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WO1998030237A1 - Vaccins antipaludiques a base de polyoxime - Google Patents

Vaccins antipaludiques a base de polyoxime Download PDF

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Publication number
WO1998030237A1
WO1998030237A1 PCT/US1997/024283 US9724283W WO9830237A1 WO 1998030237 A1 WO1998030237 A1 WO 1998030237A1 US 9724283 W US9724283 W US 9724283W WO 9830237 A1 WO9830237 A1 WO 9830237A1
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Prior art keywords
epitope
polyoxime
malaria
peptide
cell epitope
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PCT/US1997/024283
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English (en)
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WO1998030237A9 (fr
Inventor
Elizabeth Nardin
Ruth S. Nussenzweig
Keith Rose
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New York University
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Application filed by New York University filed Critical New York University
Priority to AU58128/98A priority Critical patent/AU5812898A/en
Publication of WO1998030237A1 publication Critical patent/WO1998030237A1/fr
Publication of WO1998030237A9 publication Critical patent/WO1998030237A9/fr

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    • 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
    • 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 vaccines effective in eliciting protective immunity against malaria, in particular vaccines comprising polyoximes that elicit anti-malarial responses in individuals of differing genetic backgrounds.
  • malaria infection is initiated by the motile sporozoite stage of the organism, which is injected into the circulation by the bite of infected mosquitoes.
  • the sporozoite is targeted to the host's liver cells through interaction of a major component of the sporozoite surface membrane, the circumsporozoite (CS) protein, with specific receptors on the hepatocyte surface.
  • CS circumsporozoite
  • the parasites Following intracellular multiplication and release from ruptured hepatocytes, the parasites invade red blood cells and initiate the malaria erythrocytic cycle; this phase of infection is responsible for clinical disease and, in the case of P. falciparum, may be lethal.
  • CS protein A major focus of malaria vaccine development has been the CS protein, which is present in both sporozoite and liver stages of the parasite.
  • the present inventors have defined parasite-derived T-cell epitopes using CD4 + T-cell clones derived from four human volunteers immunized by repeated exposure to the bites of irradiated P. fa/c/parum malaria infected mosquitoes. When three of these volunteers were challenged with infective P. falciparum sporozoites, they were protected against malaria, as shown by the total absence of blood stage infection (Herrington et a ⁇ ., Am.J. Trop.Hyg. 45:535, 1 991 ).
  • T1 NH 2 -terminal repeat region
  • the T1 epitope is contiguous to, but antigenically distinct from, the COOH-terminal repeat region which contains the (NANP) 3 B cell epitope.
  • the T1 repeat epitope is conserved in all P. falciparum isolates sequenced thus far and therefore its inclusion in a vaccine is expected to induce immune responses reactive with parasites of diverse geographical regions.
  • the second T-cell epitope identified by sporozoite-specific human CD4 + T-cell clones is contained in a peptide spanning amino acid residues numbered 326-345, EYLNKIQNSLSTEWSPCSVT, of the P. falciparum NF54 strain CS protein (Moreno et al., Int.lmmunol. 3:997, 1 991 ; Moreno et al., J.Immunol. 151 :489, 1 993).
  • This epitope was shown to be recognized by cytotoxic and non- cytotoxic class ll-restricted human CD4 + T-cell clones and class l-restricted CD8 + CTL clones.
  • the 326-345 sequence is unique in that it overlaps both a polymorphic, as well as a conserved region, Rll (Dame et al., Science 225:593, 1 984), of the CS protein.
  • the conserved Rll-plus contains a parasite ligand that interacts with hepatocyte receptors to initiate the intracellular stage of the malaria life cycle.
  • the peptide-specific human CD4 + T-cells recognize a series of epitopes within the 326-345 peptide, all of which overlap the conserved Rll found in the CS protein of all Plasmodium species.
  • T-cells play a central role in the induction of both cellular and humoral immunity to the pre-erythrocytic stages of the malaria parasite (Nardin et al., Ann. Rev. Immunol. 11:687, 1 993). If the T-cell epitopes contained within a synthetic malaria vaccine bind to only a limited range of class II molecules, the vaccine may fail to elicit immune responses in individuals of diverse genetic backgrounds. Earlier studies have shown that the (NANP) 3 repeats of the P.
