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

Webster, Rebecca, Sekuloski, Silvana, Odedra, Anand, Woolley, Stephen, Jennings, Helen, Amante, Fiona, Trenholme, Katharine, 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, Storm, Janet, Chan, Jo-Anne, Evans, Krystal, Papenfuss, Anthony T., Schofield, Louis, Griffin, Paul, Barber, Bridget E., Andrew, Dean, Boyle, Michelle J., Rivera, Fabian de Labastida, Engwerda, Christian, and McCarthy, James S. (2021) Safety, infectivity and immunogenicity of a genetically attenuated blood-stage malaria updates vaccine. BMC Medicine, 19. 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 naive males were intravenously inoculated (day 0) with 1800 (2 subjects), 1.8 x 10(5) (2 subjects), or 3 x 10(6) 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 x 10(5) parasites developed parasitemia; 3/4 subjects administered 3x 10(6) 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 ID: 72256
Item Type: Article (Research - C1)
ISSN: 1741-7015
Keywords: Malaria, Vaccine, Plasmodium falciparum, Genetically attenuated, KAHRP, PfEMP1
Copyright Information: © The Author(s). 2021 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Funders: National Health and Medical Research Council (NHMRC), Australian Research Council (ARC)
Projects and Grants: NHMRC 1132975, ARC L150100106
Date Deposited: 09 Feb 2022 12:01
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