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WO1992005193A1 - Antigenes de plasmodium au stade hepatique - Google Patents

Antigenes de plasmodium au stade hepatique Download PDF

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Publication number
WO1992005193A1
WO1992005193A1 PCT/GB1991/001605 GB9101605W WO9205193A1 WO 1992005193 A1 WO1992005193 A1 WO 1992005193A1 GB 9101605 W GB9101605 W GB 9101605W WO 9205193 A1 WO9205193 A1 WO 9205193A1
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WIPO (PCT)
Prior art keywords
pbl
liver stage
genomic
berghei
cdna fragment
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Ceased
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PCT/GB1991/001605
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English (en)
Inventor
Robert Edward Sinden
Andreas Suhrbier
Larry Aldon Winger
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Imperial College of London
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Imperial College of London
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/20—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans from protozoa
    • C07K16/205—Plasmodium
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/44—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from protozoa
    • C07K14/445—Plasmodium
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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
    • 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

  • This invention relates to the isolation and production of a ⁇ tigenic proteinaceous material from parasites of the genus Plasmodium, the production of monoclonal antibodies responsive thereto, and anti-malarial vaccines containing them.
  • the mammalian malarial sporozoite invades the hepatocyte wherein it multiplies for the next 2-15 days (dependant on the parasite species). Thereafter liver merozoites are released into the blood stream in which the intra-erthrocytic sexual and pathogenic asexual stages then proliferate initiating the blood stage of the disease responsible for the symptoms and pathology of malaria. Malaria vaccines based on antigens from the sporozoite (Herrington, et al., 1987), asexual blood stages (Patarroyo, et al., 1988) and sexual stages (Carter, et al., 1988) are currently being evaluated.
  • liver stages antigens have been little studied as possible vaccine candidates because these intracellular stages were considered to be inaccessible to the immune system of the host (Cox, 1988). It is now clear from studies in rodent models (P. berghei and P. yoelii), however, that a substantial part of the protection afforded by immunising with irradiated sporozoites results from CD8+ T cell activity directed against the infected hepatocyte rather than from antibodies directed against the circumsporozoite proteins (CSP) on the circulating sporozoites (Weiss, 1987; Schofield, et al., 1987; Hoffman, et al., 1989).
  • CSP circumsporozoite proteins
  • Processed CSP associated with the class 1 major histocompatability complex on the surface of the infected liver cell appears to be one target for such cytotoxic T cells (Kumar, et al., 1988; Sadoff, et al., 1988 ; Hoffman, et al., 1989a; Romero, et al., 1989).
  • the single CD8+ T cell epitope of P. falciparum CSP shows a high degree of polymorphism (Loc yer, et al., 1989) and the response to it may also be geneticaDy restricted (Good, et al., 1988).
  • liver stage parasite can be killed by cytokines (principally gamma interferon) (Mazier, et al., 1988; Scholfield, et al., 1987) and phagocytes (Shortt & Garnham, 1984; Terzakis, et al., 1979; Meis, et al., 1987) further highlight the need to identify the antigens relevant to liver stage immunity.
  • cytokines principally gamma interferon
  • phagocytes Shortt & Garnham, 1984; Terzakis, et al., 1979; Meis, et al., 1987
  • a liver stage antigen (Pbl 1) has been identified and isolated from cultures of Plasmodium berghei and a monoclonal antibody (anti-Pbl 1) produced specific to that antigen.
  • a purified isolate comprising the P. berghei liver stage antigen Pbl 1, and Pbl 1 homologues from the genus Plasmodium, especially P. falciparum and P. vivax (referred to herein as homologous Pbl 1).
  • Liver stage antigens according to 1 obtained by the expression of genomic or cDNA encoding therefor in an expression vehicle.
  • Anti-malarial vaccines comprising a Plasmodium liver stage antigen according to 1 or 2, or a monoclonal antibody according to 3.
  • the present invention provides:
