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

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.  ### Competing Interest Statement SJD is an inventor on patent applications relating to RH5 malaria vaccines and antibodies; is a co-founder of and shareholder in SpyBiotech; and has been a consultant to GSK on malaria vaccines. AMM has been a consultant to GSK on malaria vaccines; and has an immediate family member who is an inventor on patent applications relating to RH5 malaria vaccines and antibodies and is a co-founder of and shareholder in SpyBiotech. MH is an inventor on patents relating to peptide targeting via spontaneous amide bond formation, and is a co-founder of and shareholder in SpyBiotech. SB is an inventor on patent applications relating to vaccines made using spontaneous amide bond formation and is a co-founder of, shareholder in and employee of SpyBiotech. JJ is an inventor on patent applications relating to vaccines made using spontaneous amide bond formation and is a co-founder of and shareholder in SpyBiotech. RAD is an inventor on patent applications relating to vaccines made using spontaneous amide bond formation and shareholder in SpyBiotech. LDWK, JRB, DQ, AML, SES, BGW, KMc, IC, SJF and DP are inventors on patent applications relating to RH5 malaria vaccines and/or antibodies. All other authors have declared that no conflict of interest exists.