AU8400291A - Enterovirus peptides - Google Patents
Enterovirus peptidesInfo
- Publication number
- AU8400291A AU8400291A AU84002/91A AU8400291A AU8400291A AU 8400291 A AU8400291 A AU 8400291A AU 84002/91 A AU84002/91 A AU 84002/91A AU 8400291 A AU8400291 A AU 8400291A AU 8400291 A AU8400291 A AU 8400291A
- Authority
- AU
- Australia
- 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.)
- Granted
Links
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- 102000004196 processed proteins & peptides Human genes 0.000 title claims description 42
- 241000709661 Enterovirus Species 0.000 title claims description 13
- 239000000427 antigen Substances 0.000 claims description 49
- 102000036639 antigens Human genes 0.000 claims description 49
- 108091007433 antigens Proteins 0.000 claims description 49
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- 238000001514 detection method Methods 0.000 claims 1
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- 102100029905 DNA polymerase epsilon subunit 3 Human genes 0.000 description 27
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- 150000001413 amino acids Chemical class 0.000 description 13
- 230000009257 reactivity Effects 0.000 description 9
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- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 8
- 241000700605 Viruses Species 0.000 description 8
- 101710132601 Capsid protein Proteins 0.000 description 7
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- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 2
- 239000004473 Threonine Substances 0.000 description 2
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- 241000238876 Acari Species 0.000 description 1
- 108091032955 Bacterial small RNA Proteins 0.000 description 1
- 235000011297 Brassica napobrassica Nutrition 0.000 description 1
- 108091035707 Consensus sequence Proteins 0.000 description 1
- 241000709677 Coxsackievirus B1 Species 0.000 description 1
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- 241000710829 Dengue virus group Species 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 206010057199 Flaviviral infections Diseases 0.000 description 1
- 208000007212 Foot-and-Mouth Disease Diseases 0.000 description 1
- 241000710198 Foot-and-mouth disease virus Species 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
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- 108010023958 glycyl-threonyl-alanyl-methionyl-arginyl-isoleucyl-leucyl-glycyl-glycyl-valyl-isoleucine Proteins 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
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- 229910052739 hydrogen Inorganic materials 0.000 description 1
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- 238000002955 isolation Methods 0.000 description 1
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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
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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)
Description
EMTEROVTRUS PEPTIDES
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.
Background art
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). Picornaviruses then are
significant pathogens, and the diagnosis of infections caused by them is an important medical task. 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. Among these, 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
epidemiological information.
The diagnosis of a picornavirus infection can be made either by virus isolation or by serology. In the latter case, for enteroviruses, a serum sample taken early in the course of the infection (an acute phase serum) and a serum taken 1-3 weeks later (a convalescent phase serum) are analyzed with an antibody assay, most commonly a complement fixation assay (see e.g. Sever JL. Application of a microtechnique to viral serological investigations.
J. Immunol, 88:320-329). 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. There are some indications that antibodies to this portion of VP1 can influence the course of infection [Chow M, Yabrov R, Bittle J, Hogle JM, Baltimore D. Synthetic peptides from four separate regions of the poliovirus capsid protein VP1 induce neutralizing antibodies. Proc Natl Acad Sci USA 82:910-914 (1985)1, this making it interesting also as a candidate for vaccination purposes. For flaviviruses, a variety of serological techniques exist, all of which however have great limitations due to lack of sensitivity or specificity.
Thus, there is a need for a means for a more exact diagnosis of diseases caused by picornavirus and flavi
virus, which could further specify and facilitate the treatment of the disease concerned.
Further, there is a need for vaccines for different diseases caused by picornavirus and flavivirus.
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.
All these objects are achieved by the present invention.
