EP0546031A1 - Peptide von enteroviren - Google Patents

Peptide von enteroviren

Info

Publication number
EP0546031A1
EP0546031A1 EP91915656A EP91915656A EP0546031A1 EP 0546031 A1 EP0546031 A1 EP 0546031A1 EP 91915656 A EP91915656 A EP 91915656A EP 91915656 A EP91915656 A EP 91915656A EP 0546031 A1 EP0546031 A1 EP 0546031A1
Authority
EP
European Patent Office
Prior art keywords
thr
val
ala
gly
amino acid
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Withdrawn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
EP91915656A
Other languages
English (en)
French (fr)
Inventor
Jonas Blomberg
Rüdiger Pipkorn
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.)
Replico Medical AB
Original Assignee
Replico Medical AB
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Replico Medical AB filed Critical Replico Medical AB
Publication of EP0546031A1 publication Critical patent/EP0546031A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/24011—Flaviviridae
    • C12N2770/24111—Flavivirus, e.g. yellow fever virus, dengue, JEV
    • C12N2770/24122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/32011—Picornaviridae
    • C12N2770/32311—Enterovirus
    • C12N2770/32322—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/32011—Picornaviridae
    • C12N2770/32611—Poliovirus
    • C12N2770/32622—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/32011—Picornaviridae
    • C12N2770/32711—Rhinovirus
    • C12N2770/32722—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • 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 new peptides, to a diagnostic antigen, to the use of said diagnostic antigen in immunoassays and to a vaccine containing said diagnostic antigen.
  • Picornaviruses are a family of small RNA viruses which are responsible for a variety of diseases in humans and animals.
  • the diseases may be severe, like poliomyelitis (caused by polioviruses types 1, 2, and 3), hepatitis (caused by hepatitis A virus) and generalized neonatal enterovirus infection (often caused by Coxsackie and ECHO viruses), as well as mild, like the common cold (caused by rhinoviruses).
  • poliomyelitis caused by polioviruses types 1, 2, and 3
  • hepatitis caused by hepatitis A virus
  • generalized neonatal enterovirus infection often caused by Coxsackie and ECHO viruses
  • a clinical virological laboratory receives many samples every year for diagnosis of picornavirus infections.
  • the picornavirus family is divided into the enterovirus, rhinovirus and hepatitis A subfamilies.
  • the enteroviruses and hepatitis A viruses are the ones where a diagnosis is most often sought.
  • the enteroviruses are further divided into polio-, Coxsackie A, Coxsackie B and ECHO viruses on the basis of their pathogenicity in mice.
  • the enteroviral disease where a diagnosis is most often required is aseptic meningitis, but myocarditis, encephalitis, generalized neonatal infection and hand-, foot and mouth disease also constitute rather frequent clinical problems.
  • Flavivirus is another virus family which e.g. causes yellow fever and encephalitis. These diseases are spread by mosquitos and ticks and constitute a major worldwide problem.
  • the Dengueviruses and TBE-virus are types of flaviviruses. There is currently no therapy for these infections, so the diagnosis of picornavirus and flavivirus infections serves mostly to exclude other diseases or to give
  • the diagnosis of a picornavirus infection can be made either by virus isolation or by serology.
  • a serum sample taken early in the course of the infection an acute phase serum
  • a serum taken 1-3 weeks later a convalescent phase serum
  • an antibody assay most commonly a complement fixation assay (see e.g. Sever JL. Application of a microtechnique to viral serological investigations.
  • the antigen then is a purified or semipurified preparation from picornavirus-infected cells. If non-heat-treated virus antigens are used, a relatively type-specific antibody assay is obtained. If a heattreated viral antigen is used, a more group-specific assay is obtained. Presumably, the virus undergoes a conformational change upon heating, exposing group-specific antigenie determinants. The conformational change mostly seems to involve the N-terminus of VP1 [Fricks CE, Hogle JM. Cell-induced conformational change in poliovirus: Externalization of the amino terminus of VP1 is responsible for liposome binding. J. Virol. 64:193-1945 (1990)1.
  • One object of the present invention is to provide new peptides which can be used as a diagnostic antigen in immunoassays.
  • Another object of the present invention is to use a diagnostic antigen for more specific diagnosing of diseases or infections caused by picornavirus and/or flavivirus and/or discriminating between false and true diagnosed HIV-1 positive sera.
  • Still another object of the present invention is to provide a vaccine based on said peptides against diseases or infections caused by picornavirus and/or flavivirus.
  • the present invention relates to peptides of the formula:
  • the present invention relates to a diagnostic antigen having the ability to detect antibodies against at least one type of picornavirus and flavivirus in sera, and/or having the ability of binding to antibodies with a binding affinity for compounds containing an amino acid sequence corresponding to an epitope or cluster of epitopes of HIV-1 p17, wherein said antigen mainly comprises an antigen selected from the peptides according to claim 1 and antigenic parts thereof.