  • falciparum CS protein induced low or undetectable T-cell responses in naturally-infected individuals living in malaria endemic areas (Herrington et al., Nature 328:257, 1 987; Etlinger et al., J. Immunol. 140:626, 1 988; Good et al., Proc. Nat/. Acad. Sci. USA 85: 1 1 99, 1 988).
  • immunogenic compositions and vaccines that provide protective immunity against malaria in individuals of diverse genetic backgrounds.
  • Figure 1 A is an illustration of an electrospray ionization mass spectrography (EIS-MS) spectrum of a di-epitope (T1 B) 4 polyoxime construct, shown on a true mass scale.
  • Figure 1 B is an illustration of an EIS-MS spectrum of a di-epitope (T1 B) 4 -P 3 C polyoxime construct, containing a lipopeptide adjuvant, showing the expected series of multi-charged forms of the product characteristic of this ionization mode.
  • Figure 1 C is an illustration of a matrix-assisted laser desorption time of flight (MALDI-TOF) mass spectrum of a tri-epitope (T1 BT*) 4 polyoxime construct.
  • MALDI-TOF matrix-assisted laser desorption time of flight
  • FIG 1 D is an illustration of a MALDI-TOF mass spectrum of a tri-epitope (T1 BT*) 4 -P 3 C polyoxime construct, containing a lipopeptide adjuvant.
  • Figure 2 is a graphic illustration of the Geometric Mean Titers (GMTs) measured in sera obtained 20 days after subcutaneous injections of a (T1 B) 4 -P 3 C polyoxime construct on days 0, 21 , and 42. The titers were measured by enzyme- linked immunoassay (ELISA) using (T1 B) 4 polyoxime-coated plates.
  • GTTs Geometric Mean Titers
  • FIG 3 is a graphic illustration of the GMT of sera obtained from mice 20 days after a third injection of a (T1 B) 4 -P 3 C polyoxime construct, measured by ELISA using (T1 B) 4 as antigen (closed bars), or by indirect immunofiuorescence (IFA) using glutaraldehyde-fixed P. falciparum sporozoites (hatched bars).
  • Figure 4A is a graphic representation of the peak antibody response obtained following immunization of different murine strains with the (T1 BT*) 4 polyxoxime construct when conjugated to P 3 C (closed bars); in PBS (open bars); or adsorbed to alum (hatched bars) .
  • the antibody response was measured by ELISA, using (T1 B) 4 as antigen.
  • Figure 4B is a graphic representation of the peak antibody response obtained following immunization of different murine strains with the (T1 BT*) 4 polyxoxime construct when conjugated to P 3 C (closed bars); in PBS (open bars); or adsorbed to alum (hatched bars).
  • the antibody response was measured by indirect immunofluorescence as described for Figure 3.
  • Figure 5A is a graphic illustration of the kinetics of anti-repeat antibody response in mice immunized with (T1 BT*) 4 in PBS.
  • Figure 5B is a graphic illustration of the kinetics of anti-repeat antibody response in mice immunized with (T1 BT*) 4 adsorbed to alum.
  • Figure 5C is a graphic illustration of the kinetics of anti-repeat antibody response in mice immunized with (T1 BT*) 4 constructed as a P 3 C conjugate.
  • the present invention encompasses immunogenic compositions constructed as polyoximes that elicit protective immunity against malaria.
  • the compositions comprise one or more malaria-derived peptides comprising T-cell epitopes, which elicit anti-malarial T-cell responses. Malaria-derived universal T-cell epitopes, which elicit T-cell responses in mammals of diverse genetic backgrounds, may also be included.
  • the compositions of the invention further comprise at least a second malaria-derived peptide comprising a B-cell epitope, which stimulates the production of anti-malarial antibodies in mammals.
  • the polyoxime-based compositions are preferably formulated into vaccines, which may also comprise a pharmaceutically acceptable carrier or diluent and, optionally, an adjuvant. Adjuvants may also be covalently incorporated into the polyoxime constructs, including without limitation tri-palmitoyl-S-glyceryl cysteine.
  • the invention provides methods for inhibiting the propagation of malarial organisms in a susceptible mammal, preferably by eliciting protective immunity against malaria in the mammal.
  • the methods are carried out by administering to mammals immunogenically effective amounts of the immunogenic compositions and vaccines described above.
  • An "immunogenic composition” is a composition that elicits a humoral and/or cellular immune response in a host organism.