Description of the invention
In one aspect, the present invention relates to peptides of the formula:
a) H-X-R1-Ala-Y1-Glu-Thr-Gly-His-Thr-Ser-Gln-Val- R2-X-Z, wherein Y1 is Ala or Val,
b) H-X-R1-Ala-Y1-Glu-Thr-Gly-Ala-Thr-Asn-Pro-Leu- R2-X-Z, wherein Y1 is Ala or Val,
c) H-X-R1-Ala-Ala-Glu-Thr-Gly-His-Thr-Ser-Y1-Val- R 2-X-Z, wherein Y1 is Ser or Asn,
d) H-X-R1-Y1-Asp-Thr-Gly-His-Gly-Thr-Val-Y2-R2-X-Z, wherein Y 1 is Ala or Thr and Y2 is Val or Ile, e) H-X-R1-Thr-Asp-Y1-Gly-His-Asp-Thr-Val-Y2-R2-X-Z, wherein Y1 is Ser or Thr and Y2 is Ile or Val, and
f) H-X-R1-Ala-Glu-Thr-Gln-Y1-Gly-Thr-Y2-Val-R2-X-Z, wherein Y 1 is His or Tyr and Y2 is Ile or Thr, in which one X represents a chemical bond and the other X represents a chemical bond or a coupling-facilitating amino acid sequence, R 1 and R2 represent optional amino acid residues, wherein R 1 and R2 together represent at
most 25 amino acid residues, and Z represents -NH2 or -OH. In another aspect, 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.
In still another aspect, 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
a) H-X-R1-Ala-Y1-Glu-Thr-Gly-His-Thr-Ser-Gln-Val-R2-X-Z, wherein Y1 is Ala or Val, is primarily used for diagnosis of diseases caused by Coxsackievirus, b) H-X-R1-Ala-Y1-Glu-Thr-Gly-Ala-Thr-Asn-Pro-Leu-R2-X-Z, wherein Y1 is Ala or Val, is primarily used for diagnosis of diseases caused by poliovirus,
c) H-X-R1-Ala-Ala-Glu-Thr-Gly-His-Thr-Ser-Y1-Val-R2-X-Z, wherein Y1 is Ser or Asn, is primarily used for
diagnosis of deseases caused by rhinovirus,
d) H-X-R1-Y1-Asp-Thr-Gly-His-Gly-Thr-Val-Y2-R2-X-Z,
wherein Y 1 is Ala or Thr and Y2 is Val or Ile, is primarily used for diagnosis of diseases caused by yellow fever virus and Japanese encephalitis virus, e) H-X-R1-Thr-Asp-Y1-Gly-His-Asp-Thr-Val-Y2-R2-X-Z,
wherein Y 1 is Ser or Thr and Y2 is Ile or Val, is primarily used for diagnosis of diseases caused by
TBE-virus,
and
f) H-X-R1-Ala-Glu-Thr-Gln-Y1-Gly-Thr-Y2-Val-R2-X-Z,
wherein Y 1 is His or Tyr and Y2 is Ile or Thr, is primarily used for diagnosis of diseases caused by
Dengue- and rhinovirus,
in which one X represents a chemical bond and the other X represents a chemical bond or a coupling-facilitating amino acid sequence, R 1 and R2 represent optional amino acid residues, wherein R 1 and R2 together represent at most 25 amino acid residues, and Z represents -NH- or -OH.
In still another aspect, 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.
In still another aspect, 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.
Other characteristics and features of the present invention appear from the attached claims.
In the peptides according to the present invention, 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-. When 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
sequence which adversely affects the result of the diagnosis method. Accordingly, it should not have too high a charge or be too hydrophobiσ and it should not disturb the conformation of the peptides. The 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 R2 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 R2 can be a chemical bond, i.e. contain no amino acids. If R1
is a sequence containing e.g. 25 amino acid residues, R2 must be a chemical bond and vice versa.
The expression "and antigenic parts thereof as used herein means antigenic parts in the essential amino acid sequence between R 1 and R2 in the peptides according to the present invention.
The 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. Examples of covalent binding are ester, ether and disulfide binding.
The expression "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.
The expression "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.
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.
Further, 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.
Further, 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 location of this sequence on the envelope protein, its pronounced evolutionary conservation in flaviviruses and the proven antigeniσity of analogous sequences in picornaviruses make this sequence especially accessible for antibodies suitable for diagnostic and immunisation purposes.
