AU619826B2 - A synthetic vaccine against foot and mouth disease and a process for the preparation thereof - Google Patents

A synthetic vaccine against foot and mouth disease and a process for the preparation thereof Download PDF

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AU619826B2
AU619826B2 AU33265/89A AU3326589A AU619826B2 AU 619826 B2 AU619826 B2 AU 619826B2 AU 33265/89 A AU33265/89 A AU 33265/89A AU 3326589 A AU3326589 A AU 3326589A AU 619826 B2 AU619826 B2 AU 619826B2
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membrane
synthetic vaccine
mouth disease
foot
vaccine
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Gunter Hess
Gunther Jung
Karl-Heinz Wiesmuller
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Sanofi Aventis Deutschland GmbH
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Hoechst AG
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • 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
    • C12N2770/00MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011Details
    • C12N2770/32011Picornaviridae
    • C12N2770/32111Aphthovirus, e.g. footandmouth disease virus
    • C12N2770/32122New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

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Description

Form COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952-69 COMPLETE SPECIFICATION
(ORIGINAL)
Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority: o Rdig.ed Art: 0 0 I o HOECHST AKTIENGESELLSCHAFT bJame of Applicant: Address of Applicant: 0 Actual Inventor: 'Address for Service: 0 50 Bruningstrasse, D-6230 Frankfurt/Main Republic of Germany 80, Federal KARL-HEINZ WIESMULLER, GUNTER HESS and GUNTHER JUNG EDWD. WATERS SONS, 50 QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.
Complete Specification for the invention entitled: A SYNTHETIC VACCINE AGAINST FOOT AND MOUTH DISEASE AND A PROCESS FOR THE PREPARATION THEREOF The following statement is a full description of this invention, including the best method of performing it known to 1.
VI
HOECHST AKTIENGESELLSCHAFT HOE 88/F 091 Dr. WN/rh Description A synthetic vaccine against foot and mouth disease and a process for the preparation thereof The present invention relates to a vaccine against foot and mouth disease and a process for the preparation thereof.
Foot and mouth disease (FMD) causes great losses 4n cattle breeding, despite vaccines which have now been available for a long time. One reason for the occurrence of foot and mouth disease at present is the unreliability of classical vaccines which contain killed or inactivated o O* FMD viruses: the inactivation of the virus is occasioni .O ally incomplete so that "post-vaccination" outbreaks of FMD may occur (cf. Bbhm, Strohmaier, Tierarztl. Umschau 39, 3 8 (1984)). This danger does not exist with 00 Os j o synthetic FMD vaccines because in the latter only partial 0 0 sequences of certain viral proteins, which do not have the function of an intact virus, are used.
120 Although synthetic FMD vaccines already exist (cf.
European Patent Application 0,204,480) they are still in need of improvement.
It has now been found that particularly effective FMD vaccines can be prepared using membrane-anchoring compounds and certain partial sequences of the FMD virus.
I Although the preparation of synthetic vaccines is mentioned in German Offenlegungsschrift DE 3,546,150 Al as one of many possible uses of membrane anchor/active substance conjugates, it was not to be expected that the conjugates of membrane-anchoring compounds and partial sequences of the FMD virus (membrane anchor/active substance conjugates) would exhibit the exceptional activity which has been found on administration of relatively small amounts of vaccine.
2 Furthermore, the said vaccines are distinguished, surprisingly, by providing an adequate protection even after a single administration of the vaccine. Moreover, they have the advantage by comparison with conventional vaccines that virtually unliimited storage without cooling is possible.
Accordingly, the invention relates to a synthetic vaccine against foot and mouth disease, which vaccine comprises a conjugate of at least one membrane-anchoring compound and at least one partial sequence of a protein of the foot and mouth disease virus.
0 0 900 0 0 00 00 00 0000 00 0 O 0 S15 00 00 0 0 0 o0 0 0 0 0 0 0000 0 0 00 0 0 00 *0o2 0 0 0 0 125 0* Membrane-anchoring compounds are compounds which can be embedded in biological or synthetic membranes.
Further information on membrane-anchoring compounds is to be found in the German Offenlegungsschrift 3,546,150 already cited and in G. Jung et al. in "Peptides, Structure and Function", V.J. Hruby and D.H. Rich, pages 179 to 182, Pierce Chem. Co. Rockford, Illinois, (1983).
