APC-targeted DNA vaccination against reticulocyte-binding protein homolog 5 induces plasmodium falciparum-specific neutralizing Antibodies and T Cell Responses

Bjerkan, Louise, Visweswaran, Ganesh Ram R., Gudjonsson, Arnar, Labbé, Geneviève M., Quinkert, Doris, Pattinson, David J., Spång, Heidi C.L., Draper, Simon J., Bogen, Bjarne, and Braathen, Ranveig (2021) APC-targeted DNA vaccination against reticulocyte-binding protein homolog 5 induces plasmodium falciparum-specific neutralizing Antibodies and T Cell Responses. Frontiers in Immunology, 12. 720550.

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Abstract

Targeted delivery of antigen to antigen presenting cells (APCs) is an efficient way to induce robust antigen-specific immune responses. Here, we present a novel DNA vaccine that targets the Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5), a leading blood-stage antigen of the human malaria pathogen, to APCs. The vaccine is designed as bivalent homodimers where each chain is composed of an amino-terminal single chain fragment variable (scFv) targeting unit specific for major histocompatibility complex class II (MHCII) expressed on APCs, and a carboxyl-terminal antigenic unit genetically linked by the dimerization unit. This vaccine format, named “Vaccibody”, has previously been successfully applied for antigens from other infectious diseases including influenza and HIV, as well as for tumor antigens. Recently, the crystal structure and key functional antibody epitopes for the truncated version of PfRH5 (PfRH5ΔNL) were characterized, suggesting PfRH5ΔNL to be a promising candidate for next-generation PfRH5 vaccine design. In this study, we explored the APC-targeting strategy for a PfRH5ΔNL-containing DNA vaccine. BALB/c mice immunized with the targeted vaccine induced higher PfRH5-specific IgG1 antibody responses than those vaccinated with a non-targeted vaccine or antigen alone. The APC-targeted vaccine also efficiently induced rapid IFN-γ and IL-4 T cell responses. Furthermore, the vaccine-induced PfRH5-specific IgG showed inhibition of growth of the P. falciparum 3D7 clone parasite in vitro. Finally, sera obtained after vaccination with this targeted vaccine competed for the same epitopes as PfRH5-specific mAbs from vaccinated humans. Robust humoral responses were also induced by a similar P. vivax Duffy-binding protein (PvDBP)-containing targeted DNA vaccine. Our data highlight a novel targeted vaccine platform for the development of vaccines against blood-stage malaria.

Item ID: 75149
Item Type: Article (Research - C1)
ISSN: 1664-3224
Keywords: antibody responses, APC-targeting, DNA vaccines, GIA, malaria, PfRH5, T cell responses
Copyright Information: Copyright © 2021 Bjerkan, Visweswaran, Gudjonsson, Labbe, Quinkert, Pattinson, Spång, Draper, Bogen and Braathen. This is an open-access article distributed under the terms of the Creative Commons AttributionLicense (CC BY).The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Date Deposited: 07 Jul 2022 07:30
FoR Codes: 32 BIOMEDICAL AND CLINICAL SCIENCES > 3204 Immunology > 320404 Cellular immunology @ 100%
SEO Codes: 20 HEALTH > 2001 Clinical health > 200104 Prevention of human diseases and conditions @ 100%
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