Immunization of
            <i>Aotus</i>
            Monkeys with Recombinant
            <i>Plasmodium falciparum</i>
            Hybrid Proteins Does Not Reproducibly Result in Protection from Malaria Infection

Kocken, Clemens H M; Hundt, Erika; Knapp, Bernhard; Brazel, Dieter; Enders, B.; Narum, David L.; Wubben, Jaqueline A. M.; Thomas, Alan W.

doi:10.1128/iai.66.1.373-375.1998

Cited by 10 publications

(7 citation statements)

References 12 publications

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“…Blocking HRPII action could be a prophylactic or therapeutic strategy. Results of attempts in the 1980s to use HRPII as an immunogen in Aotus monkey vaccination trials were encouraging, but results of follow-up studies were equivocal ( 59 – 61 ). New studies informed by the proposed role in cerebral malaria could lead to development of a vaccine that prevents CM.…”

Section: Discussionmentioning

confidence: 99%

Plasmodium falciparum Histidine-Rich Protein II Compromises Brain Endothelial Barriers and May Promote Cerebral Malaria Pathogenesis

Pal

Daniels

Oskman

et al. 2016

mBio

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Cerebral malaria (CM) is a disease of the vascular endothelium caused by Plasmodium falciparum. It is characterized by parasite sequestration, inflammatory cytokine production, and vascular leakage. A distinguishing feature of P. falciparum infection is parasite production and secretion of histidine-rich protein II (HRPII). Plasma HRPII is a diagnostic and prognostic marker for falciparum malaria. We demonstrate that disruption of a human cerebral microvascular endothelial barrier by P. falciparum-infected erythrocytes depends on expression of HRPII. Purified recombinant or native HRPII can recapitulate these effects. HRPII action occurs via activation of the inflammasome, resulting in decreased integrity of tight junctions and increased endothelial permeability. We propose that HRPII is a virulence factor that may contribute to cerebral malaria by compromising endothelial barrier integrity within the central nervous system.

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Section: Discussionmentioning

confidence: 99%

Plasmodium falciparum Histidine-Rich Protein II Compromises Brain Endothelial Barriers and May Promote Cerebral Malaria Pathogenesis

Pal

Daniels

Oskman

et al. 2016

mBio

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“…NOESY spectra with a mixing time of 250 ms were collected on a Bruker DRX-600 spectrometer. 1 H- 13 C HMQC spectra for the assignment of 13 C chemical shifts (28,29) were collected using 2.5 mM samples of natural-abundance F1 and tF1 in 100% 2 H 2 O on a Bruker AMX-500 spectrometer. Diffusion measurements were performed using a PFG longitudinal eddy-current delay pulse sequence (30,31) as implemented by Yao et al (32).…”

Section: Methodsmentioning

confidence: 99%

Structures of Phage-Display Peptides that Bind to the Malarial Surface Protein, Apical Membrane Antigen 1, and Block Erythrocyte Invasion

Keizer

Miles

et al. 2003

Biochemistry

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Apical membrane antigen 1 (AMA1) of the human malaria parasite Plasmodium falciparum is synthesized by schizont stage parasites and has been implicated in merozoite invasion of host erythrocytes. Phage-display techniques have recently been used to identify two 15-residue peptides, F1 and F2, which bind specifically to P. falciparum AMA1 and inhibit parasite invasion of erythrocytes [Li, F., et al. (2002) J. Biol. Chem. 277, 50303-50310]. We have synthesized F1, F2, and three peptides with high levels of sequence identity, determined their relative binding affinities for P. falciparum AMA1 with a competition ELISA, and investigated their solution structures by NMR spectroscopy. The strongest binding peptide, F1, contains a beta-turn that includes residues identified via an alanine scan as being critical for binding to AMA1 and inhibition of merozoite invasion of erythrocytes. The three F1 analogues include a 10-residue analogue of F1 truncated at the C-terminus (tF1), a partially scrambled 15-mer (sF1), and a disulfide-constrained 14-mer (F1tbp) which is related to F1 but has a sequence identical to that of a disulfide-constrained loop in the first epidermal growth factor module of the latent transforming growth factor-beta binding protein. tF1 and F1tbp bound competitively with F1 to AMA1, and all three contain a type I beta-turn encompassing key residues involved in F1 binding. In contrast, sF1 lacked this structural motif, and did not compete for binding to AMA1 with F1; rather, sF1 contained a type III beta-turn involving a different part of the sequence. Although F2 was able to bind to AMA1, it was unstructured in solution, consistent with its weak invasion inhibitory effects. Thus, the secondary structure elements observed for these peptides in solution correlate well with their potency in binding to AMA1 and inhibiting merozoite invasion. The structures provide a valuable starting point for the development of peptidomimetics as antimalarial antagonists directed at AMA1.

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“…High immunogenicity [123] SERP/HRP2/MSP-1 Preclinical (Aotus) Two hybrid recombinant proteins Protection in one study, nonprotection in the other [111,112] and coworkers, in the 1960s, showed that an immunization procedure could induce sterile protection against malaria. In fact, the injection of irradiated sporozoites in mice [41], nonhuman primates [42] or humans [43] was shown to fully protect the host against a subsequent challenge with infectious sporozoites.…”

Section: Sporozoitementioning

confidence: 99%

“…Human vaccine trials have been conducted with combinations of recombinant MSP-1, MSP-2 and RESA in the Montanide ISA720 adjuvant, with the most recent being a Phase IIb trial in children in a highly endemic area of Papua New Guinea [73]. A hybrid molecule containing the blood-stage antigens SERP, MSP-1 and HRP-2 has been tested in Aotus, and the results were controversial in two different studies, with protection being showed in the first [111] but not in the second [112].…”

Section: Multistage Approachesmentioning

confidence: 99%

Malaria Vaccine: Candidate Antigens, Mechanisms, Constraints and Prospects

Carvalho¹,

Daniel-Ribeiro²,

Goto

2002

Scand J Immunol

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More than 30 years after the first report of successful vaccination against malaria using radiation-attenuated sporozoites, an effective malaria vaccine is not yet available. However, field and experimental data indicate that it can be developed. An astonishing amount of data has accumulated concerning parasite biology, host-parasite interactions, immunity and escape mechanisms, targets and modulators of immune responses. Nevertheless, so far this knowledge has not been enough to make us understand how to properly manipulate the whole system to build an effective vaccine. In this article, we describe candidate antigens, mechanisms, targets and trials performed with potential malaria vaccines and discuss the approaches, in vivo and in vitro models, constraints and how technologies such as DNA vaccination, genomics/proteomics and reverse immunogenetics are providing exciting results and opening new doors to make malaria vaccine a reality.

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Immunization of Aotus Monkeys with Recombinant Plasmodium falciparum Hybrid Proteins Does Not Reproducibly Result in Protection from Malaria Infection

Cited by 10 publications

References 12 publications

Plasmodium falciparum Histidine-Rich Protein II Compromises Brain Endothelial Barriers and May Promote Cerebral Malaria Pathogenesis

Plasmodium falciparum Histidine-Rich Protein II Compromises Brain Endothelial Barriers and May Promote Cerebral Malaria Pathogenesis

Structures of Phage-Display Peptides that Bind to the Malarial Surface Protein, Apical Membrane Antigen 1, and Block Erythrocyte Invasion

Malaria Vaccine: Candidate Antigens, Mechanisms, Constraints and Prospects

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