  • a purified isolate comprising the liver stage antigen of P.berghei identified herein as Pbl 1.
  • the P. berghei liver stage antigen identified herein as Pbl 1 has been identified in vivo as localised to the parasitophorous vacuole, i.e. the space surrounding the infecting parasite in the infected hepatocyte, and on the surface of the parasitophorous vacuole membrane .
  • Molecular weight studies on the isolated antigen indicate a molecular weight (Mr) of 35 + 5 kDA.
  • the antigen is specifically recognised by monoclonal antibody 23.46.7 (hereinafter described).
  • the antigen is expressed throughout the liver stage of the infection by P. berghei from 3-5 hours post-invasion by the infecting sporozoites to the release of the merzoites from the liver into the blood stream.
  • the present invention also extends to Pbl 1 homologues from parasites of the genus Plasmodium, and more especially the human parasites P. falciparum and P. vivax.
  • homologous DNA refers to equivalent linear sequences of DNA from organisms of the same genus, or of the same species, and which are identical, or substantially identical, differing one from the other merely by the substitution of equivalent alleles or by virtue of the degeneracy of the genetic code, and which encode identical or substantially identical proteins in two or more species within that genus, or two or more strains within that species, such proteins, referred to as homologous proteins or antigenic homologues, having substantially the same structures and properties and performing substantially the same or equivalent biological functions in each of the strains or species referred to, the terms homology, homologous, homologue etc, being construed accordingly.
  • liver stage schizonts of P. berghei were cultured in human HepG2 cells using the techniques of Hollingdale and Suhrbier (see Hollingdale, 1983; and Suhrbier, et al., 1988, listed hereinafter).
  • mice were immunized with HepG2 cells alone and were then treated with cyclophosphamide to suppress the subsequent response against the HepG2 cells.
  • the animals were immunised three times with freeze- thawed 48-hour EE schizonts grown as above (approximately 2.5 x lO*-- cells with a 10-20% infection rate) given at 2 week intervals.
  • Assay of the serum by indirect immunofluorescence on acetone-fixed cultured EE schizonts in HepG2 cells showed that although some HepG2 background reactivity occured, individual mice exhibited significant antibody reactivity to the parasite.
  • mice were innoculated intravenously with 10 4 sporozoites on each of two succeeding days.
  • day 6 and/or 7 after sporozoite inoculation when a Giemsa-stained blood smear showed positive blood parasitemia, the mouse was sacrificed and the spleen removed for fusion.
  • the fusion protocol was performed as described by Winger, et al (1987).
  • the supernatants of the resulting hybridomas were screened by indirect immunofluorescence on live and acetone fixed cultured liver schizonts, washed parasitized blood smears and smeared air-dried sporozoites.
  • Monoclonal antibodies 17.9.15 (specific to an ookinete surface antigen Winger, et al., 1987), 17.6.1 (binding to an integral antigen of liver merozoites and all blood stage parasites; Suhrbier, et al., 1989b), 23.8.1 (an anti-cicumsporozoite protien antibody, data not shown) and anti-Pbl 1 (Plasmodium berghei liver 1 obtained as above) were purified from ascites fluid (Reik, et al 1987). All the antibodies were of the IgG 1 subclass. Protein levels were determined using a Biorad protein standard and by spectrophotometric analysis at 280nm.
  • 13mm coverslips with a confluent monolayer of HepG2 cells were infected with approximately 2x10 ⁇ sporozoites in the presence of lmg/ml of purified anti-Pbl 1 or the same concentration of control antibody 17.6.1.
  • the parasites were then cultured for 48 hours in the presence of antibodies before being fixed and parasite numbers, size and maturity determined by light microscopy.
  • the fusion produced a total of 34 clones, of which 16 reacted with both liver and blood stages, 5 with sporozoites, 12 with HepG2 cells and 1, which reacted specifically with the liver stage.
  • This monoclonal antibody designated anti-Pbll (Plasmodium berghei liver 1), showed no cross-reaction, using indirect i munofluorescent staining, with blood stage parasites, sporozoites or ookinetes of P. berghei.
  • Liver stages of the closely related rodent .parasite P. yoelii cultured in primary mouse hepatocytes did not react with anti-Pbl 1.
