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

Abstract

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.