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

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.

doi:10.1101/2024.01.04.574181

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bioRxiv · 10.1101/2024.01.04.574181

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

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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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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.. 2024-01-05. Preclinical Development of a Stabilized RH5 Virus-Like Particle Vaccine that Induces Improved Anti-Malarial Antibodies. https://doi.org/10.1101/2024.01.04.574181

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