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      A Plasmodium berghei sporozoite-based vaccination platform against human malaria

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          Abstract

          There is a pressing need for safe and highly effective Plasmodium falciparum ( Pf) malaria vaccines. The circumsporozoite protein (CS), expressed on sporozoites and during early hepatic stages, is a leading target vaccine candidate, but clinical efficacy has been modest so far. Conversely, whole-sporozoite (WSp) vaccines have consistently shown high levels of sterilizing immunity and constitute a promising approach to effective immunization against malaria. Here, we describe a novel WSp malaria vaccine that employs transgenic sporozoites of rodent P. berghei ( Pb) parasites as cross-species immunizing agents and as platforms for expression and delivery of PfCS ( PbVac). We show that both wild-type Pb and PbVac sporozoites unabatedly infect and develop in human hepatocytes while unable to establish an infection in human red blood cells. In a rabbit model, similarly susceptible to Pb hepatic but not blood infection, we show that PbVac elicits cross-species cellular immune responses, as well as PfCS-specific antibodies that efficiently inhibit Pf sporozoite liver invasion in human hepatocytes and in mice with humanized livers. Thus, PbVac is safe and induces functional immune responses in preclinical studies, warranting clinical testing and development.

          Malaria: Programming non-pathogenic parasites as vaccine candidates

          A genetically engineered parasite, related to malaria-causing Plasmodium falciparum, excels as a vaccine in preclinical tests. A team led by Miguel Prudêncio, of the University of Lisbon, Portugal, developed a genetically altered vaccine candidate based on Plasmodium berghei, which is pathogenic to rodents but, in humans, fails to progress from a harmless, transient liver infection to causing full, blood-borne malaria. The candidate expresses a human form of ‘circumsporozoite protein,’ a known antigen, and is designed to provoke a more comprehensive immune response as it presents a whole pathogen to the host. In preclinical tests, the candidate generated antibodies able to neutralize infection in human hepatocytes and also provoked a cellular immune response in rabbits. The team’s candidate proved safe and efficacious, warranting further trials and clinical testing.

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          Most cited references 57

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          NetMHCpan-4.0: Improved Peptide-MHC Class I Interaction Predictions Integrating Eluted Ligand and Peptide Binding Affinity Data.

          Cytotoxic T cells are of central importance in the immune system's response to disease. They recognize defective cells by binding to peptides presented on the cell surface by MHC class I molecules. Peptide binding to MHC molecules is the single most selective step in the Ag-presentation pathway. Therefore, in the quest for T cell epitopes, the prediction of peptide binding to MHC molecules has attracted widespread attention. In the past, predictors of peptide-MHC interactions have primarily been trained on binding affinity data. Recently, an increasing number of MHC-presented peptides identified by mass spectrometry have been reported containing information about peptide-processing steps in the presentation pathway and the length distribution of naturally presented peptides. In this article, we present NetMHCpan-4.0, a method trained on binding affinity and eluted ligand data leveraging the information from both data types. Large-scale benchmarking of the method demonstrates an increase in predictive performance compared with state-of-the-art methods when it comes to identification of naturally processed ligands, cancer neoantigens, and T cell epitopes.
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            Protection against a malaria challenge by sporozoite inoculation.

            An effective vaccine for malaria is urgently needed. Naturally acquired immunity to malaria develops slowly, and induction of protection in humans can be achieved artificially by the inoculation of radiation-attenuated sporozoites by means of more than 1000 infective mosquito bites. We exposed 15 healthy volunteers--with 10 assigned to a vaccine group and 5 assigned to a control group--to bites of mosquitoes once a month for 3 months while they were receiving a prophylactic regimen of chloroquine. The vaccine group was exposed to mosquitoes that were infected with Plasmodium falciparum, and the control group was exposed to mosquitoes that were not infected with the malaria parasite. One month after the discontinuation of chloroquine, protection was assessed by homologous challenge with five mosquitoes infected with P. falciparum. We assessed humoral and cellular responses before vaccination and before the challenge to investigate correlates of protection. All 10 subjects in the vaccine group were protected against a malaria challenge with the infected mosquitoes. In contrast, patent parasitemia (i.e., parasites found in the blood on microscopical examination) developed in all five control subjects. Adverse events were mainly reported by vaccinees after the first immunization and by control subjects after the challenge; no serious adverse events occurred. In this model, we identified the induction of parasite-specific pluripotent effector memory T cells producing interferon-gamma, tumor necrosis factor alpha, and interleukin-2 as a promising immunologic marker of protection. Protection against a homologous malaria challenge can be induced by the inoculation of intact sporozoites. (ClinicalTrials.gov number, NCT00442377.) 2009 Massachusetts Medical Society
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              High efficiency transfection of Plasmodium berghei facilitates novel selection procedures.