  • the present invention relates to the use of at least one diagnostic antigen for diagnosis of infections caused by picornaviruses and/or flaviviruses, wherein the diagnostic antigen or antigens having the ability to detect antibodies against at least one type of picornavirus and flavivirus are added to a serum from a subject suspected to have a recent or previous picornavirus and/or flavivirus infection, and possible antigen/ antibody complexes formed are detected using an immunoassay, the diagnosis of said recent or previous infection(s) caused by picornaviruses and/or flaviviruses being established based either upon demonstration of antibodies in a single serum or upon a comparison of the amounts of antibodies detected in both acute and convalescent phase sera, and if said amount in the convalescent phase serum is significantly larger than in the acute phase serum, the subject donating the serum suffers or has suffered from a picorna- and/or flavivirus infection, wherein the antigen containing the peptides
  • Y 1 is Ala or Thr and Y 2 is Val or Ile, is primarily used for diagnosis of diseases caused by yellow fever virus and Japanese encephalitis virus, e) H-X-R 1 -Thr-Asp-Y 1 -Gly-His-Asp-Thr-Val-Y 2 -R 2 -X-Z,
  • Y 1 is Ser or Thr and Y 2 is Ile or Val, is primarily used for diagnosis of diseases caused by
  • Y 1 is His or Tyr and Y 2 is Ile or Thr, is primarily used for diagnosis of diseases caused by
  • R 1 and R 2 represent optional amino acid residues, wherein R 1 and R 2 together represent at most 25 amino acid residues, and Z represents -NH- or -OH.
  • the present invention relates to the use of a diagnostic antigen for discriminating between a false and true diagnosed HIV-1 positive serum sample, which has first been diagnosed as positive in a standard HIV-1 antibody screening EIA test and then found to exhibit a p17 pattern of serological activity in an electrophoretic immunoblot assay, wherein at least one diagnostic antigen having the ability of binding to antibodies which have a binding affinity for compounds containing an amino acid sequence corresponding to an epitope or cluster of epitopes of HIV-1 p17, optionally coupled to a carrier, is added to said serum sample, and possible antigen/antibody complexes formed are detected using an immunoassay, the discrimination being established such that said serum sample is false HIV-1 positive if said complexes are detected, and true HIV-1 positive if said complexes are not detected.
  • the present invention relates to a vaccine composition which comprises as an immunizing component at least one picornavirus and/or flavivirus antigen selected from at least one of the peptides above.
  • one X represents a chemical bond and the other X represents a chemical bond or a coupling-facilitating sequence of at least 4, and preferably 8, particular amino acid residues, which are all chosen from the group consisting of -Thr- and -Ser-.
  • X is an amino acid sequence, it can be located either in the C- or N-terminus of the peptides but not in both ends at the same time. If it is for example located in the C-terminus, X in the N-terminus corresponds to a chemical bond and vice versa. However, X can be a bond at both ends of the peptide according to the present invention.
  • the amino acid sequence acts as a coupling-facilitating spacer, which permits proper binding to the carrier to which the peptides according to the present invention will be bound during the discrimination method.
  • the sequence X should not be an amino acid
  • amino acids threonine and serine also fulfill these requirements particularily well, and any one of the amino acids in said sequence X can be threonine or serine.
  • the number of amino acids in this spacer sequence should be at least 4, but in a preferred embodiment according to the present invention 8 amino acids are used.
  • R 1 and R 2 are optional amino acid residues and together represent at most 25 amino acid residues, preferably 20. Further, this means that one or both of R 1 and R 2 can be a chemical bond, i.e. contain no amino acids. If R 1 is a sequence containing e.g. 25 amino acid residues, R 2 must be a chemical bond and vice versa.
  • antigenic parts thereof as used herein means antigenic parts in the essential amino acid sequence between R 1 and R 2 in the peptides according to the present invention.
  • polypeptides according to the present invention can be bound via the amino acid sequence X to a carrier by physical/chemical interaction, as for example covalent binding, ionic binding, hydrogen binding or hydrophobic binding.
  • covalent binding are ester, ether and disulfide binding.
  • carrier as used herein should be interpreted broadly, and it may be any material which is compatible with and not adversely affects the method according to the present invention, for example resins, microplates, plastic surfaces, gels, matrixes etc.
  • epitope as used herein means antigenic or immunogenic determinant and relates to a specific part of a structure of an antigen inducing an immuno response, and the antibodies produced are directed against this part.
  • the immunoassay method according to the present invention can be an enzyme immunoassay (EIA), radioimmunoassay (RIA), immunoassay involving metal labelling, fluorescence immunoassay (FIA) or an immunoassay in which the peptide is soluble and inhibits another reaction.
  • EIA enzyme immunoassay
  • RIA radioimmunoassay
  • FIA fluorescence immunoassay
  • the vaccine composition according to the present invention comprises at least one picornavirus and/or flavivirus antigen selected from the peptides according to the present invention together with a non-toxic pharmaceutically acceptable carrier and/or a diluent in an amount effective to protect a subject from diseases caused by picornavirus and/or flavivirus.
  • the vaccine composition comprises an antigen adjuvant in an amount which together with an amount of said picornavirus and/or flavivirus antigen(s) is effec tive to protect a subject from diseases caused by picornaviruses and/or flaviviruses.
  • the vaccine composition additionally comprises one or more buffers and/or preservatives.
