Abstract
The Plasmodium falciparum reticulocyte-binding
protein homolog 5 (PfRH5) is the leading target
for next-generation vaccines against the diseasecausing 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.
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