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Reticulocyte-binding protein homologue 5 (RH5), a leading blood-stage Plasmodium falciparum malaria vaccine target, interacts with cysteine-rich protective antigen (CyRPA) and RH5-interacting protein (RIPR) to form an essential heterotrimeric "RCR-complex". We investigate whether RCR-complex vaccination can improve upon RH5 alone. Using monoclonal antibodies (mAbs) we show that parasite growth-inhibitory epitopes on each antigen are surface-exposed on the RCR-complex and that mAb pairs targeting different antigens can function additively or synergistically. However, immunisation of female rats with the RCR-complex fails to outperform RH5 alone due to immuno-dominance of RIPR coupled with inferior potency of anti-RIPR polyclonal IgG. We identify that all growth-inhibitory antibody epitopes of RIPR cluster within the C-terminal EGF-like domains and that a fusion of these domains to CyRPA, called "R78C", combined with RH5, improves the level of in vitro parasite growth inhibition compared to RH5 alone. These preclinical data justify the advancement of the RH5.1 + R78C/Matrix-M™ vaccine candidate to Phase 1 clinical trial.

Titel:	Development of an improved blood-stage malaria vaccine targeting the essential RH5-CyRPA-RIPR invasion complex.
Autor/in / Beteiligte Person:	Williams, BG ; King, LDW ; Pulido, D ; Quinkert, D ; Lias, AM ; Silk, SE ; Ragotte, RJ ; Davies, H ; Barrett, JR ; McHugh, K ; Rigby, CA ; Alanine, DGW ; Barfod, L ; Shea, MW ; Cowley, LA ; Dabbs, RA ; Pattinson, DJ ; Douglas, AD ; Lyth, OR ; Illingworth, JJ ; Jin, J ; Carnrot, C ; Kotraiah, V ; Christen, JM ; Noe, AR ; MacGill, RS ; King, CR ; Birkett, AJ ; Soisson, LA ; Skinner, K ; Miura, K ; Long, CA ; Higgins, MK ; Draper, SJ
Zeitschrift:	Nature communications, Jg. 15 (2024-06-07), Heft 1, S. 4857
Veröffentlichung:	[London] : Nature Pub. Group, 2024
Medientyp:	academicJournal
ISSN:	2041-1723 (electronic)
DOI:	10.1038/s41467-024-48721-3
Schlagwort:	Animals Female Rats Humans Epitopes immunology Carrier Proteins immunology Carrier Proteins metabolism Malaria Vaccines immunology Malaria Vaccines administration & dosage Plasmodium falciparum immunology Protozoan Proteins immunology Malaria, Falciparum prevention & control Malaria, Falciparum immunology Malaria, Falciparum parasitology Antigens, Protozoan immunology Antibodies, Protozoan immunology Antibodies, Monoclonal immunology
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article Language: English [Nat Commun] 2024 Jun 07; Vol. 15 (1), pp. 4857. <i>Date of Electronic Publication: </i>2024 Jun 07. MeSH Terms: Malaria Vaccines* / immunology ; Malaria Vaccines* / administration & dosage ; Plasmodium falciparum* / immunology ; Protozoan Proteins* / immunology ; Malaria, Falciparum* / prevention & control ; Malaria, Falciparum* / immunology ; Malaria, Falciparum* / parasitology ; Antigens, Protozoan* / immunology ; Antibodies, Protozoan* / immunology ; Antibodies, Monoclonal* / immunology ; Animals ; Female ; Rats ; Humans ; Epitopes / immunology ; Carrier Proteins / immunology ; Carrier Proteins / metabolism References: Malar J. 2023 Jul 15;22(1):210. (PMID: 37454145) ; Infect Immun. 2005 Jun;73(6):3677-85. (PMID: 15908397) ; Int J Parasitol. 2017 Jun;47(7):435-446. (PMID: 28153778) ; PLoS Pathog. 2023 Sep 15;19(9):e1011182. (PMID: 37713419) ; PLoS Pathog. 2012;8(11):e1003031. 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(PMID: 30965383) ; Cell Host Microbe. 2020 Apr 8;27(4):642-658.e12. (PMID: 32109369) Grant Information: MC_PC_17167 RCUK \| MRC \| Medical Research Foundation; MC_PC_17167 RCUK \| MRC \| Medical Research Foundation; MR/K017632/1 RCUK \| MRC \| Medical Research Foundation; MR/N013468/1 RCUK \| Medical Research Council (MRC); MR/N013468/1 RCUK \| Medical Research Council (MRC); 733273 EC \| Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020); AID-OAA-C-15-00071 United States Agency for International Development (U.S. Agency for International Development); AID-GH-T-15-00001 Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID); 105399/Z/14/Z Wellcome Trust (Wellcome); 201477/Z/16/Z Wellcome Trust (Wellcome); 220797/Z/20/Z Wellcome Trust (Wellcome); 106917/Z/15/Z Wellcome Trust (Wellcome) Substance Nomenclature: 0 (Malaria Vaccines) ; 0 (Protozoan Proteins) ; 0 (RH5 protein, Plasmodium falciparum) ; 0 (Antigens, Protozoan) ; 0 (CyRPA protein, Plasmodium falciparum) ; 0 (Antibodies, Protozoan) ; 0 (Antibodies, Monoclonal) ; 0 (Ripr protein, Plasmodium falciparum) ; 0 (Epitopes) ; 0 (Carrier Proteins) Entry Date(s): Date Created: 20240607 Date Completed: 20240607 Latest Revision: 20240617 Update Code: 20240617 PubMed Central ID: PMC11161584

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Development of an improved blood-stage malaria vaccine targeting the essential RH5-CyRPA-RIPR invasion complex.