Preclinical development of a stabilized RH5 virus-like particle vaccine that induces improved antimalarial antibodies

King, Lloyd D.W.; Pulido, David; Barrett, Jordan R.; Davies, Hannah; Quinkert, Doris; Lias, Amelia M.; Silk, Sarah E.; Pattinson, David J.; Diouf, Ababacar; Williams, Barnabas G.; McHugh, Kirsty; Rodrigues, Ana; Rigby, Cassandra A.; Strazza, Veronica; Suurbaar, Jonathan; Rees-Spear, Chloe; Dabbs, Rebecca A.; Ishizuka, Andrew S.; Zhou, Yu; Gupta, Gaurav; Jin, Jing; Li, Yuanyuan; Carnrot, Cecilia; Minassian, Angela M.; Campeotto, Ivan; Fleishman, Sarel J.; Noe, Amy R.; MacGill, Randall S.; King, C. Richter; Birkett, Ashley J.; Soisson, Lorraine A.; Long, Carole A.; Miura, Kazutoyo; Ashfield, Rebecca; Skinner, Katherine; Howarth, Mark R.; Biswas, Sumi; Draper, Simon J.

Abstract

Plasmodium falciparum reticulocyte-binding protein homolog 5 (RH5) is a leading blood-stage malaria vaccine antigen target, currently in a phase 2b clinical trial as a full-length soluble protein/adjuvant vaccine candidate called RH5.1/Matrix-M. We identify that disordered regions of the full-length RH5 molecule induce non-growth inhibitory antibodies in human vaccinees and that a re-engineered and stabilized immunogen (including just the alpha-helical core of RH5) induces a qualitatively superior growth inhibitory antibody response in rats vaccinated with this protein formulated in Matrix-M adjuvant. In parallel, bioconjugation of this immunogen, termed “RH5.2,” to hepatitis B surface antigen virus-like particles (VLPs) using the “plug-and-display” SpyTag-SpyCatcher platform technology also enables superior quantitative antibody immunogenicity over soluble protein/adjuvant in vaccinated mice and rats. These studies identify a blood-stage malaria vaccine candidate that may improve upon the current leading soluble protein vaccine candidate RH5.1/Matrix-M. The RH5.2-VLP/Matrix-M vaccine candidate is now under evaluation in phase 1a/b clinical trials.

Citation

King, L. D., Pulido, D., Barrett, J. R., Davies, H., Quinkert, D., Lias, A. M., Silk, S. E., Pattinson, D. J., Diouf, A., Williams, B. G., McHugh, K., Rodrigues, A., Rigby, C. A., Strazza, V., Suurbaar, J., Rees-Spear, C., Dabbs, R. A., Ishizuka, A. S., Zhou, Y., Gupta, G., …Draper, S. J. (2024). Preclinical development of a stabilized RH5 virus-like particle vaccine that induces improved antimalarial antibodies. Cell Reports Medicine, 5(7), Article 101654. https://doi.org/10.1016/j.xcrm.2024.101654

• Journal Article Type: Article
• Acceptance Date: Jun 19, 2024
• Online Publication Date: Jul 16, 2024
• Publication Date: Jul 16, 2024
• Deposit Date: Apr 8, 2025
• Publicly Available Date: Apr 8, 2025
• Journal: Cell Reports Medicine
• Print ISSN: 2666-3791
• Electronic ISSN: 2666-3791
• Publisher: Cell Press
• Peer Reviewed: Peer Reviewed
• Volume: 5
• Issue: 7
• Article Number: 101654
• DOI: https://doi.org/10.1016/j.xcrm.2024.101654
• Public URL: https://nottingham-repository.worktribe.com/output/47551053
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S2666379124003689?via%3Dihub