Abstract
SummaryThe 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.
Highlights
Malaria, responsible for some 435,000 deaths annually, is the biggest parasitic killer in the world today with Plasmodium falciparum accountable for the vast majority of these deaths (World Health Organization, 2018)
We explore the functional interplay between classes of monoclonal antibodies (mAbs) likely to be contained in polyclonal antibody (pAb) targeting PfRH5 following vaccination and highlight the implications of this for rationally designed next-generation blood-stage malaria subunit vaccines
Vaccine-Induced Human mAbs to PfRH5 Anti-PfRH5 mAbs were isolated from single-cell-sorted plasmablasts of immunized volunteers enrolled in a first-in-human Phase Ia clinical trial of a PfRH5-based vaccine delivered using recombinant chimpanzee adenovirus and poxvirus viral-vectors (Figure S1A) (Payne et al, 2017)
Summary
Responsible for some 435,000 deaths annually, is the biggest parasitic killer in the world today with Plasmodium falciparum accountable for the vast majority of these deaths (World Health Organization, 2018). The advancement of leading blood-stage subunit vaccine candidates has been impeded by redundant invasion pathways (Wright and Rayner, 2014), considerable sequence polymorphism in target antigens (Takala et al, 2009), and the elicitation of antibody responses in human vaccinees of insufficient magnitude and/ or breadth for effective neutralization (Draper et al, 2018). This has raised the imperative to identify new conserved and essential vaccine immunogens, to discover the most effective epitopes of these immunogens for protective human antibodies and to design molecules that will elicit these antibodies to produce the most effective immune response
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
