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Cell. 2019 Jun 27;178(1):216-228.e21. doi: 10.1016/j.cell.2019.05.025. Epub 2019 Jun 13.

Human Antibodies that Slow Erythrocyte Invasion Potentiate Malaria-Neutralizing Antibodies.

Author information

1
The Jenner Institute, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK; Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
2
The Jenner Institute, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
3
Burnet Institute, 85 Commercial Road, Melbourne, VIC 3004, Australia.
4
Department of Chemistry, University of Oxford, Oxford OX1 3QZ, UK.
5
Center for Global Infectious Disease Research, Seattle Children's Research Institute, 307 Westlake Ave. N., #500, Seattle, WA 98109, USA.
6
Laboratory of Malaria and Vector Research, NIAID/NIH, Rockville, MD 20852, USA.
7
Cell Surface Signalling Laboratory, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
8
Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
9
ExpreS(2)ion Biotechnologies, SCION-DTU Science Park, Agern Allé 1, Hørsholm 2970, Denmark.
10
Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK. Electronic address: matthew.higgins@bioch.ox.ac.uk.
11
The Jenner Institute, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK. Electronic address: simon.draper@ndm.ox.ac.uk.

Abstract

The Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) is the leading target for next-generation vaccines against the disease-causing blood-stage of malaria. However, little is known about how human antibodies confer functional immunity against this antigen. We isolated a panel of human monoclonal antibodies (mAbs) against PfRH5 from peripheral blood B cells from vaccinees in the first clinical trial of a PfRH5-based vaccine. We identified a subset of mAbs with neutralizing activity that bind to three distinct sites and another subset of mAbs that are non-functional, or even antagonistic to neutralizing antibodies. We also identify the epitope of a novel group of non-neutralizing antibodies that significantly reduce the speed of red blood cell invasion by the merozoite, thereby potentiating the effect of all neutralizing PfRH5 antibodies as well as synergizing with antibodies targeting other malaria invasion proteins. Our results provide a roadmap for structure-guided vaccine development to maximize antibody efficacy against blood-stage malaria.

KEYWORDS:

RH5; X-ray crystallography; blood-stage; live-cell microscopy; malaria; merozoite; monoclonal antibody; neutralization; structural vaccinology; synergy

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