution between the immunised and the control mice at -1.0 log ⁇ 0 OD 450 gave the magnitude of the response .
  • Binding kinetics of the immunotyping monoclonal antibodies The affinity constants for 4A8-B2 and 9-2-L379 were 4.0 x 10 6 M "1 and 1.3 x 10 8 M -1 ; the latter antibody having a 44 - fold faster K 0N rate (5) . Since 9-2-L379 had a greater affinity towards the LOS3,7,9, we chose it to undertake the biopanning of the random heptapeptide library.
  • Biopanning experiments Data from the biopanning experiments revealed the presence of several consensus peptide sequences (see Table I) . This initial study focused on consensus peptide #12 S ⁇ M ⁇ Y ⁇ G ⁇ S ⁇ Y ⁇ N.
  • Fig. 1 shows the binding interaction of 9-2-L379 with immobilised consensus peptide #12.
  • the consensus peptide #12 conjugated to biotin was immobilised to a biotin-coated biosensor cuvette via a streptavidin bridge.
  • Various concentrations of the monoclonal antibody 9-2-L379 were reacted with the immobilised peptide in PBS / 0.5% (v/v) Tween- 20 at 25°C.
  • K 0FF dissociation
  • Fig. 2 shows in real-time the binding interaction of antibody 9-2-L379 with immobilised N ⁇ -LOS3 , 7, 9.
  • Antibody 9-2-L379 (130nM) was preincubated with either 50nM ( ), 25nM (-) of the consensus peptide #12, or buffer (-) for 3h at room temperature prior to interacting with LOS3,7,9 immobilised on the biosensor cuvette surface.
  • the binding interaction profiles of 50nM and 25nM peptide #12 were subtracted from the respective 9-2-L379 + peptide binding profiles.
  • the consensus peptide #12 competed with the binding interaction of the 9-2- L379 antibody to the immobilised nLOS3, 7 , 9 (Fig. 2).
  • mice immunised with diptheria toxoid (CRM 197 ) + adjuvant generated a small, but insignificant cross-reactive response to ⁇ LOS3,7,9.
  • the geometric mean was not parallel to either the peptide immunised or the control sera (Fig 3, right panel) .
  • Fig. 4 shows the averaged immunological data of pooled sera from 2 independent experiments. Mice were immunised with either PBS + adjuvant (control), or with 20 ⁇ g peptide #12 - DT + adjuvant. The data were linearised by a double logio plot and the geometric mean was determined. Error bars indicate the range of the average values .
  • the Figure shows individual sera diluted 1 : 100 from control and peptide #12-diptheria toxoid + adjuvant immunised groups mice.
  • Example 2 investigates the potential of cyclic peptides to act as structural mimics (mimotopes) of meningococcal LOS.
  • a phage library displaying random cyclised heptapeptides that are structurally constrained by a disulphide bridge between two cysteine residues as shown in Figure 6 was subjected to biopanning to establish whether such peptides are better mimotopes than linear peptides.
  • Biopanning a cyclic peptide phage-display library An M13 bacteriophage library displaying random cyclic heptapeptides at the free N-terminus of the PHI membrane protein (PhD C7C, Biolabs) was bio-panned against the anti-MnLOS mAb 9-2-L379 coated onto microtitre wells. M13 plaques were picked from an E . col i lawn after four rounds of enrichment with the anti-MnLOS 3,7,9 mAb 9-2-L379. DNA was prepared by standard procedures and sequenced from primers provided in the phage library kit (Ph.D- C7C, New England Biolabs) .
  • the peptide sequences are expressed at the N-terminus of the PHI protein of the M13 phage.
  • the more prevalent sequence (CIO) obtained after four rounds of enrichment is shown schematically in Figure 6.
  • the residues SWLHQPY are randomly displayed by the phage whereas the others are non-variable .
  • the line between the cysteine residues represents a covalent linkage via a disulphide bridge.
  • Table II shows the peptide sequences of enriched phae clones.
  • Kinetic analysis Kinetic analyses were performed on a resonant mirror biosensor at 25°C according to the methods described by the manufacturer (Affinity Sensors, Saxon Way, Bar Hill, Cambridge) ) . Briefly, Streptavidin was captured on to a biotin- coated biosensor cuvette, to which the biotinylated peptides or MnLOS 3,7,9 were immobilised. The buffer used in the kinetic analysis was PBS with 0.5% (v/v) Tween-20, identical to the bio- panning buffer. The kinetic data were analysed by curve fitting software (FASTfit v2.01, Affinity Sensors).
  • K 0FF rates (arc second response per second) were determined by dilution to zero concentration of various concentrations of the mAb 9-2-L379 in the biosensor cuvette.
  • the dissociation rate constants (K d i SS ) were then calculated by averaging the K 0FF rates.
  • the association rate constants (K aS s) were determined from the slope of the linear regression analyses of the K 0N rates plotted as a function of mAb concentration.
  • Figure 7 shows the results of kinetic analyses performed on a resonant mirror biosensor.
  • the association rate constants (K ass ) were calculated from the slopes of the K ON rates versus mAb 9-2-L379 concentration.
  • the binding interactions are monitored routinely 3 times per second and the data averaged during the initial monophasic part of the binding interaction. Linear regression analysis was then used to best- fit the data. Error bars indicate standard deviations.
  • the dissociation equilibrium constant (K D ) was calculated from K diss / K ass .
  • Table HI shows binding affinity constants (K D ) of the anti-MnLOS 3,7,9 mAb 9-2-L379 to its native LOS3,7,9 antigen and to consensus cyclic and linear peptides identified with this mAb.
  • Phage binding assay Following four rounds of bio-panning with the anti-MnLOS mAb 9-2-L379 phage clones expressing the cyclic heptapeptides CIO, B5, C19, Bll, and C22 were enriched. A cyclic peptide was picked at random (RC) from the unscreened phage library as a negative control. In the phage binding assay 10 11 phage were interacted with either antiMnLOS mAb 9-2-L379, or as negative controls, an anti-MnPorin mAb specific for the PI.7 subtype, or with BSA. Both mAbs and the BSA were made up to 50 ⁇ g/ml and used to coat microtitre plate wells.
  • Cys-Ser-Tryp-Leu-His-Gln-Pro-Tyr-Cys- (CIO; amino acid residues in blue are coded by the phage DNA to enable the peptide to cyclise) , with several other peptides only varying from this consensus peptide by a single amino acid substitution at one or two positions only (Table II). Furthermore, the frequency of the
  • CIO sequence was increased as the stringency of the bio-panning was raised by decreasing the concentration of the 9-2-L379 mAb in the fourth round from 50 ⁇ g/ml to 0.5 ⁇ g/ml (Table II).
  • a phage binding assay was performed. Phage clones expressing the consensus peptides were amplified and 10 11 phage particles were interacted for 60 minutes with either immobilised 9-2-L379 mAb, or as negative controls with a sub-typing mAb specific for the meningococcal Porin protein antigen PI.7, or with BSA.
  • a phage clone was picked at random from the original phage library and interacted with either mAb