  • a "B-cell epitope” as used herein refers to a peptide or other immunogenic molecule, or a fragment thereof, that elicits the production of specific antibodies (i.e., antibodies that recognize the parasite as well as the immunogenic molecule) in a mammalian host.
  • a "T-cell epitope” refers to a peptide or immunogenic molecule, or fragment thereof, that activates T-cells in a manner that is specific for the parasite-derived peptide as well as the immunogenic molecule.
  • a "universal" T-cell epitope as used herein refers to a peptide or other immunogenic molecule, or a fragment thereof, that binds to a multiplicity of MHC class II molecules in a manner that elicits activated T-cell function.
  • the activated T-cells may be helper cells (CD4 + ) and/or cytotoxic cells (class II- restricted CD4 + and/or class l-restricted CD8 + ).
  • a malaria-specific or parasite- specific universal T-cell epitope has the potential to expand, or induce, parasite- specific T-cells in naturally-infected and naive individuals, respectively, in the general population. 4.
  • a peptide epitope that is "derived from" a particular organism or from a particular polypeptide comprises an amino acid sequence found in whole or in part within the particular polypeptide and encoded by the genome of the organism, including polymorphisms. It will be understood that changes may be effected in the sequence of a peptide relative to the polypeptide from which it is derived that do not negate the ability of the altered peptide, when used as part of an immunogenic composition, to elicit an immune response that is specific for the polypeptide from which the peptide is derived.
  • MAP Multiple Antigen Peptide
  • Polyoxime refers to a macromolecule of defined structure which comprises a first organic molecule, termed a baseplate, to which other organic molecules are attached via oxime linkages. Methods for synthesis of immunogenic polyoxime compositions are disclosed in International Patent Application WO 94/25071 .
  • the present invention provides immunogenic compositions and methods for eliciting protective immunity against malaria, in particular against P. falciparum.
  • the compositions comprise immunogenic components that are formed into polyoximes.
  • the polyoximes may contain one or more of the following components: (i) at least one malaria-derived peptide comprising a T-cell epitope capable of eliciting an anti-malarial T-cell response; and (ii) at least one malaria- derived peptide comprising a B-cell epitope capable of stimulating the production of anti-malarial (i.e., neutralizing) antibodies directed against the sporozoite stage of the malarial organism.
  • the immunogenic compositions of the present invention comprise at least one B-cell epitope and at least one T-cell epitope, most preferably a universal T-cell epitope.
  • the B-cell epitopes preferably elicit the production of antibodies that specifically recognize and bind to the malarial circumsporozoite (CS) protein.
  • the compositions may also comprise B-cell and/or T-cell epitopes derived from, and reactive with, other malarial components, such as, for example, the P.
  • the polyoximes of the present invention may comprise homo- polyoximes, in which a single type of organic molecule is conjugated via oxime linkages to a baseplate molecule, as well as hetero-polyoximes, in which a plurality of different organic molecules are conjugated via oxime linkages to a baseplate molecule.
  • the baseplate structure is a peptide having a backbone in which at least some of the amino acid residues have side-chain groups suitable for modification to oxime-forming reactive groups, such as, for example, lysine, ornithine, and cysteine.
  • Suitable reactive groups include without limitation amino- oxy-acetyl (AOA) or aldehyde groups such as glyoxylyl (GXL) .
  • Malaria-specific "complementary orthogonal specifically active molecules", or "COSMs” that are reacted with the baseplate molecule may comprise peptides or other immunogenic molecules having site-specifically placed oxime-forming reactive groups. The synthesis and analysis of malaria-specific polyoxime constructs are described in Example 1 below.
  • the present invention encompasses B-cell and T-cell epitopes derived from plasmodial species, including without limitation P. falciparum, P. vivax, P. malariae, P. ovale, P. vraowi, P. know/esi, P. cynomo/gi, P. brasilianum, P. yoelii, P. berghei, and P. chabaudi.
  • Epitopes typically comprise at least 5 amino acid residues, preferably at least 7 residues, and most preferably at least 1 0 residues, derived from a plasmodial protein. Overlapping epitopes may be contained within a single peptide.
  • B-cell epitopes may be identified by methods well known in the art, such as, for example, by (i) preparing synthetic peptides whose sequences are derived from the CS protein of a plasmodial species; and (ii) testing the ability of the synthetic peptides to elicit anti-malarial antibodies in a model system. Malaria-specific B-cell and T-cell epitopes are disclosed in Nardin et al., Ann. Rev. Immunol. 1 :687, 1 993.