Preferred membrane anchor/active substance conjugates are those in which a membrane-anchoring compound and an active substance, i.e. a partial sequence of an FMD virus, are linked together covalently.
Particularly suitable membrane anchor/active substance conjugates have proven to be those in which the membraneanchoring compound is a lipoprotein. Very particularly suitable are membrane-anchoring compounds of the following formulae R -CO-0-CH 2 R'-CO-0-CH*
I
(CH2n
(IH
2 )n
A
R"-CO-NH-CH*-CO-X
R -CO-NH-CH*-CO-X R -O-CH 2 R'-0-6H* (CH2n
H
2 )n
A
(IH
2)m
R"-CO-NH-CH*-CO-X
R -O-CO-OH 2 R'-0-CO-CH* A (CH 2 )m H (CH2
R"-CO-NH-CH*-CO-X
II. III, -3 R -CO-CH 2
B
1 -C 0-OH.
R -Nil-CO-CH R' -NH-CO-OH (OH)n (dH2) B A A A (CH (OH 2 (Cm R"-CO-NH-CH -CO-X R"-CO-NH-CH -OO-X B"-NH-OO-OH -O-X IV. V. VI.
B-CmI 1 2 B -CH*
(CH
o A 4 0 (O B -CC- N H 000 'a 00
VI
0 0 a 0 O 0 0 0 a0 a00 in whi4ch A can be sulfur, oxygen, disulfide methylene (-CH 2 or -NH-; n =0 to 5, m 1 or 2; C* is an asymmetric carbon atom with the R~ or S conf ig-uration, R, R' and R" are identical or different and each is hydrogen or an alkyl, alkenyl or alkynyl group which has 7 to 25 carbon atoms and which can be substituted by hydroxyl, amino, oxo, acyl, alkyl or cycloalkyl groups, B in formula VI can have the meaning of each of the
-(CH
2 )n-(substituted alkyl) radicals listed in formulae I-V, and RI and R 2 are identical or different and have the same meanings as R, R' and R" but can also be -OR, -O-COR, -COOR, NHCOR or -CONHR, where X is a chain of 1 to 10 amino acids to which the partial sequence of the virus is bonded.
Examples of these to be particularly emphasized are: N-termini occuring in bacterial lipoprotein, such as, for example: Y-Ser-Ser-Ser-Asn, Y-Ile-Leu-Leu-Ala, Y-Ala-Asn- Asn-Gln, Y-Asn-Ser-Asn-Ser, Y-Gly-Ala-Met-Ser, Y-Gln-Ala- Asn-Tyr, Y-Gln-Val-Asn-Asn, Y-Asp-Asn-Ser-Ser, where Y can be one of the radicals listed under formula I to VII.
15 These lipopentapeptides can also be used in shortened ,t form (lipodi, lipotri or lipotetrapeptides) as membranei anchoring compound. Very particularly preferred is Npalmitoyl-S-[2,3-(bispalmitoyloxy)propyl]-cysteinyl- S, seryl-serine (Pam 3 Cys-Ser-Ser), N-palmitoyl-S-[2,3-(bis- 0 a palmitoyloxy)propyl]-cysteinyl-seryl-glycine and Npalmitoyl-S-[2,3-(bispalmitoyloxy)propyl]-cysteinylo @09a alanyl-D-isoglutamine. Examples of other preferred membrane-anchoring compounds are to be found in German Offenlegungsschrift 3,546,150.
Many different partial sequences can be employed as the partial sequences of the FMD virus which are bonded to o.oa the membrane-anchoring compound. The following partial 04 sequences are preferred: SPartial sequence -(134-154) -(135-154) -(134-158) -(134-160) -(141-160) -(141-158) -(200-213) -(200-210) -(161-180) it being possible to use the sequences of all known ili:ii serotypes and subtypes. Examples of serotypes which may be indicated in this connection are: Serotype A:
A
5 Westerwald 134 160 NKYSTGGP RRGDMGSAAARAAI(QLP 161 180 ASFNYGAI HAlTIHELLVRM 200 213 RHKQKI IAPARQLL
A
12 'USA 134 160
NKYSASGSG-VRGDFGSLAPRVARQLP
161 180
ASFNYGAIKAETIHELLVRM
200 212 RHKQKI IAPGKQL 0 00a 000 06 0 06) 00 0 0 0 0 Serotype C: C3. Oberbayern 134 160 TTY TAST RGDLAHLTAT RAGHLP 161 180 TSFNFGAUXAETI TGLLVAM 200 213
RHKQPLVAPAKQLL
060 0v~fl 0 0gC.~J 66 0 0 00 o 0 0 6 06 00CC 0 066060 0 0 006 o25 0 00 Serotype 0: 01 Xauf beuren 01 Lausanne 02 Normandy 0 Wuppertal 0 Israel 01 Kaufbeuren 01 Kaufbeuren 134
CRYNRNAVPNLRGDLQVLAQKVARTLP
CRYSRNAVPNLRGDLQVLAQKVARTLP
RRYSRI4AVPNVRGDLQALGQKARTLP CLYSDARVSNVRGDLQVLAQKAERALj
CRYGNVAVTNVRGDLQVLAQKAERAILP
200 213
RHKQKIVAPVKQTL
161 180
TSFNYGAIKATRVTELLYRM
160 Particularly suitable synthetic vaccines are those which are composed of a mixture of peptides from various sero- 6 and/or subtypes of the foot and mouth disease virus, each of which is covalently bonded to the membrane-anchoring compound(s).
