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