  • the immunogenic composition of the invention comprises (i) a peptide comprising the malarial B-cell epitope (NANP) 3 ; (ii) a peptide comprising the T1 malarial epitope (DPNANPNV) 2 ; and (iii) a peptide comprising the universal T-cell epitope represented by amino acid residues numbered 326-345, EYLNKIQNSLSTEWSPCSVT, of the P. falciparum NF54 strain CS protein, or immunogenic variants derived from any of the above.
  • NANP malarial B-cell epitope
  • DPNANPNV T1 malarial epitope
  • a peptide comprising the universal T-cell epitope represented by amino acid residues numbered 326-345, EYLNKIQNSLSTEWSPCSVT, of the P. falciparum NF54 strain CS protein, or immunogenic variants derived from any of the above.
  • T-cell epitopes for use in the present invention may be identified by one or more of the following methods: (i) experimentally measuring the interaction of different malaria-derived peptides with isolated class II polypeptides in vitro; and (ii) computationally analyzing different peptide sequences to identify high-affinity class II allele-specific motifs.
  • the interactions that have been measured in vitro have been correlated with in vivo immunogenicity, as measured by the immune response of mice of different genetic backgrounds when immunized with multiple antigen peptides (MAP) containing these T-cell epitopes.
  • MAP multiple antigen peptides
  • a peptide derived from P. falciparum TRAP/SS2 that was predicted to comprise a universal T-cell epitope has been shown experimentally to bind multiple class II molecules in vitro.
  • compositions of the present invention may be used as immunogens to elicit immunity, including protective immunity, in a susceptible host.
  • Immunity may include eliciting the production of antibodies in the host (or in another host or in vitro, as in passive immunization) that will recognize and bind to plasmodial cells. Immunity may also include the activation of malaria-specific T- cells.
  • the immunogenic compositions comprising B-cell epitopes and/or universal T-cell epitopes may be used in vaccine preparations to confer prophylactic immunity against the blood stage of malaria or therapeutic immunity by preventing (totally or partially) propagation of the disease in the host through inhibition of the pre-erythrocytic stages.
  • vaccines are prepared as injectables, either as liquid solutions or suspensions. Solid forms suitable for dissolving or suspending in liquid prior to injection may also be prepared. The preparation may also be emulsified, or the protein encapsulated in liposomes.
  • the active immunogenic ingredients may be mixed with excipients, such as, for example, water, saline, dextrose, glycerol, ethanol, or the like, and combinations thereof.
  • the vaccine may contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, and/or adjuvants to enhance the effectiveness of the vaccine.
  • adjuvants may be covalently linked to the immunogenic components via oxime linkages.
  • the immunogenic compositions could also be administered following incorporation into liposomes or other microcarriers.
  • the vaccines may be administered by subcutaneous, intramuscular, oral, intradermal, or intranasal routes. Dosages may range from about 5 ⁇ g to about 5 mg per dose, and a single or multiple dosage regimen may be utilized.
  • the amounts administered, number of administrations, and schedule of administrations can be determined empirically, such as, for example, by establishing a matrix of dosages and frequencies and comparing a group of experimental units or subjects to each point in the matrix.
  • the present invention also provides methods of inhibiting the propagation of a malarial organism in a susceptible mammal, which comprises administering to the mammal an immunogenically effective amount of an immunogenic composition comprising one or more of the following components: (i) at least one malaria-derived peptide containing a B-cell epitope capable of stimulating the production of anti-malarial (i.e., neutralizing) antibodies directed against the sporozoite stage of the organism; and (ii) at least one malaria-derived peptide that encompasses a T-cell epitope capable of eliciting an anti-malarial T-cell response in vaccinates.
  • An immunogenically effect amount is an amount effective to elicit protective immunity against the malarial organism determined as described above.
  • the composition may be administered to a mammal which has been previously exposed to the malarial organism.
  • the polypeptide may be administered to a mammal prior to exposure of the mammal to the malarial organism.
  • Peptides were purified by reversed-phase HPLC and characterized by mass spectrometry (Rose, J.Am. Chem.Soc. 1 16:30, 1 994). Baseplates (also referred to as templates) were synthesized according to published procedures (Zeng et al., J. Peptide Sci. 2:66, 1 996; Rose et al. Mol. Immunol. 32: 1031 , 1 995).
