A synthetic vaccine protects humans against challenge with asexual blood stages of Plasmodium falciparum malaria

Patarroyo, Manuel Elkín; Amador, Roberto; Clavijo, Pedro; Moreno, Alberto; Guzmán, Fanny; Romero, Pedro; Tascon, Ricardo E.; Franco, Antônio; Murillo, Luis A.; Ponton, Gabriel; Trujillo, G.

doi:10.1038/332158a0

Cited by 384 publications

(179 citation statements)

References 12 publications

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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. [27][28][29] One lot produced elsewhere proved nonprotective.…”

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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“…One of the few vaccines to undergo large-scale clinical trials, the three-component vaccine (SPf66) developed by Pattaroyo, 31 did not show any efficacy. 32,33 The most advanced development to date is the RTS'S, based on a particulate construct of the circumsporozoite protein fused to the hepatitis B surface antigen.…”

Section: Personal Viewmentioning

confidence: 99%

Malaria: current status of control, diagnosis, treatment, and a proposed agenda for research and development

Guérin¹,

Olliaro

Nosten

et al. 2002

The Lancet Infectious Diseases

320

201

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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: 99%

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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A synthetic vaccine protects humans against challenge with asexual blood stages of Plasmodium falciparum malaria

Cited by 384 publications

References 12 publications

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

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

Malaria: current status of control, diagnosis, treatment, and a proposed agenda for research and development

Sharing of antigens between Plasmodium falciparum and Anopheles albimanus

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