Particularly preferred synthetic vaccines are those which are composed of a mixture of sequences VP1 134-160 of serotypes 0, A and C, bonded to the membrane-anchoring compound N-palmitoyl-S-[2,3-(bispalmitoyloxy)propyl]cysteinyl-seryl-serine.
When the sequence 134-154 from serotype 0 and the sequence 134-155 from serotype A are used, the latter can, as long as it contains C-terminal lysine, be linked covalently via the e-amino group to the membrane-anchoring compound.
C P Particularly suitable synthetic vaccines according to the invention have proven to be those which contain the partial sequence of FMD virus VP 1 (135-154).
Additionally particularly preferred is a vaccine composed of N-palmitoyl-S-[2,3-(bispalmitoyloxy)propyl]-cysteinyl- Sseryl-seryl-VP 1 (135-154), i.e. the compound of the 20 formula below.
S°135 ArgTyr Asn'A Asn Asp Val T h Ala 0*0 t: (Asn Gy Leu tp o I pro Val li Ser Arg Arg l s Co0
A
la
CH
2
-CH-CH
2
CH
2
-CH
6 0 N H Gin C- C:O 0-C .s 7 The membrane-anchoring compounds can, in principle, be in the form of R,S or R,R diastereomers or of a mixture of diastereomers. However, it has emerged that the vaccines which contain a R,R-diastereomeric membrane-anchoring compound have particularly high activity.
The invention additionally relates to a process for the preparation of a synthetic vaccine, which comprises bonding partial sequences of the FMD virus by a conjugation reaction to the membrane-anchoring compound. The conjugation reaction can be, for example, a condensation, addition, substitution, oxidation or disulfide formation, Preferred conjugation methods are indicated in Example 1.
Further conjugation methods are described in German Offenlegungsschrift 3,546,150 which has already been *o .'15 cited.
0 to 0 a The preparation of the membrane-anchoring compounds is O likewise described in detail in the last-mentioned German 0 0 0 oo Offenlegungsschrift.
0 0 0 0 0 The separation of the diastereomers, which is necessary °00,'20 where appropriate, can also be carried out by a variety o .o of methods as described, for example, in Hoppe-Seyler's Z. Physiolog. Chem. 364 (1983) 593. A preferred separation process is described in Example 2.
0002 The partial sequences of the particular FMD proteins can be constructed in a variety of ways known from the literature, cf., for example, Winsch et al. in Houben- Weyl, vol. 15/1,2, Stuttgart, Thieme-Verlag or Wunsch in Angew. Chem. 83 (1971), 773, E. Gross and J. Meienhofer (editors), The Peptides, vol. 1 (1979), 2 (1979), 3 (1981) and 5 (1983), Academic Press, New York, or German Offenlegungsschrift 3,546,150. A preferred process for the preparation of a partial sequence and of a conjugate is explained in more detail in Example 3.
The invention additionally relates to pharmaceutical or 8 veterinary medical formulations which contain a conjugate of membrane-anchoring compound and partial sequence of a FMD virus. Besides a solvent, there is normally no additional need for additional auxiliaries and carriers or adjuvants for the formulations according to the invention. However, in some cases, it may be worthwhile to add such auxiliaries and/or carriers as well as, where appropriate, adjuvants to the formulations according to the invention. The relevant substances are mixed and dispensed by processes known to those skilled in the art.
