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

Despite recent success in licencing of two malaria vaccines, there continues to be an urgent need for improved vaccine immunogens as the world aims for malaria eradication. The invasion of erythrocytes by Plasmodium falciparum is an essential step in the life cycle of the parasite, preceding symptoms of disease and parasite transmission. Antibodies which target the PfRH5 protein are highly effective at preventing erythrocyte invasion and the most effective growth-inhibitory antibodies bind to a single epitope. Here we used Rosetta-based protein design to produce a focused synthetic immunogen on which this epitope is presented on a small scaffold. Structural biology and biophysics were used to demonstrate that the immunogen is correctly folded and binds neutralising monoclonal antibodies with at least nanomolar affinity. In immunised rats, the immunogen induced PfRH5-targeting antibodies that inhibit parasite growth at a thousand-fold lower concentration that those induced through immunisation with PfRH5. Finally, we show that priming with the focused immunogen and boosting with PfRH5 achieves the best balance between antibody quality and quantity and induces the most effective growth-inhibitory response. This rationally designed vaccine immunogen is now available for use as part of future malaria vaccines, alone or in combination with other immunogens.

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Vaccine-induced human monoclonal antibodies to PfRH5 show broadly neutralizing activity againstP. falciparumclinical isolates

Thiam,

McHugh,

et al. 2024

Preprint

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Vaccines to thePlasmodium falciparumreticulocyte binding-like protein homologue 5 (PfRH5) target the blood-stage of the parasite life cycle. PfRH5 has the potential to trigger the production of strain-transcendent antibodies and has proven its efficacy both in pre-clinical and early clinical studies. Vaccine-induced monoclonal antibodies (mAbs) to PfRH5 showed promising outcomes against culturedP. falciparumlaboratory strains from distinct geographic areas. Here, we assessed the functional impact of vaccine-induced anti-PfRH5 mAbs on more genetically diverseP. falciparumclinical isolates. We used mAbs previously isolated from single B cells of UK adult PfRH5 vaccinees and used ex-vivo growth inhibition activity (GIA) assays to assess their efficacy againstP. falciparumclinical isolates. Next-generation sequencing (NGS) was used to assess the breadth of genetic diversity inP. falciparumclinical isolates and to infer the genotype/phenotype relationship involved in antibody susceptibility. We showed a dose-dependent inhibition of clinical isolates with three main GIA groups: high, medium and low. Except for one isolate, our data show no significant differences in the mAb GIA profile betweenP. falciparumclinical isolates and the 3D7 reference strain, which harbors the vaccine allele. We also observed an additive relationship for mAb combinations, whereby the combination of GIA-low and GIA-medium antibodies resulted in increased GIA, having important implications for the contribution of specific clones within polyclonal IgG responses. While our NGS analysis showed the occurrence of novel mutations in thepfrh5gene, these mutations were predicted to have little or no functional impact on the antigen structure or recognition by known mAbs. Our present findings complement earlier reports on the strain transcendent potential of anti-PfRH5 mAbs and constitute, to our knowledge, the first report on the susceptibility ofP. falciparumclinical isolates from natural infections to vaccine-induced human mAbs to PfRH5.

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

Cited by 3 publications

References 56 publications

Vaccine-induced human monoclonal antibodies to PfRH5 show broadly neutralizing activity against P. falciparum clinical isolates

Vaccine-induced human monoclonal antibodies to PfRH5 show broadly neutralizing activity against P. falciparum clinical isolates

Rational structure-guided design of a blood stage malaria vaccine immunogen presenting a single epitope from PfRH5

Vaccine-induced human monoclonal antibodies to PfRH5 show broadly neutralizing activity againstP. falciparumclinical isolates

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