Analysis of the diverse antigenic landscape of the malaria protein RH5 identifies a potent vaccine-induced human public antibody clonotype

Jordan R Barrett; Dimitra Pipini; Nathan D Wright; Andrew J R Cooper; Giacomo Gorini; Doris Quinkert; Amelia M Lias; Hannah Davies; Cassandra A Rigby; Maya Aleshnick; Barnabas G Williams; William J Bradshaw; Neil G Paterson; Thomas Martinson; Payton Kirtley; Luc Picard; Christine D Wiggins; Francesca R Donnellan; Lloyd D W King; Lawrence T Wang; Jonathan F Popplewell; Sarah E Silk; Jed de Ruiter Swain; Katherine Skinner; Vinayaka Kotraiah; Amy R Noe; Randall S MacGill; C Richter King; Ashley J Birkett; Lorraine A Soisson; Angela M Minassian; Douglas A Lauffenburger; Kazutoyo Miura; Carole A Long; Brandon K Wilder; Lizbé Koekemoer; Joshua Tan; Carolyn M Nielsen; Kirsty McHugh; Simon J Draper

doi:10.1016/j.cell.2024.06.015

Analysis of the diverse antigenic landscape of the malaria protein RH5 identifies a potent vaccine-induced human public antibody clonotype

Cell. 2024 Sep 5;187(18):4964-4980.e21. doi: 10.1016/j.cell.2024.06.015. Epub 2024 Jul 25.

Authors

Jordan R Barrett¹, Dimitra Pipini¹, Nathan D Wright², Andrew J R Cooper³, Giacomo Gorini⁴, Doris Quinkert¹, Amelia M Lias¹, Hannah Davies¹, Cassandra A Rigby⁵, Maya Aleshnick⁶, Barnabas G Williams¹, William J Bradshaw², Neil G Paterson⁷, Thomas Martinson⁶, Payton Kirtley⁶, Luc Picard⁸, Christine D Wiggins⁸, Francesca R Donnellan¹, Lloyd D W King¹, Lawrence T Wang⁹, Jonathan F Popplewell¹⁰, Sarah E Silk¹, Jed de Ruiter Swain¹¹, Katherine Skinner¹, Vinayaka Kotraiah¹², Amy R Noe¹², Randall S MacGill¹³, C Richter King¹³, Ashley J Birkett¹³, Lorraine A Soisson¹⁴, Angela M Minassian¹⁵, Douglas A Lauffenburger⁸, Kazutoyo Miura¹⁶, Carole A Long¹⁶, Brandon K Wilder⁶, Lizbé Koekemoer², Joshua Tan³, Carolyn M Nielsen¹, Kirsty McHugh¹, Simon J Draper¹⁷

Affiliations

¹ Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford OX1 3QU, UK; The Jenner Institute, University of Oxford, Oxford OX3 7DQ, UK.
² Centre for Medicines Discovery, University of Oxford, Oxford OX3 7FZ, UK.
³ Antibody Biology Unit, Laboratory of Immunogenetics, NIAID/NIH, Rockville, MD 20852, USA.
⁴ The Jenner Institute, University of Oxford, Oxford OX3 7DQ, UK.
⁵ Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford OX1 3QU, UK.
⁶ Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006, USA.
⁷ Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot, Oxfordshire OX11 0DE, UK.
⁸ Department of Biological Engineering, MIT, Cambridge, MA, USA.
⁹ Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford OX1 3QU, UK; Antibody Biology Unit, Laboratory of Immunogenetics, NIAID/NIH, Rockville, MD 20852, USA.
¹⁰ Carterra, 825 N. 300 W. Ste. C309, Salt Lake City, UT 84103, USA.
¹¹ Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK; The Jenner Institute, University of Oxford, Oxford OX3 7DQ, UK.
¹² Leidos Life Sciences, Frederick, MD, USA.
¹³ Center for Vaccine Innovation and Access, PATH, Washington, DC 20001, USA.
¹⁴ USAID, 1300 Pennsylvania Avenue NW, Washington, DC 20004, USA.
¹⁵ Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford OX1 3QU, UK; The Jenner Institute, University of Oxford, Oxford OX3 7DQ, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.
¹⁶ Laboratory of Malaria and Vector Research, NIAID/NIH, Rockville, MD 20852, USA.
¹⁷ Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford OX1 3QU, UK; The Jenner Institute, University of Oxford, Oxford OX3 7DQ, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK. Electronic address: simon.draper@bioch.ox.ac.uk.

PMID: 39059380
PMCID: PMC11380582 (available on 2025-09-05)
DOI: 10.1016/j.cell.2024.06.015

Abstract

The highly conserved and essential Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) has emerged as the leading target for vaccines against the disease-causing blood stage of malaria. However, the features of the human vaccine-induced antibody response that confer highly potent inhibition of malaria parasite invasion into red blood cells are not well defined. Here, we characterize 236 human IgG monoclonal antibodies, derived from 15 donors, induced by the most advanced PfRH5 vaccine. We define the antigenic landscape of this molecule and establish that epitope specificity, antibody association rate, and intra-PfRH5 antibody interactions are key determinants of functional anti-parasitic potency. In addition, we identify a germline IgG gene combination that results in an exceptionally potent class of antibody and demonstrate its prophylactic potential to protect against P. falciparum parasite challenge in vivo. This comprehensive dataset provides a framework to guide rational design of next-generation vaccines and prophylactic antibodies to protect against blood-stage malaria.

Keywords: PfRH5; Plasmodium falciparum; RH5; antibody; blood stage; mAb; malaria; monoclonal antibody; public clonotype; vaccine.

MeSH terms

Animals
Antibodies, Monoclonal* / immunology
Antibodies, Protozoan* / immunology
Antigens, Protozoan* / immunology
Carrier Proteins / immunology
Epitopes / immunology
Erythrocytes / immunology
Erythrocytes / parasitology
Humans
Immunoglobulin G* / immunology
Malaria Vaccines* / immunology
Malaria, Falciparum* / immunology
Malaria, Falciparum* / parasitology
Malaria, Falciparum* / prevention & control
Mice
Plasmodium falciparum* / immunology
Protozoan Proteins* / immunology

Substances

Antibodies, Monoclonal
Antibodies, Protozoan
Antigens, Protozoan
Carrier Proteins
Epitopes
Immunoglobulin G
Malaria Vaccines
Protozoan Proteins
RH5 protein, Plasmodium falciparum

Abstract

MeSH terms

Substances

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