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Abstract

Constituant pour un vaccin contre les méningocoques du sérogroupe B, qui comporte un mimotope d'un lipooligosaccharide de surface d'un méningocoque du sérogroupe B.
PCT/GB1999/003559 1998-10-30 1999-10-27 Constituant pour un vaccin WO2000025814A2 (fr)

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EP99951011A EP1124574A2 (fr) 1998-10-30 1999-10-27 Constituant pour un vaccin
JP2000579253A JP2002528517A (ja) 1998-10-30 1999-10-27 ワクチン成分

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GB9823835.5 1998-10-30
GBGB9823835.5A GB9823835D0 (en) 1998-10-30 1998-10-30 Component for vaccine

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Cited By (4)

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WO2002028888A2 (fr) * 2000-10-03 2002-04-11 Glaxosmithkline Biologicals S.A. Compose pour vaccin
WO2002072616A2 (fr) * 2001-03-14 2002-09-19 Ich Productions Limited Complexes de transfection
EP1554305A1 (fr) * 2002-10-23 2005-07-20 Centre for Research and Technology Hellas/Institute of Agrobiotechnology Sequences peptidiques liant la proteine prion
WO2009040529A1 (fr) * 2007-09-28 2009-04-02 Ulive Enterprises Limited Vaccin bactérien

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US11433139B2 (en) * 2018-03-16 2022-09-06 Zoetis Services Llc Peptide vaccines against interleukin-31
WO2021162054A1 (fr) * 2020-02-10 2021-08-19 学校法人順天堂 Inhibiteur de l'activité du récepteur de la ryanodine de type 2

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WO1997046582A1 (fr) * 1996-06-05 1997-12-11 Peptide Therapeutics Limited Vaccin meningococcique
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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002028888A2 (fr) * 2000-10-03 2002-04-11 Glaxosmithkline Biologicals S.A. Compose pour vaccin
WO2002028888A3 (fr) * 2000-10-03 2004-02-19 Glaxosmithkline Biolog Sa Compose pour vaccin
WO2002072616A2 (fr) * 2001-03-14 2002-09-19 Ich Productions Limited Complexes de transfection
WO2002072616A3 (fr) * 2001-03-14 2003-07-03 Ich Productions Ltd Complexes de transfection
US7256043B2 (en) 2001-03-14 2007-08-14 Ich Productions Limited Transfection complexes
EP1964849A3 (fr) * 2001-03-14 2009-01-21 ICH Productions Limited Complexes de transfection
US7704969B2 (en) 2001-03-14 2010-04-27 Ich Productions Limited Transfection complexes
US8026341B2 (en) 2001-03-14 2011-09-27 Ich Productions Limited Transfection complexes
EP1554305A1 (fr) * 2002-10-23 2005-07-20 Centre for Research and Technology Hellas/Institute of Agrobiotechnology Sequences peptidiques liant la proteine prion
WO2009040529A1 (fr) * 2007-09-28 2009-04-02 Ulive Enterprises Limited Vaccin bactérien

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GB9823835D0 (en) 1998-12-23

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