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

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, Daniel G. W. Alanine, Lea Barfod, Michael W. Shea, Li An Cowley, Rebecca A. Dabbs, David J. Pattinson, Alexander D. Douglas, Oliver R. Lyth, Joseph J. Illingworth, Jing Jin, Cecilia Carnrot, Vinayaka Kotraiah, Jayne M. Christen, Amy R. Noe, Randall S. MacGill, C. Richter King, Ashley J. Birkett, Lorraine A. Soisson, Katherine Skinner, Kazutoyo Miura, Carole A. Long, Matthew K. Higgins and Simon J. Draper ()
Additional contact information
Barnabas G. Williams: University of Oxford, Dorothy Crowfoot Hodgkin Building
Lloyd D. W. King: University of Oxford, Dorothy Crowfoot Hodgkin Building
David Pulido: University of Oxford, Old Road Campus Research Building
Doris Quinkert: University of Oxford, Dorothy Crowfoot Hodgkin Building
Amelia M. Lias: University of Oxford, Dorothy Crowfoot Hodgkin Building
Sarah E. Silk: University of Oxford, Dorothy Crowfoot Hodgkin Building
Robert J. Ragotte: University of Oxford, Dorothy Crowfoot Hodgkin Building
Hannah Davies: University of Oxford, Dorothy Crowfoot Hodgkin Building
Jordan R. Barrett: University of Oxford, Dorothy Crowfoot Hodgkin Building
Kirsty McHugh: University of Oxford, Dorothy Crowfoot Hodgkin Building
Cassandra A. Rigby: University of Oxford, Dorothy Crowfoot Hodgkin Building
Daniel G. W. Alanine: University of Oxford, Dorothy Crowfoot Hodgkin 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
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
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
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
Kazutoyo Miura: NIAID/NIH
Carole A. Long: NIAID/NIH
Matthew K. Higgins: University of Oxford, Dorothy Crowfoot Hodgkin Building
Simon J. Draper: University of Oxford, Dorothy Crowfoot Hodgkin Building

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-48721-3

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