  • Liver stages of the human parasite P.vivax cultured in HepG2 cells also failed to react with anti-Pbl 1.
  • Pbl 1 could first be clearly detected by indirect immunofluorescent antibody staining on intracellular P. berghei liver stage trophozoites 3 hours after invasion. As the trophozoites and schizont developed a peripheral staining pattern was observed, which was often associated with protrusions into the cytoplasm of the host cell. These protrusions frequently had the appearance of chains of small vesicles and whose presence correlated with the growth (presumably trophic) phase of parasite development. Parasites grown in W138 cells, a less satisfactory host cell, in which parasites are smaller and take longer to mature, showed an abundance of such structures.
  • Pbl 1 was also expressed on intra-hepatic trophozoites derived from irradiated sporozoites.
  • mice were infected with P. berghei ANKA strain, by blood passage. At 20-50% parasitaemia the mice were bled and the total of 25 mis of heparinized blood was filtered through a Whatman CF11 column to remove white blood cells. The blood was centrifuged at 1,500-3,000 g for 10 minutes and the cells resuspended in phosphate buffered saline (PBS) to a haematocrit of 50% and passed through the column to achieve a maximal final white blood cell/parasite ratio of 1:10,000. The filtrate was collected and spun again as described above to achieve a final packed preparation containing the parasites.
  • PBS phosphate buffered saline
  • DNA was extracted from the pelleted parasites as follows: To the pellet 30 ml of lysis buffer (50mm Tris-HCl pH 9, 100mm EDTA, 200 mm NaCl) was added; to this mixture proteinase K was added to a final concentration of lOO ⁇ g/ml, and the mixture incubated at 65°C for 30 mins. This was then followed by a second incubation at 37 °C for 1.5 hours. After this incubation, nucleic acids were extracted by the standard method of phenol/chloroform extraction (Maniatis et al.; 1982 Molecular Cloning, A Laboratory Manual, Cold Spring Harbour Laboratory, New York p. 458).
  • RNAse enzyme a concentration of lOO ⁇ g/ml.
  • phenol/chloroform extraction and ethanol precipitation were repeated to give a final DNA extract hereafter referred to as P. berghei DNA.
  • a P. berghei genomic library was constructed from the P. berghei DNA as follows: lO ⁇ g of P. berghei DNA was digested with EcoRl using excess EcoRl enzyme (50U/ ⁇ g P. berghei DNA) in the presence of 20mM Tris-KCl pH 8.5, 2mM MgCl 2 and BSA (lO ⁇ g/ml) at 370°C for 22 hours (Polisky, B., et al, 1975, Proc. Nat. Acad. Sci. USA, 72, 3310-3314). The DNA was then used to construct a igtll genomic DNA library as described by Young, R.A. ⁇ c Davis, R.W. (1983, Proc. Nat. Acad. Sci. USA, 80, 1194- 1198). The conditions and reagents used to construct the library were as described by the manufacturers in the Amersham* cDNA yl gtll cloning kit (code No. RPN 1280).
  • the library was screened with monoclonal antibody 23.46.7 using established protocols (Huynh, T.V., et al 1985 in DNA Cloning, a practical approach, edited by D.M. Glover, IRC Press, Oxford, Vol. 1, p. 49-108).
  • the ⁇ gtll library was screened as plaques on a lawn of E. coli Y1090 cells.
  • the library was plated out and incubated at 42 °C for 3 hours or until pin-prick plaques were seen.
  • Nitrocellulous filter discs, with marked orientation, impregnated with 10m M IPTG were placed on the lawn and incubated for 2 hours at 37°C.
  • the nitrocellulous filter was then removed and non-specific binding sites blocked with 5% milk powder in 0.1% Tween 20 in phosphate buffered saline.
  • the filters were then incubated in 10 mis of monoclonal antibody 23.46.78 at 50 ⁇ g/ml in 0.1% Tween in PBS. This incubation was for 1.5 hours at room temperature.
  • the positive clone descibed above, now identified as EcoPBl.l in gtll was amplified using standard PCR methods using the protocols and reagents provided in the Perkin-Elmer Cetus GeneAmp amplification reagent kit with AmpliTaqTM DNA polymerase (Cat. No. N. 801-0055, Perkin-Elmer Cetus).
  • the reaction was set up under mineral oil according to their protocol, namely: 10 x reaction buffer; dNTP's mixture with 1.25mM of each dATP, dCTP, dGTP, dTTP; EcoPbl 1, Phage stock, freeze thawed; Forward primer; reverse primer, and Taq polymerase.
  • Amplification involved the usual 3 steps of denaturation at 94°C for 1 min., annealing of primers at 50°C for 1 min., and extension using Taq polymerase at 72°C for 2 mins. This cycle was repeated for a total time of 5 hours.