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
aaDTGHxLxV where the capital letters relate to amino acids of strong or complete conservation, the small letters relate to amino acids present in more than half of the cases, and x relates to any amino acid. This common basic structure has been discovered on one and the same occasion and has been described in an article by Blomberg &
Medstrand in New Biologist 2:1044-1046 (1990). In
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. Thus, the peptides according to the present
invention can be considered to belong to a previously unknown class of sequences having a common structure and function. Although 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
variation of the 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
picornavirus- and flavivirus-induced diseases.
As to the presence of the peptides according to the present invention in vaccine compositions, it may initially be stated that the above-mentioned natural basic sequence is included in a region where it has earIler been demonstrated that peptides give rise to neutralising anti¬bodies in rabbit immunisation. In these experiments, however, the peptides according to the present invention were not used, but yet closely related peptide sequences. The evolutionary conservation of said basic sequence confers e.g. the advantage of producing a vaccine inhibiting infection involving many different cold viruses.
As to peptides deriving from flavivirus, the inventor, together with Dr Vincent Deubel at the Arbovirus laboratory at the Pasteur Institute in Paris, has tested the ability of previously known monoclonal antibodies having a virus-neutralising effect, of binding to the
peptides according to the present invention. One of them, lamely peptide (f) directed against Denguevirus, was found, for instance, to strongly bind to a peptide
containing the Dengue variant of the common basic
structure. Since 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.
Blomberg, I. Nilsson and M. Andersson. 1983. Viral antibody screening system that uses a standardized single dilution immunoglobulin 6 enzyme immunoassay with multiple antigens. J. Clin. Microbiol. 17:1081-1091.)
If 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
investigation of an antibody reaction with HIV-1 p17. If 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.
After the introduction of large-scale HIV-1 antibody testing, it has been observed that a small portion of sera from humans unlikely to be HIV-1 infected contains antibodies to one or some HIV-1 proteins, mostly derived from the gag part of the molecule. Such reactivities may give rise to HIV-1 electrophoretic immunoblot patterns which are hard to interpret. One of the most common types of such 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. By direct binding and absorption experiments it has been shown that, in contrast to EIB confirmed HIV-1 antibody positive sera, the p17 positive sera reacted with peptides from the C-terminus of p17. It has furthermore been shown that they contain a stretch highly similar to a conserved sequence from the N-terminus of VP1 of some enteroviruses, and to a lesser extent, flaviviruses.
Brief description of the drawings
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
densitometer.
Figure 2 shows the serological reactivity of a peptide derived from Coxsackie B1 VP1 25-53 with
a/ acute and convalescent phase sera from five cases of aseptic meningitis with significant Coxsackie CF titre rises,
b/ 10 p17 reactive sera,
c/ 19 HIV seronegative blood donors and
d/ 6 confirmed HIV-1 antibody positive sera.
Experiment with a Coxsackie B1 VPl derived peptide
A peptide from amino acids 25-53 of the Coxsackie B1 VP1 sequence (Iizuka, N. , S. Kuge and A. Nomoto. 1987.
Complete nucleotide sequence of the genome of Coxsackievirus B1. Virology 156:64-73.) was synthesized, and its ability to absorb p17 antibodies was compared with that of HIV-1 hxb2 gag 118-140 (Fig. 1). In five out of five sera tested, this peptide in resin-bound form absorbed out all p17 EIB reactivity. HIV-1 hxb2 gag 118-140 also absorbed these antibodies, but less completely. Absorption with resin alone, or with HTLV-I gag 111-130 did not affect the p17 EIB reactivity. The p17 reactive antibodies in these sera thus must bind to epitopes simulated by the resinbound Coxsackie-derived peptide. The peptide was present in vast molar excess compared to antibodies, thus favouring absorption also of low-affinity antibodies.
The reactivity of p17-derived peptides was 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.
