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PreprintCited by 27Malaria Research and ControlImmunotherapy and Immune Responsesvaccines and immunoinformatics approaches

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Preclinical Development of a Stabilized RH5 Virus-Like Particle Vaccine that Induces Improved Anti-Malarial Antibodies

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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.·2024·Cell Reports Medicine
DOI 10.1101/2024.01.04.574181PMC PMC11293324

Preprint — published as 10.1016/j.xcrm.2024.101654 · Paper page

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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.

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Metadata

Authors
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., Jin, J., Li, Y., Carnrot, C., Minassian, A. M., Campeotto, I., Fleishman, S. J., Noe, A. R., MacGill, R. S., King, C. R., Birkett, A. J., Soisson, L. A., Long, C. A., Miura, K., Ashfield, R., Skinner, K., Howarth, M., Biswas, S., & Draper, S. J.
Affiliations
  • University of Oxford (GB)
  • National Institute of Allergy and Infectious Diseases (US)
  • University of Ghana (GH)
  • Novavax (Sweden) (SE)
  • Weizmann Institute of Science (IL)
  • Leidos (United States) (US)
  • Program for Appropriate Technology in Health (US)
  • United States Agency for International Development (US)
Corresponding author
Draper, Simon J.
ORCID
Venue
Cell Reports Medicine
Publisher
openRxiv
Published
2024-01-05
Volume
5
Issue
7
Pages
101654-101654
ISSN
2666-3791 (ISSN-L)
DOI
10.1101/2024.01.04.574181
PMC
PMC11293324
OpenAlex
W4400683710
Cited by
27
References
1
Citations by year
2026: 9 · 2025: 12 · 2024: 6
FWCI
11.18
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Cell Reports Medicine (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Repository@Nottingham (University of Nottingham) (submittedVersion)
Funders
  • United States Agency for International Development (GH-BAA-2018-Addendum03, 7200AA20C00017)
  • NHS Blood and Transplant
  • Wellcome Trust (106917/Z/15/Z, 205981/Z/17/Z, Z/17/Z, DEL‐15‐007, /Z/15/Z)
  • Novavax
  • Leidos
  • National Institute for Health and Care Research
  • Department of Health and Social Care
  • University of Oxford
  • European Commission (EDCTP2-programme, EDCTP2, 733273, HORIZON2020)
  • African Academy of Sciences (DEL-15–007)
  • National Institutes of Health (00001)
  • Medical Research Council (MR/N013468/1, MC_PC_15040, MR/N013468/, MR/P001351/1)
  • National Institute of Allergy and Infectious Diseases
  • NHLBI Division of Intramural Research
  • European and Developing Countries Clinical Trials Partnership (EDCTP2)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
Keywords
RH5, Plasmodium falciparum, blood-stage malaria vaccine, virus-like particles, hepatitis B surface antigen, SpyTag/SpyCatcher, Matrix-M adjuvant, intrinsically disordered regions, vaccine immunogenicity
MeSH terms
Animals, Antibodies, Protozoan, Antigens, Protozoan, Carrier Proteins, Female, Humans, Mice, Inbred BALB C, Plasmodium falciparum, Protozoan Proteins, Malaria, Falciparum, Malaria Vaccines, Mice, Rats, Vaccines, Virus-Like Particle

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