Induction of protective immunity against experimental infection with malaria using synthetic peptides

Patarroyo, Manuel Elkín; Romero, Pedro; Torres, Martha Lucía; Clavijo, Pedro; Moreno, Alberto; Martı́nez, Alberto; Rodríguez, Ricaurte; Guzmán, Fanny; Cabezas, Edelmira

doi:10.1038/328629a0

Cited by 271 publications

(129 citation statements)

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“…25 Those partially protective peptides were later synthesized in a single 45-mer synthetic peptide polymerized via N-and C-terminal cysteine addition, named SPf66. 26 After all monkey trials and safety and immunogenicity trials involving thousands of humans, this first synthetic vaccine (produced 20 years ago) was safe and immunogenic and provided ∼35% protection in people older than 1 year in large field trials carried out in different parts of the world.…”

Section: The Basis Of Our Approachmentioning

confidence: 99%

Emerging Rules for Subunit-Based, Multiantigenic, Multistage Chemically Synthesized Vaccines

2008

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S eventeen million people die of transmittable diseases and 2/3 of the world's population suffer them annually. Malaria, tuberculosis, AIDS, hepatitis, and reemerging and new diseases are a great threat to humankind. A logical and rational approach for vaccine development is thus desperately needed.Protein chemistry provides the best tools for tackling these problems. The tremendous complexity of microbes, the different pathways they use for invading host cells, and the immune responses they induce can only be resolved by using the minimum subunit-based (chemically produced ∼20-mer peptides), multiantigenic (most proteins involved in invasion), multistage (different invasion mechanisms) vaccine development approach.The most lethal form of malaria caused by Plasmodium falciparum (killing 3 million and affecting 500 million people worldwide annually) was used as target disease since many of its proteins, its invasion pathways, and its genome have been described recently. A New World primate (the Aotus monkey) is highly susceptibly to human malaria; its immune system molecules are 80 -100% identical to those of its human counterpart, making it an excellent model for vaccine development.Chemically synthesized ∼20-mer peptides, covering all the P. falciparum malaria proteins involved in red blood cell (RBC) invasion were synthesized by the classical t-Boc technology (based on synthetic SPf66 antimalarial vaccine information for identifying targets) and assayed in a highly sensitive, specific, and robust test for detecting receptor-ligand interactions between high-activity binding peptides (HABPs) and RBCs. HABPs were identified, some in which the molecule displays genetic variability (to be discarded due to their tremendous complexity) and elicits a strain-specific immune response and others that are conserved (no amino acid sequence variation).Conserved HABPs were synthesized in a polymeric form by adding cysteines at their N-and C-terminal ends to be used for monkey immunization. They became nonimmunogenic (no antibodies were induced) nonprotection inducers (monkeys were not protected against P. falciparum malaria challenge with a highly infective strain) suggesting a code of immunological silence or nonresponsiveness for these conserved HABPs.A large number of monkey trials involving a considerable number of Aotus monkeys were performed to break this code of immunological silence by replacing critical residues (determined by glycine peptide analogue scanning) to find that the following amino acid changes had to be made to render them antibody and protection inducing: FTR; WTY; LTH; ITN; MTK; PTD; QTE; CTT.The three-dimensional (3D) structure of >100 of these native modified HABPs (determined by 1 H NMR) revealed that the following structural changes had all to be achieved to allow a better fit into the major histocompatibility complex class II (MHC II)-peptide-TCR complex to properly activate the immune system: R-helix shortening, modifying their -turn, adopting segmental R-helix configuration, changing residue or...

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Section: The Basis Of Our Approachmentioning

confidence: 99%

Emerging Rules for Subunit-Based, Multiantigenic, Multistage Chemically Synthesized Vaccines

2008

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“…To the lysate was added an equal volume of 25 mM Tris-HCl, pH 7.2, containing 5 mM MgCl 2 , 5 mM MnCl 2 , 0.8% Triton X-100. The parasite cell lysate (200 l) corresponding to 10 8 parasites was incubated with [2][3][4][5] Ci of UDP-[ 3 H]GlcNAc and 1 mM synthetic peptide Pro-Tyr-Thr-ValVal at 37°C for 30 -60 min. Control incubations not containing the synthetic peptide were carried out in parallel.…”

Section: Analysis Of P Falciparum Cell Lysate For Peptide O-glycosidmentioning

confidence: 99%

“…A major focus has been on synthetic peptides or recombinant proteins of cell surface antigens (2)(3)(4)(5)(6). However, this approach has not been highly effective, although immunization with native cell surface proteins purified from the erythrocytic stage parasite is known to confer significant protective immunity (7)(8)(9)(10).…”

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confidence: 99%

Glycosylphosphatidylinositol Anchors Represent the Major Carbohydrate Modification in Proteins of Intraerythrocytic Stage Plasmodium falciparum