As to antibody activity against the Coxsackie peptide among the p17 reactive sera diluted 1/200, it was found that they did not react significantly more than blood donor sera (Fig 2). This may indicate that the Coxsackie peptide, when absorbed to plastic, does not assume a conformation suitable for binding of p17 reactive antibodies, or that it can bind many other antibodies, which obscures a possible correlation. Six HIV-1 confirmed positive sera with clear p17 bands reacted weakly. Five of the sera were selected from children, to reduce the likelihood of previous exposure to a Coxsackie-like virus. Thus, there was no cross-reactivity of p17 antibodies arising during HIV-1 infection to the Coxsackie peptide.
Finally, six serum pairs were tested from patients with aseptic meningitis who had significant titre rises in the complement fixation test with Coxsackie B1-B6 antigen. It was found that five exhibited clear rises in absorbance difference and one reacted strongly on both sera (Fig. 2). A CF antibody titre rise in this system indicates an enterovirus infection, not necessarily with Coxsackie Bl. When the same sera were tested at a dilution of 1/50, almost all reacted strongly (not shown), attesting to the high antigenicity and frequent recognition of this peptide sequence. The Coxsackie peptide may then be a group-reactive reagent suitable for serological diagnosis of
enterovirus infections. The cross-reaction between the Coxsackie B1 VP1 peptide and HIV-1 hxb2 p17 thus was unidirectional, from the enterovirus to HIV-1, but not vice versa. Antibody reactions with the Coxsackie peptide were very common in Swedish sera diluted 1/50. Only a few of them can bind also to HIV-1 p17 in EIB.
The immunoassays used are described in the Swedish patent application above. 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.
Claims (11)
1. Peptides of the formula
a) H-X-R1-Ala-Y1-Glu-Thr-Gly-His-Thr-Ser-Gln- Val-R2-X-Z, wherein Y1 is Ala or Val,
b) H-X-R1-Ala-Y1-Glu-Thr-Gly-Ala-Thr-Asn-Pro- Leu-R2-X-Z, wherein Y1 is Ala or Val,
c) H-X-R1-Ala-Ala-Glu-Thr-Gly-His-Thr-Ser-Y1- Val-R2-X-Z, wherein Y1 is Ser or Asn,
d) H-X-R1-Y1-Asp-Thr-Gly-His-Gly-Thr-Val-Y2-R2- X-Z, wherein Y1 is Ala or Thr and Y2 is Val or Ile,
e) H-X-R1-Thr-Asp-Y1-Gly-His-Asp-Thr-Val-Y2-R2- X-Z, wherein Y1 is Ser or Thr and Y2 is Ile or Val,
and
f) H-X-R1-Ala-Glu-Thr-Gln-Y1-Gly-Thr-Y2-Val-R2- X-Z, wherein Y1 is His or Tyr and Y2 is Ile or Thr,
in which one X represents a chemical bond and the other X represents a chemical bond or a coupling-facilitating amino acid sequence, R 1 and R2 represent optional amino acid residues, wherein R 1 and R2 together represent at most 25 amino acid residues, and Z represents -NH2 or -OH.
2. Peptides according to claim 1, wherein the
coupling-facilitating amino acid sequence represents at least 4, preferably 8, amino acid residues, which are each selected from the group consisting of -Thr- and -Ser-, and R 1 and R2 together preferably represent at most 20 amino acid residues.
3. 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, c h a r a c t e r i s e d in that it mainly comprises an antigen selected from the peptides according to claim 1 and antigenic parts thereof.