              The use of transfection in the study of the biology of malaria parasites has been limited due to poor transfection efficiencies (frequency of 10(-6) to 10(-9)) and a paucity of selection markers. Here, a new method of transfection, using non-viral Nucleofector technology, is described for the rodent parasite Plasmodium berghei. The transfection efficiency obtained (episomal and targeted integration into the genome) is in the range of 10(-2) to 10(-3). Such high transfection efficiency strongly reduces the time, number of laboratory animals and amount of materials required to generate transfected parasites. Moreover, it allows different experimental strategies for reverse genetics to be developed and we demonstrate direct selection of stably and non-reversibly transformed, fluorescent protein (FP)-expressing parasites using FACS. Since there is no need to use a drug-selectable marker, this method increases the (low) number of selectable markers available for transformation of P. berghei and can in principle be extended to utilise additional FP. Furthermore the FACS-selected, FP-expressing parasites may serve as easily visualized reference lines that may still be genetically manipulated with the existing drug-selectable markers. The combination of enhanced transfection efficiency and a versatile rodent model provides a basis for the further development of novel tools for high throughput genome manipulation.
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                Author and article information

                Contributors
                mprudencio@medicina.ulisboa.pt
                Journal
                NPJ Vaccines
                NPJ Vaccines
                NPJ Vaccines
                Nature Publishing Group UK (London )
                2059-0105
                24 August 2018
                24 August 2018
                2018
                : 3
                Affiliations
                [1 ]ISNI 0000 0001 2181 4263, GRID grid.9983.b, Instituto de Medicina Molecular, Faculdade de Medicina, , Universidade de Lisboa, Avenida Professor Egas Moniz, ; 1649−028 Lisboa, Portugal
                [2 ]ISNI 0000 0004 0444 9382, GRID grid.10417.33, Department of Medical Microbiology, , Radboud University Medical Center, ; Geert Grooteplein 28, Microbiology 268, 6500 HB Nijmegen, The Netherlands
                [3 ]ISNI 0000 0001 2069 7798, GRID grid.5342.0, Center for Vaccinology, , Ghent University and Ghent University Hospital, ; De Pintelaan 185, 9000 Ghent, Belgium
                [4 ]Departments of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent University Hospital, Ghent, Belgium
                [5 ]ISNI 0000000089452978, GRID grid.10419.3d, Leiden Malaria Research Group, Parasitology, Center of Infectious Diseases, , Leiden University Medical Center, ; Leiden, The Netherlands
                [6 ]ISNI 0000 0004 1936 8948, GRID grid.4991.5, The Jenner Institute, Nuffield Department of Medicine, , University of Oxford, ; ORCRB, Roosevelt Drive, Oxford, OX3 7DQ UK
                [7 ]ISNI 0000 0001 2175 4264, GRID grid.411024.2, Institute for Genome Sciences, , University of Maryland School of Medicine, ; Baltimore, MD 21201 USA
                [8 ]ISNI 0000 0004 1768 1287, GRID grid.419327.a, Diseases of the Developing World, , GlaxoSmithKline, ; Severo Ochoa, 2, 28760 Tres Cantos, Madrid Spain
                [9 ]ISNI 0000 0001 2341 2786, GRID grid.116068.8, Health Sciences and Technology/Institute for Medical Engineering and Science, , Massachusetts Institute of Technology, ; Cambridge, MA 02139 USA
                [10 ]GRID grid.422900.d, Yecuris Corporation, ; PO Box 4645, Tualatin, OR 97062 USA
                [11 ]ISNI 0000 0001 2175 4264, GRID grid.411024.2, Department of Microbiology and Immunology, , University of Maryland School of Medicine, ; Baltimore, MD 21201 USA
                [12 ]ISNI 000000041936754X, GRID grid.38142.3c, Present Address: Department of Immunology and Infectious Diseases, , Harvard T.H. Chan School of Public Health, ; 665 Huntington Avenue, 02115 Boston, MA USA
                Article
                68
                10.1038/s41541-018-0068-2
                6109154
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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                Comments

                Malaria vaccine development collection topic 5) Identifying and developing the new generation of malaria vaccines - Advances in adjuvants and delivery platforms.

                See https://www.scienceopen.com/collection/malariavaccine

                2018-10-10 00:38 UTC
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