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Safety, infectivity and immunogenicity of a genetically attenuated blood-stage malaria vaccine

Webster, Rebecca, Sekuloski, Silvana, Odedra, Anand, Woolley, StephenDerek, Jennings, Helen, Amante, Fiona, Trenholme, Katharine R., Healer, Julie, Cowman, Alan F., Eriksson, Emily M., Sathe, Priyanka, Penington, Jocelyn, Blanch, Adam J., Dixon, Matthew W. A., Tilley, Leann, Duffy, Michael F., Craig, Alister ORCID: https://orcid.org/0000-0003-0914-6164, Storm, Janet ORCID: https://orcid.org/0000-0001-7812-4220, Chan, Jo-Anne, Evans, Krystal, Papenfuss, Anthony T., Schofield, Louis, Griffin, Paul, Barber, Bridget E., Andrew, Dean, Boyle, Michelle J., de Labastida Rivera, Fabian, Engwerda, Christian and McCarthy, James S. (2021) 'Safety, infectivity and immunogenicity of a genetically attenuated blood-stage malaria vaccine'. BMC Medicine, Vol 19, Issue 293.

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Abstract

Background
There is a clear need for novel approaches to malaria vaccine development. We aimed to develop a genetically attenuated blood-stage vaccine and test its safety, infectivity, and immunogenicity in healthy volunteers. Our approach was to target the gene encoding the knob-associated histidine-rich protein (KAHRP), which is responsible for the assembly of knob structures at the infected erythrocyte surface. Knobs are required for correct display of the polymorphic adhesion ligand P. falciparum erythrocyte membrane protein 1 (PfEMP1), a key virulence determinant encoded by a repertoire of var genes.

Methods
The gene encoding KAHRP was deleted from P. falciparum 3D7 and a master cell bank was produced in accordance with Good Manufacturing Practice. Eight malaria naïve males were intravenously inoculated (day 0) with 1800 (2 subjects), 1.8 × 105 (2 subjects), or 3 × 106 viable parasites (4 subjects). Parasitemia was measured using qPCR; immunogenicity was determined using standard assays. Parasites were rescued into culture for in vitro analyses (genome sequencing, cytoadhesion assays, scanning electron microscopy, var gene expression).

Results
None of the subjects who were administered with 1800 or 1.8 × 105 parasites developed parasitemia; 3/4 subjects administered 3× 106 parasites developed significant parasitemia, first detected on days 13, 18, and 22. One of these three subjects developed symptoms of malaria simultaneously with influenza B (day 17; 14,022 parasites/mL); one subject developed mild symptoms on day 28 (19,956 parasites/mL); and one subject remained asymptomatic up to day 35 (5046 parasites/mL). Parasitemia rapidly cleared with artemether/lumefantrine. Parasitemia induced a parasite-specific antibody and cell-mediated immune response. Parasites cultured ex vivo exhibited genotypic and phenotypic properties similar to inoculated parasites, although the var gene expression profile changed during growth in vivo.

Conclusions
This study represents the first clinical investigation of a genetically attenuated blood-stage human malaria vaccine. A P. falciparum 3D7 kahrp– strain was tested in vivo and found to be immunogenic but can lead to patent parasitemia at high doses.

Item Type: Article
Subjects: QU Biochemistry > Genetics > QU 450 General Works
QW Microbiology and Immunology > Immunotherapy and Hypersensitivity > QW 805 Vaccines. Antitoxins. Toxoids
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria
Faculty: Department: Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI): https://doi.org/10.1186/s12916-021-02150-x
Depositing User: Stacy Murtagh
Date Deposited: 03 Dec 2021 14:09
Last Modified: 03 Dec 2021 14:09
URI: https://archive.lstmed.ac.uk/id/eprint/19565

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