  • Oxidations and oximations were performed essentially as described (Rose, J.Am. Chem.Soc. H6:30, 1 994; Zeng et al., J. Peptide Sci. 2:66, 1 996; Rose et al. Mol. Immunol. 32: 1031 , 1 995), with minor modifications imposed by the solubility properties of the reaction partners.
  • T1 BT* 6 mg peptide ( 1 .1 was dissolved in 1 .25 ml acetonitrile plus 3.75 ml imidazole buffer (50 mM, pH 6.95, counter-ion chloride) .
  • mice Six-to-eight week old mice were obtained from Jackson Labs (Bar Harbor ME). C57BI/6, A/J (H-2d) and BALB/c (H-2d) mice were immunized with 50 ⁇ g of the tri- or di-epitope polyoxime or MAP constructs. Mice were injected subcutaneously at three week intervals, and sera were obtained at 10 and 20 days after each immunization. The final bleed was obtained at 85 days after the third and final immunization.
  • Tetrabranched polypeptides were synthesized by different chemical methods to contain the (T1 B) sequence, (DPNANPNV) 2 (NANP) 3 , representing the NH 2 -terminal and COOH-terminal repeat region of the P. falciparum CS protein.
  • Two (T1 B) 4 polyoximes were constructed by condensation of four copies of the (T1 B) sequence on a branched polypeptide template, while the (T1 B) 4 MAP was synthesized by standard step wise procedure.
  • T1B di-epitope 4 synthetic peptides constructed as polyoximes or MAP
  • mice were immunized s.c. with 50 ug of MAP or Polyoxime diluted in PBS (no adjuvant) or adsorbed to alum. Results shown as geometric mean titers (GMT) of sera collected
  • the 109 isomer was constructed by ligation of an aldehyde-modified (T1 B) 4 peptide with branched template modified by four AoA groups, while the 103 isomer contained an oxime bond with the reverse polarity by condensation of an AoA-peptide with an aldehyde- modified template.
  • the ability of the isomers to elicit the identical antibody responses indicates that the location of the aldehyde and AoA modifications on the peptide, or template, did not affect the immunogencity of the polyoximes.
  • the (T1 B) 4 constructs were adsorbed to alum, the most common adjuvant used for human vaccine formulations, to determine if increased antibody responses could be obtained in the different strains of mice.
  • Immunization with (T1 B) 4 MAP/ alum significantly increased the anti-repeat antibody titers of C57BI mice, while no significant increase was obtained with the polyoxime/alum formulation (Table 1 ) .
  • the (T1 B) 4 MAP/alum also elicited antibodies in A/J mice. However, the alum-adjuvanted polyoxime was not immunogenic in these mice.
  • the "non-responder" BALB/C mice also did not produce detectable antibody responses following immunization with either the (T1 B) 4 polyoxime or MAP adsorbed to alum.
  • the synthetic lipophilic adjuvant, tripalmitoyl-S-glyceryl cysteine (P 3 C) is a potent adjuvant for synthetic peptide vaccines.
  • Immunization with a (T1 B) 4 -P 3 C MAP construct has been shown to overcome genetic restriction and elicit high titers of antibodies in both responder and non-responder strains of mice.
  • Four copies of an aldehyde modified (T1 B) 4 peptide were condensed on an AoA template containing the P 3 C lipopeptide adjuvant.
  • T1BT* Tri-epitope (T1BT*) peptides:
  • the tri- epitope (T1 BT*) 4 polyoxime constructs were prepared using ligation technology to condense four copies of the aldehydic 48-mer peptide with an AoA-template.
  • a tri-epitope MAP was also synthesized using standard protocols in which each amino acid was added to the tetrabranched core in a step-wise fashion.
  • T1BT* tri-epitope 4 peptide constructed by chemoligation (Polyoximes) or by stepwise synthesis (MAP)
  • the tri-epitope MAP was poorly immunogenic in all the murine strains, whether administered with or without alum adjuvant. Maximal titers were observed in the C57BI mice immunized with the (T1 BT*) 4 MAP/alum formulation, although the peak titer was lower than that obtained with the di-epitope (T1 B) 4 MAP/alum (Table 1 ).
