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

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

doi:10.1016/j.xcrm.2024.101654

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

Cell Rep Med. 2024 Jul 16;5(7):101654. doi: 10.1016/j.xcrm.2024.101654.

Authors

Lloyd D W King¹, David Pulido², Jordan R Barrett¹, Hannah Davies¹, Doris Quinkert¹, Amelia M Lias¹, Sarah E Silk¹, David J Pattinson², Ababacar Diouf³, Barnabas G Williams¹, Kirsty McHugh¹, Ana Rodrigues⁴, Cassandra A Rigby⁴, Veronica Strazza⁴, Jonathan Suurbaar⁵, Chloe Rees-Spear⁶, Rebecca A Dabbs², Andrew S Ishizuka², Yu Zhou², Gaurav Gupta², Jing Jin², Yuanyuan Li², Cecilia Carnrot⁷, Angela M Minassian⁸, Ivan Campeotto⁹, Sarel J Fleishman¹⁰, Amy R Noe¹¹, Randall S MacGill¹², C Richter King¹², Ashley J Birkett¹², Lorraine A Soisson¹³, Carole A Long³, Kazutoyo Miura³, Rebecca Ashfield¹, Katherine Skinner¹, Mark R Howarth⁹, Sumi Biswas², Simon J Draper¹⁴

Affiliations

¹ Department of Biochemistry, University of Oxford, Dorothy Crowfoot Hodgkin Building, OX1 3QU Oxford, UK; Kavli Institute for Nanoscience Discovery, Dorothy Crowfoot Hodgkin Building, University of Oxford, OX1 3QU Oxford, UK; The Jenner Institute, University of Oxford, Old Road Campus Research Building, OX3 7DQ Oxford, UK.
² The Jenner Institute, University of Oxford, Old Road Campus Research Building, OX3 7DQ Oxford, UK.
³ Laboratory of Malaria and Vector Research, NIAID/NIH, Rockville, MD 20852, USA.
⁴ Department of Biochemistry, University of Oxford, Dorothy Crowfoot Hodgkin Building, OX1 3QU Oxford, UK; Kavli Institute for Nanoscience Discovery, Dorothy Crowfoot Hodgkin Building, University of Oxford, OX1 3QU Oxford, UK.
⁵ The Jenner Institute, University of Oxford, Old Road Campus Research Building, OX3 7DQ Oxford, UK; West African Centre for Cell Biology of Infectious Pathogens, University of Ghana, Accra LG 54, Ghana.
⁶ The Jenner Institute, University of Oxford, Old Road Campus Research Building, OX3 7DQ Oxford, UK; London School of Hygiene and Tropical Medicine, WC1E 7HT London, UK.
⁷ Novavax AB, Kungsgatan 109, 753 18 Uppsala, Sweden.
⁸ Department of Biochemistry, University of Oxford, Dorothy Crowfoot Hodgkin Building, OX1 3QU Oxford, UK; Kavli Institute for Nanoscience Discovery, Dorothy Crowfoot Hodgkin Building, University of Oxford, OX1 3QU Oxford, UK; The Jenner Institute, University of Oxford, Old Road Campus Research Building, OX3 7DQ Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.
⁹ Department of Biochemistry, University of Oxford, Dorothy Crowfoot Hodgkin Building, OX1 3QU Oxford, UK.
¹⁰ Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel.
¹¹ Leidos Life Sciences, Frederick, MD, USA.
¹² Center for Vaccine Innovation and Access, PATH, Washington, DC 20001, USA.
¹³ USAID, 1300 Pennsylvania Avenue NW, Washington, DC 20004, USA.
¹⁴ Department of Biochemistry, University of Oxford, Dorothy Crowfoot Hodgkin Building, OX1 3QU Oxford, UK; Kavli Institute for Nanoscience Discovery, Dorothy Crowfoot Hodgkin Building, University of Oxford, OX1 3QU Oxford, UK; The Jenner Institute, University of Oxford, Old Road Campus Research Building, OX3 7DQ Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK. Electronic address: simon.draper@bioch.ox.ac.uk.

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.

Keywords: Plasmodium falciparum; RH5; VLP; antibody; blood-stage; malaria; vaccine; virus-like particle.

MeSH terms

Animals
Antibodies, Protozoan* / immunology
Antigens, Protozoan / immunology
Carrier Proteins / immunology
Female
Humans
Malaria Vaccines* / immunology
Malaria, Falciparum / immunology
Malaria, Falciparum / prevention & control
Mice
Mice, Inbred BALB C
Plasmodium falciparum* / immunology
Protozoan Proteins* / immunology
Rats
Vaccines, Virus-Like Particle* / immunology

Substances

Malaria Vaccines
Antibodies, Protozoan
Vaccines, Virus-Like Particle
Protozoan Proteins
RH5 protein, Plasmodium falciparum
Antigens, Protozoan
Carrier Proteins

Grants and funding

WT_/Wellcome Trust/United Kingdom