The amount of vaccine necessary for reliable immunization of an animal depends on the species, on the membraneanchoring compound(s) and on the partial sequence(s) of the FMD virus and should be determined empirically in the individual case. For example, sufficient for reliable immunization of a guinea pig against FMD virus serotype OK is a single administration of about 100 500 pg of vaccine according to the invention, without further Si, auxiliaries or carriers.
4 9 The invention additionally relates to the use of the described vaccine for raising antibodies in mammals.
a a a Example 1 Conjugation of peptides/proteins with Pam 3 Cys-Ser-Ser-OSu or Pam 3 Cys-Ser-Ser-OH 025 1. Peptides and proteins soluble in DMF 2 pmol of peptide/protein are dissolved in 0.5-1 ml of DMF, and 8 pmol (9.2 mg) of solid Pam 3 Cys-Ser-Ser- OSu are added. A homogeneous solution is obtained by gentle heating and sonication, and 4 pmol of organic base (N-ethylmorpholine) are added. After stirring for 12 h, 1 2 ml of chloroform: methanol are added, and the mixture is cooleu in an ice bath for 2 h.
The sediment is taken up with 1 ml of cold chloro- 9 form:methanol washed in tert.butanol/water (sonicate if necessary) and freeze-dried.
2. Peptides and proteins soluble in water 2 pmol of peptide/protein are dissolved in 0.8 ml of water, and 4 pmol (4.5 mg) Pam 3 Cys-Ser-Ser-OH are added. The mixture is thoroughly sonicated until an emulsion is produced and a pH of 5.0 to 5.5 is set up. After 5 mg of EDC (l-3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride) dissolved in 100 pl of H 2 0 has been added the mixture is stirred at room temperature for 18 h and then dialyzed twice against 1 1 of distilled H20 each time. The contents of the dialysis tube are freeze-dried.
SExample 2 Separation of the diastereomers of N-palmitoyl-S-[2,3- (bispalmitoyloxy)propyl]-cysteine tert.-butyl ester S(PamaCys-OBu t 2 g of Pam 3 Cys-OBu t are dissolved in 10 ml of mobile phase, dichloromethane/ethyl acetate and loaded onto a column (length 120 cm, diameter 4 cm) packed with MN silica gel 60, 0.063-0.2 mm/70 230 mesh ASTM. At a drop rate of 2 drops/sec, 350 fractions each of 10 ml are Scollected, and an aliquot of each fraction is checked for Pam 3 Cys-OBu t after chromatography on silica gel 60 plates in dichloromethane/ethyl acetate (20:1) and staining with ch:Lorine/TDM reagent.
Fractions 280 315 contain the R,R diastereomer, fractions 316 335 contain a mixture of R,R and R,S, and fractions 336 354 contain the R,S diastereomer of Pam 3 Cys-OBu t After the solvent has been evaporated off in a rotary evaporator and the residue has been taken up in warm tert.-butanol and freeze-dried, 600 mg of R,R-, 370 mg of a mixture of R,R- and and 540 mg of R,S- Pam 3 Cys-OBu t are obtained.
L 1 10 Example 3 Synthesis of N-palmitoyl-S- (bispalmitoyloxy)propyl]cysteinyl-seryl-seryl-VP 1 (135-154) The VP 1 peptide sequence of FMD virus serotype 0 1 K was synthesised by solid-phase peptide synthesis. F-ioc-amino acids were used. The following side-chain protective groups were used: Lys(Boc), His(Fmoc), Arg(Mtr), Ser(tBu), Asp(OtBu), Tyr(tBu). Starting from 1. g of (pbenzoyloxybenzyl alcohol)- resin loaded with Fmoc- Lys(Boc)-OH, (0.47 mmol/g), the following synthesis cycles were performed: N-Activation with 55 piperidine in N-methylpyrrolidone S' (1 x 2 min, 1 x 5 min), preactivation of Fmoc-A-A-OH mmol) in N-methylpyrrolidone (6 ml) with diisopropylcarbodiimide (1.5 mmol) and l-hydroxybenzotriazole mmol) with subsequent coupling for 1.5 h. Washing with N-ethylmorpholine (5 in N-methylpyrrolidone) was followed by repetition of the preactivation and coupling.
The blocking of unreacted amino groups was carried out r' 20 with acetic anhydride (2.5 mmol) and diisopropylamine (1.2 mmol) in N-methylpyrrolidone. After each step the peptide-resin was washed several times with N-methylpyrcE< rolidone, dichloromethane and again with N-methylpyrrolidone.
