Monoclonal antibodies block transmission of genetically diverse Plasmodium falciparum strains to mosquitoes

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Title: Monoclonal antibodies block transmission of genetically diverse Plasmodium falciparum strains to mosquitoes
Authors: De Jong, RM
Meerstein-Kessel, L
Da, DF
Nsango, S
Challenger, JD
Van de Vegte-Bolmer, M
Van Gemert, G-J
Duarte, E
Teyssier, N
Sauerwein, RW
Churcher, TS
Dabire, RK
Morlais, I
Locke, E
Huynen, MA
Bousema, T
Jore, MM
Item Type: Journal Article
Abstract: Malaria parasite transmission to mosquitoes relies on the uptake of sexual stage parasites during a blood meal and subsequent formation of oocysts on the mosquito midgut wall. Transmission-blocking vaccines (TBVs) and monoclonal antibodies (mAbs) target sexual stage antigens to interrupt human-to-mosquito transmission and may form important tools for malaria elimination. Although most epitopes of these antigens are considered highly conserved, little is known about the impact of natural genetic diversity on the functional activity of transmission-blocking antibodies. Here we measured the efficacy of three mAbs against leading TBV candidates (Pfs48/45, Pfs25 and Pfs230) in transmission assays with parasites from naturally infected donors compared to their efficacy against the strain they were raised against (NF54). Transmission-reducing activity (TRA) was measured as reduction in mean oocyst intensity. mAb 45.1 (α-Pfs48/45) and mAb 4B7 (α-Pfs25) reduced transmission of field parasites from almost all donors with IC80 values similar to NF54. Sequencing of oocysts that survived high mAb concentrations did not suggest enrichment of escape genotypes. mAb 2A2 (α-Pfs230) only reduced transmission of parasites from a minority of the donors, suggesting that it targets a non-conserved epitope. Using six laboratory-adapted strains, we revealed that mutations in one Pfs230 domain correlate with mAb gamete surface binding and functional TRA. Our findings demonstrate that, despite the conserved nature of sexual stage antigens, minor sequence variation can significantly impact the efficacy of transmission-blocking mAbs. Since mAb 45.1 shows high potency against genetically diverse strains, our findings support its further clinical development and may inform Pfs48/45 vaccine design.
Issue Date: Dec-2021
Date of Acceptance: 29-Jul-2021
URI: http://hdl.handle.net/10044/1/91051
DOI: 10.1038/s41541-021-00366-9
ISSN: 2059-0105
Publisher: Nature Research
Start Page: 1
End Page: 9
Journal / Book Title: npj Vaccines
Volume: 6
Issue: 1
Copyright Statement: © 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 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/.
Sponsor/Funder: PATH-Program for Appropriate Technology in Health
Funder's Grant Number: GAT.0888-30-01618462-COL
Publication Status: Published
Open Access location: https://doi.org/10.1038/s41541-021-00366-9
Article Number: 101
Online Publication Date: 2021-08-12
Appears in Collections:School of Public Health



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