4. Use of a diagnostic antigen according to claim 3 for the diagnosis of Infections caused by picornaviruses and/or flaviviruses, wherein a diagnostic antigen having the ability to detect antibodies against at least one type of picornavirus and flavivirus is added to a serum from a subject suspected to have a recent or previous picorna-virus and/or flavivirus infection, and possible antigen/antibody complexes formed are detected using an immunoassay, the diagnosis of said recent or previous infection or infections caused by picornavirus and/or flavivirus 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 sera, and if said amount in the convalescent serum is significantly larger than that in the acute serum, the subject donating the serum is likely to suffer from a picorna- and/or flavivirus infection, wherein the antigen containing the peptide
a) H-X-R1-Ala-Y1-Glu-Thr-Gly-His-Thr-Ser-Gln- Val-R2-X-Z, wherein Y1 is Ala or Val, is primarily used for diagnosis of diseases caused by Coxsackievirus,
b) H-X-R1-Ala-Y1-Glu-Thr-Gly-Ala-Thr-Asn-Pro- Leu-R2-X-Z, wherein Y1 is Ala or Val, is primarily used for diagnosis of diseases caused by poliovirus,
c) H-X-R1-Ala-Ala-Glu-Thr-Gly-His-Thr-Ser-Y1- Val-R 2-X-Z, wherein Y1 is Ser or Asn, is primarily used for diagnosis of diseases caused by rhinovirus,
d) H-X-R1-Y1-Asp-Thr-Gly-His-Gly-Thr-Val-Y2-R2- X-Z, wherein Y1 is Ala or Thr and Y2 is Val or Ile, is primarily used for diagnosis of diseases caused by yellow fever virus and Japanese encephalitis virus,
e) H-X-R1-Thr-Asp-Y1-Gly-His-Asp-Thr-Val-Y2-R2- X-Z, wherein Y1 is Ser or Thr and Y2 is Ile or Val, is primarily used for diagnosis of diseases caused by TBE-virus,
and
f) H-X-R1-Ala-Glu-Thr-Gln-Y1-Gly-Thr-Y2-Val-R2- X-Z, wherein Y1 is His or Tyr and Y2 is Ile or Thr, is primarily used for diagnosis of diseases caused by Dengue- and rhinovirus, in which one X represents a chemical bond and the other X represents a chemical bond or a coupling-facilitating amino acid sequence, R 1 and R2 represent optional amino acid residues, wherein R 1 and R2 together represent at most 25 amino acid residues, and Z represents -NH2 or -OH.
5. Use of a diagnostic antigen according to claim 3 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-I positive if said complexes are not detected.
6. Use according to claims 4 and 5, c h a r a c t e r i s e d in that the immunoassay for diagnosis of diseases caused by picornavirus and/or flavivirus and for detection of said antibody/antigen complex, respectively, is an enzyme immunoassay (EIA), radioimmuno assay (RIA), immunoassay involving metal labelling, fluorescence immunoassay (FIA) or an immunoassay in which the peptide is soluble and inhibits another reaction.
7. Use according to claims 4 and 5, c h a r a c t e r i s e d in that the carrier is a resin, microplate, plastic surface, gel or matrix.
8. Use according to claims 4-7, c h a r a c t e r i s e d in that in the diagnosis and discrimination use is simultaneously made of many or all, preferably 3-4, of the diagnostic antigens according to claim 3.
9. A vaccine composition, c h a r a c t e r i s e d in that it comprises as an immunizing component, at least one antigen selected from at least one peptide from the group consisting of
a) H-X-R1-Ala-Y1-Glu-Thr-Gly-His-Thr-Ser-Gln- Val-R2-X-Z, wherein Y1 is Ala or Val,
b) H-X-R1-Ala-Y1-Glu-Thr-Gly-Ala-Thr-Asn-Pro- Leu-R2-X-Z, wherein Y1 is Ala or Val,
c) H-X-R1-Ala-Ala-Glu-Thr-Gly-His-Thr-Ser-Y1- Val-R2-X-Z, wherein Y1 is Ser or Asn,
d) H-X-R1-Y1-Asp-Thr-Gly-His-Gly-Thr-Val-Y2-R2- X-Z, wherein Y1 is Ala or Thr and Y2 is Val or Ile,
e) H-X-R1-Thr-Asp-Y1-Gly-His-Asp-Thr-Val-Y2-R2- X-Z, wherein Y1 is Ser or Thr and Y2 is Ile or Val, and
f) H-X-R1-Ala-Glu-Thr-Gln-Y1-Gly-Thr-Y2-Val-R2- X-Z, wherein Y1 is His or Tyr and Y2 is Ile or Thr,
in which one X represents a chemical bond and the other X represents a chemical bond or a coupling-facilitating amino acid sequence, R 1 and R2 represent optional amino acid residues, wherein R 1 and R2 together represent at most 25 amino acid residues, and Z represents -NH- or -OH, and antigenic parts thereof, together with a non-toxic pharmaceutically acceptable carrier and/or diluent.