25 After the resin-bound FMD virus sequence had been synthesized, a part of the peptide was obtained by cleavage or r with trifluoroacetic acid and checked by HPLC, MS, amino acid analysis, chiral phase analysis and sequence analysis. The bonding of 2 serine residues to the resin-bound peptide was followed by coupling of the tripalmitoyl-Sglycerylcysteine. After 4 hours 1 equivalent of N-methylmorpholine was added, and after another hour the lipopeptide-resin was washed. The lipopeptide was separated from the resin using 2 ml of trifluoroacetic acid (containing 100 pl of thioanisole) within 4 1/2 hours. The filtrate
SJ
11 was evaporated, the residue was taken up with acetie acid, and the solution was added to cold ether. The precipitated lipopeptide was washed 3 x with ether.
Further purification was achieved by recrystallization from trifluoroethanol/chloroform in the ratio 1:3 with cold acetone and a few drops of water. The lipopeptide was freeze-dried from tert.-butanol/water in the ratio 3:1.
Example 4 Activity test: Guinea pigs with a weight of 450 to 500 g chosen at random were inoculated intramuscularly or subcutaneously.
mg of the freeze-dried vaccine (N-palmitoyl-S- [(2R,R)-2,3-(bispalmitoyloxy)propyl]-cysteinyl-serylseryl-VP1(135-154)) was emulsified in 500 pl of a 1:1 mixture of 0.05 M phosphate buffer and IntralipidR) (Kabi t Vitrum, Sweden). The mixture was sonicated for 10 s. Four t animals were infected with FMD virus by subcutaneous injection into the left rear paw of at least 500 guinea *.20 pigs units of a virulent 0 1 K FMD virus 21 days after the o inoculation. Control animals were injected with the membrane-anchoring compound or phosphate buffer in place of the vaccine. A high titer of neutralizing antibodies log 0
SN
0 o of 0.36 was found in all the inoculated animals.
The control animals had no antibody titer (blank 0.17).
The titer of neutralizing antibodies was determined as the logarithm of the serum dilution necessary to neutralize 50 of the virus cells in a monolayer of BHK (baby hamster kidney) cells. It was possible to detect antibodies in the inoculated animals by means of an antipeptide ELISA (A42G), which was not possible for the noninoculated animals. Inoculated animals showed no secondary lesions, whereas all the non-inoculated animals showed the complete picture of foot and mouth disease infection.

Claims (13)

1. A synthetic vaccine against foot and mouth disease, which vaccine comprises a conjugate of at least one membrane-anchoring compound and at least one partial sequence of a protein of the foot and mouth disease virus.
2. A synthetic vaccine as claimed in claim 1, which comprises a membrane-anchoring compound and a partial sequence of foot and mouth disease virus, which are linked together covalently.
3. A synthetic vaccine as claimed in either of claims o 1 or 2, wherein the membrane-anchoring compound is o a o a bacterial membrane lipoprotein. 0 0 C
4. A synthetic vaccine as claimed in one or more of a0 o claims 1 3, wherein the membrane-anchoring com- 0 a pound has one of the formulae below R -CO-0-CH 2 R -O-CH 2 R -O-CO-CH2 e R'-CO-O-CH* R'-O-CH R-0-CO-COH* (CH2)- 'H2 )n (CH2)n A A A 2)m (H2)m (H2) m R"-CO-NH--CR H-CH*-CO-*.X R"-CO-NH-CH*-CO-X I. ii. III. SR -NH-CO-CH2 R -CO-CH 2 R'-NH-CO-CH* R'-CO-CH* n CH 2)n B A A A (H 2 )m (H 2 )m (H 2 m R"-CO-NH-CH*-CO-X R"-CO-NH-CH*-CO-X R"-NH-CO-CH*-CO-X IV. V. 13 j j 13 R i -CH 2 R 2 -CH* (CH 2 )n (6H 2 )m R-CO-NH-CH*-CO-X VII. in which A can be sulfur, oxygen, disulfide methylene (-CH 2 or -NH-; n 0 to 5, m 1 or 2; C* is an asymmetric carbon atom with the R or S con- figuration, R, R' and R" are identical or different and each is hydrogen or an alkyl, alkenyl or alkynyl group which has 7 to 25 carbon atoms and which can be substitu- ted by hydroxyl, amino, oxo, acyl, alkyl or cyclo- alkyl groups, B in formula VI can have the meaning of each of the -(CH 2 )n-(substituted alkyl) radicals listed in formulae I-V, and R, and R 2 are identical or different and have the same meanings as R, R' and R" but can also be -OR, -0-COR, -COOR, NHCOR or -CONHR, where X is a chain of 1 to 10 amino acids to which the partial sequence of the virus is bonded.