  • the primers forward and reverse were obtained from New England Biolabs, (Cat. No. 1218 and 1222).
  • the PCR product obtained as above was frozen at -20°C and the mineral oil removed from the surface.
  • the DNA was then phenol/chloroform extracted once and 50 ⁇ l of the aqueous phase was passed down a Sephadex CL6B column.
  • the overhanging ends of the amplified DNA were filled using 2.5 U/ ⁇ l E. coli DNA polymerase Klenow fragment, obtained from Amersham International, (Cat. No. T21412), using standard methods, (Sambrook, Fritsch, Maniatus, Molecular Cloning, A lab manual, 2nd edition, Chapter 5, p 5.42). This reaction was at room temperature for 15 mins. and was stopped by heating at 65 °C for ID mins.
  • the amplified DNA was then passed through a Sepharose CL6B column spun at 1,500 rpm for 3 mins.
  • T4 polynucleotide kinase (Amersham International, Cat. No. 2020Y) was then added (10 U/ ⁇ l) and incubated in the presence of ligase buffer (200mM Tris HC1, pH 6, 50mM MgCl2, 50mM dithiothreitol, 500mg/ml BSA, lOmM ATP) at 37°C for 2 hours, the reaction being stopped by heat treatment at 65 °C for 10 mins.
  • ligase buffer 200mM Tris HC1, pH 6, 50mM MgCl2, 50mM dithiothreitol, 500mg/ml BSA, lOmM ATP
  • the following ligation was set up using M13mpl0 (Amersham N4531) and Puel3 (Pharmacia 27-4975-01). Both vectors were cut with Smal, and phosphatase treated. The PCR insert was then mixed with 10 x ligase buffer; vector (lOng/ ⁇ l); T4 DNA ligase (Amersham Cat No. T2050Y) the volume made up with H2O, and the mixture incubated overnight at 4°C.
  • DH5 ⁇ (F * host cells for M13 and DH5 host cells for Pucl3 was then diluted 1/100 and 5 ⁇ l was used to transform DH5 ⁇ (F * host cells for M13 and DH5 host cells for Pucl3 using the protocol described by Hanahan, D. (1986, in DNA Cloning, a practical approach, edited by D.M. Glover, IRC Press, Oxford, Vol 1, p 109-135).
  • DH5° nd DH5e F * cells from Gibco BRL Cat. Nos. 530 8265SA and 530 8264SA respectively.
  • Transformed cells were plated out in the presence of lOO ⁇ m IPGT and 2% X-gal and incubated overnight at 37°C. Reeombinants were identified by their coloration. Blue plaques were parentals, M13 reeombinants were colourless and Pucl3 reeombinants were white.
  • M13 reeombinants were picked and inoculated into 1.5ml 1/100 dilution of JM101 cells (Pharmacia, Cat. No. 27 1509 01) in 2 x TY medium (16 gms Bactotryptone, lOg yeast extract , 5g NaCl per litre) and grown at 37°C for 6 hours.
  • 1 ml of clear supernatent from the plaque preparation was added to 250 ⁇ l of PEG NaCl (20% PEG 6,000; 2.5mM NaCl) and then mixed and incubated at room temperature for 15 mins.
  • This preparation was then spun for 5 mins. in a microfuge, decanted and the white viral pellet (containing M13 phage) was then resuspended in lOO ⁇ l of TE buffer pH 8, (10m M Tris HCljlmM EDTA) and phenol/- chloroform was used to extract the DNA as described above.
  • DNA was removed from the aqueous phase by sodium acetate precipitation at a final concentration of 0.3 M at pH 5.35 and subsequent addition of 2 1/2 vols. of absolute ethanol. DNA was later collected by centrifugation, washed in 70% ethanol, dried under vacuum and then resuspended in 25 ⁇ l TE buffer.
  • Reeombinants were confirmed by running mini preps of the DNA on agarose gel against non-recombinant M13 single stranded DNA. Identification of reeombinants was based on the difference in size of the DNA from the two preparations. Positive clones obtained in M13 mini DNA preparations were sequenced using a Sequenase kit (USA Biochemical Corporation). The chain termination method (Sanger, F., Miklen, S. ⁇ 5c Coulson, A.R., 1977, Proc. Nat. Acad. Sci. USA 74, 5463-5467) was used. This technique (Tabor, S. & Richardson, CO., 1987, Proc. Nat. Acad. Sci. USA, 84, No.
  • the insert Pbl 1 may be PCR amplified (see above) using synthetic oligonucleotides based on the above insert sequence.
  • the PCR amplified insert can then be hexalabelled using 32 P (Feinberg and Vogelstein, 1984, Analytical Biochemistry, 137, 266-267) and then used to screen a P. falciparum gtll library and other available libraries (Sambrook, et al., 1989, (see above ref.) chapter 2, p 2.108-2.111 and p 2.114-2.117) constructed in the same way as the P. berghei library described above.
  • the labelled insert may be used to screen southern blots of P. falciparum and P.