  • the peptides according to the invention are derived from sequences which are exposed upon heat inactivation of picornavirus or are situated on the other envelope proteins of flavivirus particles, and they are able to detect broadly cross-reactive picornavirus and flavivirus antibodies. This makes it possible to diagnose picornaviral and/or flaviviral infections or diseases by the use of only one or a few peptides from the highly conserved antigenically active picornaviral and flaviviral sequence.
  • the peptide sequences according to the present invention can be said to derive from a common basic structure which can be expressed as the consensus sequence
  • picornavirus this sequence is situated at one site in VP1 in the amino acids 20-40. In flavivirus, it is situated about 80 amino acids from the transmembrane region of the E-glucoprotein. In both cases, the sequence participates in interactions with the outer membrane of the host cell. In both cases, the sequence is also concealed to antibodies during part of the replication cycle of the virus, but becomes accessible to them, for instance when the virus has come into contact with the outer membrane of the cell.
  • the invention can be considered to belong to a previously unknown class of sequences having a common structure and function.
  • the peptides can be used for diagnosing diseases caused by both picornavirus and flavivirus, the peptides can, because of their common origin, structure and function, however with a certain, appropriate
  • amino acids be comprised by the same inventive concept.
  • Many or all of the peptides, preferably 3-4, according to the present invention can be included in one and the same assay for diagnosing different
  • lamely peptide (f) directed against Denguevirus was found, for instance, to strongly bind to a peptide
  • the ability of producing neutralising antibodies is one of the characteristics required of a vaccine, it must be considered highly likely that the peptides according to the present invention are usable as antigens in vaccine compositions against the above-mentioned picornavirus- and/or flavivirus-induced diseases.
  • Table 1 refers to the alignment of some different viral amino acid sequences from the region of similarity with HIV-1 p17.
  • the peptides according to the present invention can be used as a diagnostic antigen to detect antibodies in both acute and convalescent phase sera. If the amount of antibody detected in the convalescent serum is significantly larger than in the acute serum, the person donating the blood samples is believed to suffer from a picornavirus infection.
  • the expression "significantly larger” as used herein is a standard concept in this area (see J.
  • antibodies belonging to the IgM class and reactive with at least one of the picornaviral and/or flaviviral peptides described in the present invention are detected in one or more sera from a patient, then the patient is likely to suffer from a disease caused by a picornavirus and/or a flavivirus.
  • the peptides according to the present invention can further be used as a supplementary test during the
  • anti-p17 reaction can be abrogated by preabsorption or competition with one of the peptides according to the present invention, it is unlikely that the anti-p17 reaction is caused by antibodies to a picornavirus and/or flavivirus.
  • the as yet unpublished Swedish patent application 8903985-3 filed on November 27, 1989, also by Replico AB, describes new peptides, diagnostic antigens containing said peptides and having the ability of binding to anti ⁇ bodies which have a binding affinity for compounds containing an amino acid sequence corresponding to an epitope or a cluster of epitopes of HIV-1 p17, and a method of discriminating between a false and true diagnosed HIV-1 positive serum sample using an immunoassay.
  • the technical background, proper definitions, and some of the methods used in connection with the use of the peptides according to the present invention in the p17 area are described in said Swedish patent application.
  • HIV-1 EIB reactivities may give rise to HIV-1 electrophoretic immunoblot patterns which are hard to interpret.
  • HIV-1 EIB reactivities is characterized by a reactivity with HIV-1 p17, but with no other HIV-1 protein. The reactivity with p17 peptides in sera from healthy Swedes which had the p17 pattern of serological reactivity has been studied.
  • Figure 1 shows absorption of five p17 positive sera with resin without peptide, resin with HIV-1 gag 118-140, resin with HTLV-I gag 111-130 (the C-terminus of HTLV-I), and resin with Coxsackie B1 VP125-53.
  • the intensity of the p17 band in EIB (y axis) was measured with a
  • Figure 2 shows the serological reactivity of a peptide derived from Coxsackie B1 VP1 25-53 with
  • p17-derived peptides were compared with that of a Coxsackie B1-derived peptide. 10 p17 positive sera, 19 HIV seronegative blood donors, 6 sera from confirmed HIV-1 seropositive persons (1 adult and 5 children, aged 1-7), and acute and convalescent sera from six patients with aseptic meningitis with significant (at least fourfold) titre rises in complement fixation antibody tests against Coxsackie B1-B6 antigen were analyzed.
  • Coxsackie antibodies were measured, by titration in standard microtitre complement fixation antibody tests with Coxsackie B1, B2, B3, B4, B5, and B6 antigens.
  • the diagnostic antigens according to the present invention can be utilized in methods for the same purpose as the claimed use of said diagnostic antigens.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Virology (AREA)
  • Peptides Or Proteins (AREA)
EP91915656A 1990-08-16 1991-08-16 Peptide von enteroviren Withdrawn EP0546031A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9002671 1990-08-16
SE9002671A SE470074B (sv) 1990-08-16 1990-08-16 Förfarande för diagnos av picorna- och/eller flavivirusinfektion, peptider, diagnostiska antigener och vaccinkomposition med dessa peptider

