Nature Communications (Jun 2024)
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,
- Simon J. Draper
Affiliations
- Barnabas G. Williams
- Department of Biochemistry, University of Oxford, Dorothy Crowfoot Hodgkin Building
- Lloyd D. W. King
- Department of Biochemistry, University of Oxford, Dorothy Crowfoot Hodgkin Building
- David Pulido
- The Jenner Institute, University of Oxford, Old Road Campus Research Building
- Doris Quinkert
- Department of Biochemistry, University of Oxford, Dorothy Crowfoot Hodgkin Building
- Amelia M. Lias
- Department of Biochemistry, University of Oxford, Dorothy Crowfoot Hodgkin Building
- Sarah E. Silk
- Department of Biochemistry, University of Oxford, Dorothy Crowfoot Hodgkin Building
- Robert J. Ragotte
- Department of Biochemistry, University of Oxford, Dorothy Crowfoot Hodgkin Building
- Hannah Davies
- Department of Biochemistry, University of Oxford, Dorothy Crowfoot Hodgkin Building
- Jordan R. Barrett
- Department of Biochemistry, University of Oxford, Dorothy Crowfoot Hodgkin Building
- Kirsty McHugh
- Department of Biochemistry, University of Oxford, Dorothy Crowfoot Hodgkin Building
- Cassandra A. Rigby
- Department of Biochemistry, University of Oxford, Dorothy Crowfoot Hodgkin Building
- Daniel G. W. Alanine
- Department of Biochemistry, University of Oxford, Dorothy Crowfoot Hodgkin Building
- Lea Barfod
- The Jenner Institute, University of Oxford, Old Road Campus Research Building
- Michael W. Shea
- The Jenner Institute, University of Oxford, Old Road Campus Research Building
- Li An Cowley
- Department of Biochemistry, University of Oxford, Dorothy Crowfoot Hodgkin Building
- Rebecca A. Dabbs
- The Jenner Institute, University of Oxford, Old Road Campus Research Building
- David J. Pattinson
- The Jenner Institute, University of Oxford, Old Road Campus Research Building
- Alexander D. Douglas
- The Jenner Institute, University of Oxford, Old Road Campus Research Building
- Oliver R. Lyth
- Department of Biochemistry, University of Oxford, Dorothy Crowfoot Hodgkin Building
- Joseph J. Illingworth
- The Jenner Institute, University of Oxford, Old Road Campus Research Building
- Jing Jin
- The Jenner Institute, University of Oxford, Old Road Campus Research Building
- Cecilia Carnrot
- Novavax AB, Kungsgatan 109, SE-753 18
- Vinayaka Kotraiah
- Leidos Life Sciences
- Jayne M. Christen
- Leidos Life Sciences
- Amy R. Noe
- Leidos Life Sciences
- Randall S. MacGill
- Center for Vaccine Innovation and Access, PATH
- C. Richter King
- Center for Vaccine Innovation and Access, PATH
- Ashley J. Birkett
- Center for Vaccine Innovation and Access, PATH
- Lorraine A. Soisson
- USAID, 1300 Pennsylvania Ave. NW
- Katherine Skinner
- Department of Biochemistry, University of Oxford, Dorothy Crowfoot Hodgkin Building
- Kazutoyo Miura
- Laboratory of Malaria and Vector Research, NIAID/NIH
- Carole A. Long
- Laboratory of Malaria and Vector Research, NIAID/NIH
- Matthew K. Higgins
- Department of Biochemistry, University of Oxford, Dorothy Crowfoot Hodgkin Building
- Simon J. Draper
- Department of Biochemistry, University of Oxford, Dorothy Crowfoot Hodgkin Building
- DOI
- https://doi.org/10.1038/s41467-024-48721-3
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 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.