  • the tri-epitope lipopeptide polyoxime was shown by chemical analysis to be of high purity. Mass spectrometry gave an experimental MW of 23,936 + /- 60, in excellent agreement with the calculated mass of 23,973.1 ( Figure 1 D). Despite the complexity of the (T1 BT*) 4 -P 3 C polyoxime lipopeptide construct, SDS-PAGE silver stained gels and Western blots revealed defined bands and limited heterogeneity. The (T1 BT*) 4 -P 3 C polyoxime was immunogenic in all three strains of mice and elicited similar levels of antibody specific for the immunogen in each strain (Table 3).
  • T1BT* tri-epitope
  • Antibody to the tri-epitope polyoxime was measured using (T1 BT*) 4 --P 3 C.
  • the (T1 B) 4 and (T*) 4 ELISA used MAP as antigen.
  • IFA were carried out using fixed P. falciparum sporozoites.
  • the fine specificity of the antibody response in the (T1 BT*) 4 polyoxime- immunized mice was similar regardless of the adjuvant formulation.
  • Antibody responses to the universal T helper epitope were also detected following immunization with all formulations of the (T1 BT*) 4 polyoxime, as previously found with MAPs containing the universal T-cell epitope (T*).
  • the anti-T* antibody titers in the (T1 BT*) 4 polyoxime immunized mice were relatively low (10 3 GMT) and did not correlate with sporozoite reactivity.
  • Previous studies have also noted the failure of anti-peptide antibodies specific for non-repeat sequences of the CS protein to react with P. falciparum sporozoites.
  • T1 BT* tri-epitope
  • PBS no adjuvant
  • the presence of the universal T helper epitope in the (T1 BT*) 4 polyoxime may stimulate the production of sufficient levels of cytokine/l ⁇ mphokines to mimic the immunostimulatory effect of exogenous adjuvants.
  • Example 2 Anti-Malarial Vaccines Comprising Polyoximes
  • peptide-based vaccines containing the T* epitope are immunogenic in the absence of adjuvant, i.e., when administered in phosphate buffer alone.
  • Enhanced antibody responses were obtained by the addition of adjuvants, such as alum (Rehydragel, Reheis NJ) or QS21 (Cambridge Biotech, Cambridge MA), or the covalent coupling of a synthetic lipopeptide, tri-palmitoyl-S-glyceryl cysteine, to the branched peptide core.
  • adjuvants such as alum (Rehydragel, Reheis NJ) or QS21 (Cambridge Biotech, Cambridge MA
  • a typical anti-malarial vaccine comprising a polyoxime contains 1 mg (T1 BT*)4 polyoxime containing tripalmitoyl-S-glyceryl cysteine, which is administered by subcutaneous injection.

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Abstract

Compositions vaccinales contenant des épitopes de lymphocytes T et B, dérivés du parasite du paludisme et incorporés à une polyoxime à des fins de vaccination.
PCT/US1997/024283 1996-12-24 1997-12-24 Vaccins antipaludiques a base de polyoxime WO1998030237A1 (fr)

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AU58128/98A AU5812898A (en) 1996-12-24 1997-12-24 Polyoxime-based anti-malarial vaccines

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990011778A1 (fr) * 1989-04-12 1990-10-18 The Rockefeller University Polymere dendritique d'un systeme de peptides d'antigenes multiples utile en tant que vaccin anti-paludeen
WO1994025071A1 (fr) * 1993-05-05 1994-11-10 Keith Rose Composes de polyoximes et leur preparation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990011778A1 (fr) * 1989-04-12 1990-10-18 The Rockefeller University Polymere dendritique d'un systeme de peptides d'antigenes multiples utile en tant que vaccin anti-paludeen
WO1994025071A1 (fr) * 1993-05-05 1994-11-10 Keith Rose Composes de polyoximes et leur preparation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ANNUAL REVIEW OF IMMUNOLOGY, 1993, Volume 11, NARDIN et al., "T Cell Responses to Pre-Erythrocytic Stages of Malaria: Role in Protection and Vaccine Development Against Pre-Erythrocytic Stages", pages 687-727. *
MOLECULAR IMMUNOLOGY, 1995, Volume 32, Number 14/15, ROSE et al., "A Synthetic Peptide-Based Polyoxime Vaccine Construct of High Purity and Activity", pages 1031-1037. *

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