Preclinical Development of a Stabilized RH5 Virus-Like Particle Vaccine that Induces Improved Anti-Malarial 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; Biswas, Sumi; Draper, Simon J

Abstract

The development of a highly effective vaccine against the pathogenic blood-stage infection of human malaria will require a delivery platform that can induce an antibody response of both maximal quantity and functional quality. One strategy to achieve this includes presenting antigens to the immune system on virus-like particles (VLPs). Here we sought to improve the design and delivery of the blood-stage Plasmodium falciparum reticulocyte-binding protein homolog 5 (RH5) antigen, which is currently in a Phase 2 clinical trial as a full-length soluble protein-in-adjuvant vaccine candidate called RH5.1/Matrix-M™. We identify disordered regions of the full-length RH5 molecule induce non-growth inhibitory antibodies in human vaccinees, and a re-engineered and stabilized immunogen that includes 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 new immunogen, termed “RH5.2”, to hepatitis B surface antigen VLPs using the “plug-and-display” SpyTag-SpyCatcher platform technology also enabled superior quantitative antibody immunogenicity over soluble antigen/adjuvant in vaccinated mice and rats. These studies identify a new 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. W., 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 Anti-Malarial Antibodies

• Working Paper Type: Preprint
• Publication Date: Jan 5, 2024
• Deposit Date: Mar 31, 2025
• Publicly Available Date: Apr 8, 2025
• DOI: https://doi.org/10.1101/2024.01.04.574181
• Public URL: https://nottingham-repository.worktribe.com/output/29273021
• Publisher URL: https://www.biorxiv.org/content/10.1101/2024.01.04.574181v1