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  • Health & Medical Sciences (AREA)
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  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
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Abstract

On décrit des antigènes de plasmodium au stade hépatique, ainsi que des séquences d'ADNc codant de tels antigènes de P.berghei et comprenant des séquences homologues de P.vivax et P.falciparum.
PCT/GB1991/001605 1990-09-19 1991-09-19 Antigenes de plasmodium au stade hepatique Ceased WO1992005193A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB909020438A GB9020438D0 (en) 1990-09-19 1990-09-19 Plasmodium liver stage antigens
GB9020438.9 1990-09-19

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WO1992005193A1 true WO1992005193A1 (fr) 1992-04-02

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JP (1) JPH06500996A (fr)
AU (1) AU8611491A (fr)
GB (1) GB9020438D0 (fr)
WO (1) WO1992005193A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992013884A1 (fr) * 1991-02-05 1992-08-20 Institut Pasteur Sequences peptidiques specifiques des stades hepatiques de p. falciparum porteuses d'epitopes capables de stimuler les lymphocytes t.
US6270771B1 (en) 1988-10-06 2001-08-07 Institut Pasteur Peptide sequences specific for the hepatic stages of P. falciparum bearing epitopes capable of stimulating the T lymphocytes
WO2007041216A3 (fr) * 2005-09-30 2007-08-02 Seattle Biomedical Res Inst Antigenes du plasmodium en phase hepatique

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988005785A1 (fr) * 1987-02-09 1988-08-11 Institut Pasteur Molecules comportant au moins une sequence peptidique porteuse d'un, ou plusieurs, epitopes caracteristiques d'une proteine produite par p. falciparum dans les hepatocytes et compositions les contenant

