Preclinical development of a stabilized RH5 virus-like particle vaccine that induces improved antimalarial antibodies.
King LDW., Pulido D., Barrett JR., Davies H., Quinkert D., Lias AM., Silk SE., Pattinson DJ., Diouf A., Williams BG., McHugh K., Rodrigues A., Rigby CA., Strazza V., Suurbaar J., Rees-Spear C., Dabbs RA., Ishizuka AS., Zhou Y., Gupta G., Jin J., Li Y., Carnrot C., Minassian AM., Campeotto I., Fleishman SJ., Noe AR., MacGill RS., King CR., Birkett AJ., Soisson LA., Long CA., Miura K., Ashfield R., Skinner K., Howarth MR., Biswas S., Draper SJ.
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.