Publications (1)

Publication Number Publication Date
EP0546031A1 true EP0546031A1 (de) 1993-06-16

Family

ID=20380170

Family Applications (1)

Application Number Title Priority Date Filing Date
EP91915656A Withdrawn EP0546031A1 (de) 1990-08-16 1991-08-16 Peptide von enteroviren

Country Status (4)

Country Link
EP (1) EP0546031A1 (de)
AU (1) AU649473B2 (de)
SE (1) SE470074B (de)
WO (1) WO1992003475A1 (de)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2596600A (en) 1998-12-31 2000-07-31 Chiron Corporation Modified hiv env polypeptides
US7211659B2 (en) 2001-07-05 2007-05-01 Chiron Corporation Polynucleotides encoding antigenic HIV type C polypeptides, polypeptides and uses thereof
US20030170614A1 (en) 2001-08-31 2003-09-11 Megede Jan Zur Polynucleotides encoding antigenic HIV type B polypeptides, polypeptides and uses thereof
EP3608332B1 (de) * 2013-03-15 2022-06-01 GlaxoSmithKline Biologicals SA Impfstoff gegen humanes rhinovirus

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AT384363B (de) * 1982-10-05 1987-11-10 Immuno Ag Verfahren zur verwendung von antigenreaktiven peptiden zur herstellung von gegen fsme-virusinfektionen wirksamen vakzinen
EP0220273B2 (de) * 1985-04-29 2007-01-17 Bio-Rad Laboratories, Inc. Synthetische antigene zum nachweis von aids
JPH0768267B2 (ja) * 1986-06-05 1995-07-26 財団法人阪大微生物病研究会 フラビウイルス抗原
JPH01501203A (ja) * 1986-10-27 1989-04-27 フォーニアー，モーリル・ジェイ 日本脳炎ウイルス及び類似ウイルスの診断及びワクチン
EP0284791B1 (de) * 1987-03-20 1995-05-03 IMMUNO Aktiengesellschaft DNA- und RNA-Moleküle des westlichen Subtyps des FSME-Virus, Polypeptide, die von diesen Molekülen codiert werden, und deren Verwendung
JPH084508B2 (ja) * 1987-09-16 1996-01-24 国立予防衛生研究所長 組み換えワクチニアウイルス
GB8821077D0 (en) * 1988-09-08 1988-10-05 Wellcome Found Peptides

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9203475A1 *

Also Published As

Publication number Publication date
SE9002671L (sv) 1992-02-17
SE9002671D0 (sv) 1990-08-16
AU8400291A (en) 1992-03-17
SE470074B (sv) 1993-11-01
AU649473B2 (en) 1994-05-26
WO1992003475A1 (en) 1992-03-05

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