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988005785A1 (fr) * 1987-02-09 1988-08-11 Institut Pasteur Molecules comportant au moins une sequence peptidique porteuse d'un, ou plusieurs, epitopes caracteristiques d'une proteine produite par p. falciparum dans les hepatocytes et compositions les contenant

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
BULLETIN OF THE WORLD HEALTH ORGANIZATION, Vol. 68, No. SUP, 1990, Geneva, Switzerland, pages 172-177, L. WINGER et al., "A Liver-Stage Specific Antigen of P. Berghei Identified by a Monoclonal Antibody". *
BULLETIN OF THE WORLD HEALTH ORGANIZATION, Vol. 68, No. SUPP, 1990, Geneva, Switzerland, pages 158-164, C. MARCHAND et al., "How to Select Plasmodium Falciparum Pre-Erythrocytic Antigens in an Expression Library Without Defined Probe". *
IMMUNOLOGY LETTERS, Vol. 25, No. 1-3, August 1990, Amsterdam, The Netherlands, pages 71-76, M. HOLLINGDALE et al., "Non-CS Pre-Erythrocytic Protective Antigens". *
PARASITE IMMUNOLOGY, Vol. 12, No. 5, September 1990, OXFORD, GB, pages 473-481, A. SUHRBIER et al., "An Antigen Specific to the Liver Stage of Rodent Malaria Recognized by a Monoclonal Antibody". *
PARASITOLOGY, Vol. 103, No. 1, August 1991, Cambridge, GB, pages 17-21, R. SINDEN et al., "The Development of Exo-Erythrocytic Schizonts of Plasmodium Berghei in Vitro from Gamma-Irradiated and Non-Irradiated Sporozoites: A Study Using Confocal Laser Scanning Microscopy". *
THE JOURNAL OF IMMUNOLOGY, Vol. 145, No. 5, 1 September 1990, BALTIMORE, US, pages 1557-1563, J. LONDONO et al., "Secondary Structure and Immunogenicity of Hybrid Synthetic Peptides Derived from two Plasmodium Falciparum Pre-Erythrocytic Antigens". *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7087231B2 (en) 1987-02-09 2006-08-08 Institut Pasteur Peptide sequences specific for the hepatic stages of P. falciparum bearing epitopes capable of stimulating the T lymphocytes
US6270771B1 (en) 1988-10-06 2001-08-07 Institut Pasteur Peptide sequences specific for the hepatic stages of P. falciparum bearing epitopes capable of stimulating the T lymphocytes
WO1992013884A1 (fr) * 1991-02-05 1992-08-20 Institut Pasteur Sequences peptidiques specifiques des stades hepatiques de p. falciparum porteuses d'epitopes capables de stimuler les lymphocytes t.
US6319502B1 (en) 1991-02-05 2001-11-20 Institut Pasteur Peptide sequences specific for the hepatic stages of P. falciparum bearing epitopes capable of stimulating the T lymphocytes
US7332595B2 (en) 1991-02-05 2008-02-19 Institut Pasteur DNA sequences encoding peptide sequences specific for the hepatic stages of P. falciparum bearing epitopes capable of stimulating the T lymphocytes
US7438917B2 (en) 1991-02-05 2008-10-21 Institut Pasteur Peptide sequences specific for the hepatic stages of P. falciparum bearing epitopes capable of stimulating the T lymphocytes
WO2007041216A3 (fr) * 2005-09-30 2007-08-02 Seattle Biomedical Res Inst Antigenes du plasmodium en phase hepatique
US7722889B2 (en) 2005-09-30 2010-05-25 Seattle Biomedical Research Institute Plasmodium liver stage antigens
US8318183B2 (en) 2005-09-30 2012-11-27 Seattle Biomedical Research Institute Plasmodium liver stage antigens

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JPH06500996A (ja) 1994-01-27
GB9020438D0 (en) 1990-10-31
EP0549662A1 (fr) 1993-07-07
AU8611491A (en) 1992-04-15

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