A synthetic vaccine as claimed in one or more of claims 1 4, wherein the partial sequence of the foot and mouth disease virus which is bonded to the membrane-anchoring compound is selected from the group comprising sequence-(134-154) S-(135-154) -(134-158) -(134-160) -(141-160) S-(141-158) 14 14 sequence-(200-213) "-(200-210) -(161-180), or the C-terminal amidated or alkylamidated forms thereof, it being possible to use the sequences of all known serotypes and subtypes.
6. A synthetic vaccine as claimed in one or more of claims 1 5, wherein the partial sequence of the foot and mouth disease virus VP 1 (135-154) is bonded to the membrane-anchoring compound.
7. A synthetic vaccine as claimed in one or more of claims 1 6, which comprises a mixture of peptides from various sero- and/or subtypes of the foot and j .a c mouth disease virus, each of which is covalently bonded to the membrane-anchoring compound or membrane-anchoring compounds. e1 C
8. A synthetic vaccine as claimed in one or more of claims 1 7, which comprises a mixture of sequences VP1 134-160 of serotypes 0, A or C bonded to the oo °membrane-anchoring compound N-palmitoyl-S-[2,3- 0 (bispalmitoyloxy)propyl]-cysteinyl-seryl-serine. 0 *pt
9. A synthetic vaccine as claimed in one or more of claims 1 8, which vaccine comprises N-palmitoyl- S-[2,3-(bispalmitoyloxy)propyl]-cysteinyl-seryl- seryl-VP 1 (135-154), it being possible for the a membrane-anchoring compound to be in the form of the 0 R,S or R,R diastereomer or of a mixture of diastere- omers.
A synthetic vaccine as claimed in one or more of claims 1 to 9, wherein the membrane-anchoring compound is in the form of the R,R diastereomer.
11. A process for the preparation of a synthetic vaccine as claimed in one or more of claims 1 10, which 15 comprises the partial sequences of the foot and mouth disease virus which have been prepared in a manner known per se being bonded to the membrane- anchoring compound by a conjugation reaction.
12. A pharmaceutical or veterinary medical formulation, which contains a synthetic vaccine as claimed in one or more of claims 1 11, where appropriate in addition to customary auxiliaries and/or carriers, adjuvants and/or other vaccines.
13. The use of a synthetic vaccine as claimed in one or more of claims 1 12 for raising antibodies against foot and mouth disease viruses in mammals. iI S fr S' DATED this 20th day of April 1989. Sc HOECHST-AKTIENGESELLSCHAFT Ce EDWD. WATERS SONS PATENT ATTORNEYS C; 50 QUEEN STREET C' MELBOURNE.- VIC.- 3000. o r
AU33265/89A 1988-04-22 1989-04-21 A synthetic vaccine against foot and mouth disease and a process for the preparation thereof Ceased AU619826B2 (en)

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DE3813821 1988-04-22
DE3813821A DE3813821A1 (en) 1988-04-22 1988-04-22 SYNTHETIC VACCINE AGAINST MOUTH AND CLAUS DISEASE AND METHOD FOR THEIR PRODUCTION

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AU619826B2 true AU619826B2 (en) 1992-02-06

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DE58908990D1 (en) 1995-03-23
EP0338437B1 (en) 1995-02-15
DK192889D0 (en) 1989-04-20
ES2068215T3 (en) 1995-04-16
DK192889A (en) 1989-10-23
IE891296L (en) 1989-10-22
PT90333B (en) 1994-08-31
PT90333A (en) 1989-11-10
JP2837866B2 (en) 1998-12-16
EP0338437A3 (en) 1991-05-08
ATE118507T1 (en) 1995-03-15
DK175629B1 (en) 2004-12-27
EP0338437A2 (en) 1989-10-25
AU3326589A (en) 1989-10-26
GR3015358T3 (en) 1995-06-30
IE67124B1 (en) 1996-03-06
DE3813821A1 (en) 1989-11-02
CA1333563C (en) 1994-12-20
AR243081A1 (en) 1993-07-30
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JPH026410A (en) 1990-01-10
ZA892954B (en) 1989-12-27

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