Gowda

Gupta

Davidson

1997

Journal of Biological Chemistry

135

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The nature and extent of carbohydrate modification in intraerythrocytic stage Plasmodium falciparum proteins have been controversial. This study describes the characterization of the carbohydrates in intraerythrocytic P. falciparum proteins and provides an overall picture of the nature of carbohydrate modification in the parasite proteins. P. falciparum strains were metabolically labeled with radioactive sugar precursors and ethanolamine at different developmental stages. The individual parasite proteins separated on SDS-polyacrylamide gels and whole parasite cell lysates were analyzed for the carbohydrate moieties. The results established the following: 1) glycosylphosphatidylinositol (GPI) anchors represent the major carbohydrate modification in the intraerythrocytic stage P. falciparum proteins; 2) in contrast to previous reports, O-linked carbohydrates are either absent or present only at very low levels in the parasite; and 3) P. falciparum contains low levels of N-glycosylation capability. The amount of N-linked carbohydrates in whole parasite proteins is ϳ6% compared with the GPI anchors attached to proteins based on radioactive GlcN incorporated into the proteins.The glycan cores of multiple parasite protein GPI anchors are all similar, consisting of protein-ethanolamine-phosphate-(Man␣1-2)6Man␣1-2Man␣1-6Man␣1-4GlcN. The fourth Man residues distal to GlcN of the GPI anchor glycan cores contain unidentified substituents that are susceptible to conditions of nitrous acid deamination. This unusual structural feature may contribute to the reported pathogenic properties of the P. falciparum GPI anchors.Malaria, a life-threatening disease caused by parasitic protozoa of the genus Plasmodium, is a major health problem throughout the tropical and subtropical regions of the world. Among the four species that infect humans, Plasmodium falciparum is the most virulent. New approaches such as vaccine development and novel therapeutic agents are urgently needed due to the emergence of parasite strains resistant to chloroquine and other commonly used drugs (1).Vaccines based on antigens of the blood stage parasite are under intensive study. A major focus has been on synthetic peptides or recombinant proteins of cell surface antigens (2-6). However, this approach has not been highly effective, although immunization with native cell surface proteins purified from the erythrocytic stage parasite is known to confer significant protective immunity (7-10). It is plausible that post-translational modifications play an important role in antigenicity. Accordingly, a basic understanding of such modifications may assist in the development of effective vaccines.Glycosylation is an often extensive post-translational modification of eukaryotic proteins. Carbohydrate moieties of glycoproteins perform a variety of functions including modulation of immunological properties, receptor-ligand interactions, sorting and localization of proteins, cell adhesion, and cell-cell communication (11). In addition, they contribute to protein conform...

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“…The cross-recognition of possible common molecular components between these two organisms was also confirmed by ELISA and MABA assays. These anti-mosquito sera not only recognized molecular components of the P. falciparum antigen, but unexpectedly, also identified the SPf66 synthetic malaria vaccine, which contains short sequences of four distinct surface molecules: one from the sporozoite (NANP) and three from the asexual blood stages (83, 55, 33 kDa) of the parasite 31,32 . This findings deserves special attention and further experiments will be required to evaluate the possible antianopheline effect of this well-known protective vaccine 31,32 .…”

Section: Discussionmentioning

confidence: 95%

Sharing of antigens between Plasmodium falciparum and Anopheles albimanus

Wide

Capaldo²,

Zerpa

et al. 2006

Rev. Inst. Med. trop. S. Paulo

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SUMMARYThe presence of common antigens between Plasmodium falciparum and Anopheles albimanus was demonstrated. Different groups of rabbits were immunized with: crude extract from female An. albimanus (EAaF), red blood cells infected with Plasmodium falciparum (EPfs), and the SPf66 synthetic malaria vaccine. The rabbit´s polyclonal antibodies were evaluated by ELISA, Multiple Antigen Blot Assay (MABA), and immunoblotting. All extracts were immunogenic in rabbits according to these three techniques, when they were evaluated against the homologous antigens. Ten molecules were identified in female mosquitoes and also in P. falciparum antigens by the autologous sera. The electrophoretic pattern by SDS-PAGE was different for the three antigens evaluated. Cross-reactions between An. albimanus and P. falciparum were found by ELISA, MABA, and immunoblotting. Anti-P. falciparum and anti-SPf66 antibodies recognized ten and five components in the EAaF crude extract, respectively. Likewise, immune sera against female An. albimanus identified four molecules in the P. falciparum extract antigen. As far as we know, this is the first work that demonstrates shared antigens between anophelines and malaria parasites. This finding could be useful for diagnosis, vaccines, and the study of physiology of the immune response to malaria.

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Induction of protective immunity against experimental infection with malaria using synthetic peptides

Cited by 271 publications

References 0 publications

Emerging Rules for Subunit-Based, Multiantigenic, Multistage Chemically Synthesized Vaccines

Emerging Rules for Subunit-Based, Multiantigenic, Multistage Chemically Synthesized Vaccines

Glycosylphosphatidylinositol Anchors Represent the Major Carbohydrate Modification in Proteins of Intraerythrocytic Stage Plasmodium falciparum

Sharing of antigens between Plasmodium falciparum and Anopheles albimanus

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