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WO1998030237A9 - Vaccins antipaludiques a base de polyoxime - Google Patents

Vaccins antipaludiques a base de polyoxime

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Publication number
WO1998030237A9
WO1998030237A9 PCT/US1997/024283 US9724283W WO9830237A9 WO 1998030237 A9 WO1998030237 A9 WO 1998030237A9 US 9724283 W US9724283 W US 9724283W WO 9830237 A9 WO9830237 A9 WO 9830237A9
Authority
WO
WIPO (PCT)
Prior art keywords
polyoxime
epitope
malaria
peptide
cell epitope
Prior art date
Application number
PCT/US1997/024283
Other languages
English (en)
Other versions
WO1998030237A1 (fr
Filing date
Publication date
Application filed filed Critical
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

Links

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. falciparum 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. fa/ciparum 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. Immunol. 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, RM (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 RII 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.Natl.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
  • An "immunogenic composition” is a composition that elicits a humoral and/or cellular immune response in a host organism.
  • 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.
  • 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.
  • 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.
  • 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/lymphokines to mimic the immunostimulator ⁇ 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 c ⁇ steine, to the branched peptide core.
  • 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.

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)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU58128/98A AU5812898A (en) 1996-12-24 1997-12-24 Polyoxime-based anti-malarial vaccines

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US3450696P 1996-12-24 1996-12-24
US60/034,506 1996-12-24

Publications (2)

Publication Number Publication Date
WO1998030237A1 WO1998030237A1 (fr) 1998-07-16
WO1998030237A9 true WO1998030237A9 (fr) 1998-12-17

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1997/024283 WO1998030237A1 (fr) 1996-12-24 1997-12-24 Vaccins antipaludiques a base de polyoxime

Country Status (2)

Country Link
AU (1) AU5812898A (fr)
WO (1) WO1998030237A1 (fr)

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU5649290A (en) * 1989-04-12 1990-11-05 New York University Dendritic polymer of multiple antigen peptide system useful as anti-malarial vaccine
WO1994025071A1 (fr) * 1993-05-05 1994-11-10 Keith Rose Composes de polyoximes et leur preparation

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