10. A vaccine composition according to claim 9, c h a r a c t e r i s e d in that it comprises said picorna- and/or flavivirus antigen or antigens in an amount effective to protect a subject from diseases caused by picornaviruses and/or flaviviruses.
11. A vaccine composition according to claim 9, c h a r a c t e r i s ed in that it further comprises an antigen adjuvant in an amount which together with an amount of said picornavirus and/or flavivirus antigen or is effective to protect a subject from diseases caused by picornaviruses and/or flaviviruses.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9002671 | 1990-08-16 | ||
| SE9002671A SE470074B (en) | 1990-08-16 | 1990-08-16 | Method for diagnosis of picorene and / or flavivirus infection, peptides, diagnostic antigens and vaccine composition with these peptides |
| PCT/SE1991/000542 WO1992003475A1 (en) | 1990-08-16 | 1991-08-16 | Enterovirus peptides |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU8400291A true AU8400291A (en) | 1992-03-17 |
| AU649473B2 AU649473B2 (en) | 1994-05-26 |
Family
ID=20380170
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU84002/91A Ceased AU649473B2 (en) | 1990-08-16 | 1991-08-16 | Enterovirus peptides |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0546031A1 (en) |
| AU (1) | AU649473B2 (en) |
| SE (1) | SE470074B (en) |
| WO (1) | WO1992003475A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2299276T3 (en) | 1998-12-31 | 2008-05-16 | Novartis Vaccines And Diagnostics, Inc. | MODIFIED HIV ENV POLIPEPTIDES. |
| CA2634992C (en) | 2001-07-05 | 2012-10-16 | Novartis Vaccines And Diagnostics, Inc. | 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 |
| UY35418A (en) * | 2013-03-15 | 2014-10-31 | Glaxosmithkline Biolog Sa | Vaccine that provides protection against different human Picornaviruses. |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT384363B (en) * | 1982-10-05 | 1987-11-10 | Immuno Ag | METHOD FOR USE OF ANTIGENS REACTIVE PEPTIDES FOR THE PRODUCTION OF VACCINES ACTIVE AGAINST TBE VIRUS INFECTIONS |
| WO1986006414A1 (en) * | 1985-04-29 | 1986-11-06 | Genetic Systems Corporation | Synthetic antigens for the detection of aids-related disease |
| JPH0768267B2 (en) * | 1986-06-05 | 1995-07-26 | 財団法人阪大微生物病研究会 | Flavivirus antigen |
| JPH01501203A (en) * | 1986-10-27 | 1989-04-27 | フォーニアー，モーリル・ジェイ | Diagnosis and vaccines for Japanese encephalitis virus and similar viruses |
| ES2074422T3 (en) * | 1987-03-20 | 1995-09-16 | Immuno Ag | DNA AND RNA MOLECULES OF THE ACCIDENTAL SUBTYPE OF FSMA VIRUSES, POLYPEPTIDES, WHICH ARE CODED BY THESE MOLECULES, AND THEIR USE. |
| JPH084508B2 (en) * | 1987-09-16 | 1996-01-24 | 国立予防衛生研究所長 | Recombinant vaccinia virus |
| GB8821077D0 (en) * | 1988-09-08 | 1988-10-05 | Wellcome Found | Peptides |
-
1990
- 1990-08-16 SE SE9002671A patent/SE470074B/en not_active IP Right Cessation
-
1991
- 1991-08-16 EP EP91915656A patent/EP0546031A1/en not_active Withdrawn
- 1991-08-16 AU AU84002/91A patent/AU649473B2/en not_active Ceased
- 1991-08-16 WO PCT/SE1991/000542 patent/WO1992003475A1/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| SE470074B (en) | 1993-11-01 |
| AU649473B2 (en) | 1994-05-26 |
| SE9002671L (en) | 1992-02-17 |
| SE9002671D0 (en) | 1990-08-16 |
| EP0546031A1 (en) | 1993-06-16 |
| WO1992003475A1 (en) | 1992-03-05 |
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