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

Author

Listed:
  • Barnabas G. Williams

    (University of Oxford, Dorothy Crowfoot Hodgkin Building
    Dorothy Crowfoot Hodgkin Building, University of Oxford
    University of Oxford, Old Road Campus Research Building)

  • Lloyd D. W. King

    (University of Oxford, Dorothy Crowfoot Hodgkin Building
    Dorothy Crowfoot Hodgkin Building, University of Oxford
    University of Oxford, Old Road Campus Research Building)

  • David Pulido

    (University of Oxford, Old Road Campus Research Building)

  • Doris Quinkert

    (University of Oxford, Dorothy Crowfoot Hodgkin Building
    Dorothy Crowfoot Hodgkin Building, University of Oxford
    University of Oxford, Old Road Campus Research Building)

  • Amelia M. Lias

    (University of Oxford, Dorothy Crowfoot Hodgkin Building
    Dorothy Crowfoot Hodgkin Building, University of Oxford
    University of Oxford, Old Road Campus Research Building)

  • Sarah E. Silk

    (University of Oxford, Dorothy Crowfoot Hodgkin Building
    Dorothy Crowfoot Hodgkin Building, University of Oxford
    University of Oxford, Old Road Campus Research Building)

  • Robert J. Ragotte

    (University of Oxford, Dorothy Crowfoot Hodgkin Building
    University of Oxford, Old Road Campus Research Building)

  • Hannah Davies

    (University of Oxford, Dorothy Crowfoot Hodgkin Building
    Dorothy Crowfoot Hodgkin Building, University of Oxford
    University of Oxford, Old Road Campus Research Building)

  • Jordan R. Barrett

    (University of Oxford, Dorothy Crowfoot Hodgkin Building
    Dorothy Crowfoot Hodgkin Building, University of Oxford
    University of Oxford, Old Road Campus Research Building)

  • Kirsty McHugh

    (University of Oxford, Dorothy Crowfoot Hodgkin Building
    Dorothy Crowfoot Hodgkin Building, University of Oxford
    University of Oxford, Old Road Campus Research Building)

  • Cassandra A. Rigby

    (University of Oxford, Dorothy Crowfoot Hodgkin Building
    Dorothy Crowfoot Hodgkin Building, University of Oxford)

  • Daniel G. W. Alanine

    (University of Oxford, Dorothy Crowfoot Hodgkin Building
    University of Oxford, Old Road Campus Research Building)

  • Lea Barfod

    (University of Oxford, Old Road Campus Research Building)

  • Michael W. Shea

    (University of Oxford, Old Road Campus Research Building)

  • Li An Cowley

    (University of Oxford, Dorothy Crowfoot Hodgkin Building
    University of Oxford, Old Road Campus Research Building)

  • Rebecca A. Dabbs

    (University of Oxford, Old Road Campus Research Building)

  • David J. Pattinson

    (University of Oxford, Old Road Campus Research Building)

  • Alexander D. Douglas

    (University of Oxford, Old Road Campus Research Building)

  • Oliver R. Lyth

    (University of Oxford, Dorothy Crowfoot Hodgkin Building
    University of Oxford, Old Road Campus Research Building)

  • Joseph J. Illingworth

    (University of Oxford, Old Road Campus Research Building)

  • Jing Jin

    (University of Oxford, Old Road Campus Research Building)

  • Cecilia Carnrot

    (SE-753 18)

  • Vinayaka Kotraiah

    (Leidos Life Sciences)

  • Jayne M. Christen

    (Leidos Life Sciences)

  • Amy R. Noe

    (Leidos Life Sciences
    Latham BioPharm Group)

  • Randall S. MacGill

    (PATH)

  • C. Richter King

    (PATH)

  • Ashley J. Birkett

    (PATH)

  • Lorraine A. Soisson

    (1300 Pennsylvania Ave. NW)

  • Katherine Skinner

    (University of Oxford, Dorothy Crowfoot Hodgkin Building
    Dorothy Crowfoot Hodgkin Building, University of Oxford
    University of Oxford, Old Road Campus Research Building)

  • Kazutoyo Miura

    (NIAID/NIH)

  • Carole A. Long

    (NIAID/NIH)

  • Matthew K. Higgins

    (University of Oxford, Dorothy Crowfoot Hodgkin Building
    Dorothy Crowfoot Hodgkin Building, University of Oxford)

  • Simon J. Draper

    (University of Oxford, Dorothy Crowfoot Hodgkin Building
    Dorothy Crowfoot Hodgkin Building, University of Oxford
    University of Oxford, Old Road Campus Research Building
    NIHR Oxford Biomedical Research Centre)

Abstract

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.

Suggested Citation

  • Barnabas G. Williams & Lloyd D. W. King & David Pulido & Doris Quinkert & Amelia M. Lias & Sarah E. Silk & Robert J. Ragotte & Hannah Davies & Jordan R. Barrett & Kirsty McHugh & Cassandra A. Rigby & , 2024. "Development of an improved blood-stage malaria vaccine targeting the essential RH5-CyRPA-RIPR invasion complex," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48721-3
    DOI: 10.1038/s41467-024-48721-3
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    References listed on IDEAS

    as
    1. Robert J. Ragotte & David Pulido & Amelia M. Lias & Doris Quinkert & Daniel G. W. Alanine & Abhishek Jamwal & Hannah Davies & Adéla Nacer & Edward D. Lowe & Geoffrey W. Grime & Joseph J. Illingworth &, 2022. "Heterotypic interactions drive antibody synergy against a malaria vaccine candidate," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Alexander D. Douglas & Andrew R. Williams & Joseph J. Illingworth & Gathoni Kamuyu & Sumi Biswas & Anna L. Goodman & David H. Wyllie & Cécile Crosnier & Kazutoyo Miura & Gavin J. Wright & Carole A. Lo, 2011. "The blood-stage malaria antigen PfRH5 is susceptible to vaccine-inducible cross-strain neutralizing antibody," Nature Communications, Nature, vol. 2(1), pages 1-9, September.
    3. Cécile Crosnier & Leyla Y. Bustamante & S. Josefin Bartholdson & Amy K. Bei & Michel Theron & Makoto Uchikawa & Souleymane Mboup & Omar Ndir & Dominic P. Kwiatkowski & Manoj T. Duraisingh & Julian C. , 2011. "Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum," Nature, Nature, vol. 480(7378), pages 534-537, December.
    4. Francis Galaway & Laura G. Drought & Maria Fala & Nadia Cross & Alison C. Kemp & Julian C. Rayner & Gavin J. Wright, 2017. "P113 is a merozoite surface protein that binds the N terminus of Plasmodium falciparum RH5," Nature Communications, Nature, vol. 8(1), pages 1-11, April.
    5. Katherine E. Wright & Kathryn A. Hjerrild & Jonathan Bartlett & Alexander D. Douglas & Jing Jin & Rebecca E. Brown & Joseph J. Illingworth & Rebecca Ashfield & Stine B. Clemmensen & Willem A. de Jongh, 2014. "Structure of malaria invasion protein RH5 with erythrocyte basigin and blocking antibodies," Nature, Nature, vol. 515(7527), pages 427-430, November.
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