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Dryad

PfRH5-induced human monoclonal antibodies show broadly neutralizing activity in P. falciparum clinical isolates

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Apr 17, 2024 version files 101.87 KB

Abstract

Vaccines to the Plasmodium falciparum reticulocyte binding-like protein homolog 5 (PfRH5) target the blood stage of the parasite’s 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 in cultured P. falciparum strains from distinct geographic areas. Here, we assessed the functional impact of vaccine-induced mAbs to PfRH5 on the genetically more complex P. falciparum clinical isolates. We used mAbs isolated from single-cell sorted B-cells of volunteers enrolled in the phase 1a (NCT02181088) clinical trial of the viral-vectored PfRH5 vaccine and used ex-vivo growth inhibition assays (GIA) to assess their efficacy in P. falciparum clinical isolates. Next-generation sequencing (NGS) was used to assess the breadth of genetic diversity in P. falciparum clinical 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 shows no significant differences in antibody GIA profile between the P. falciparum clinical isolates and the 3D7 reference strain, which harbours the vaccine allele. We observed an additive relationship, where the combination of GIA-low and GIA-medium antibodies resulted in increased GIA activities, having important implications for the contribution of specific monoclonal antibodies in polyclonal IgG responses. While our NGS analysis showed the occurrence of novel mutations in the pfrh5 gene, these mutations were predicted to have little or no functional impact on the antigen’s structure or recognition by known mAbs. Our present findings complement earlier reports on the strain transcendent potential of mAbs to PfRH5 and constitute, to our knowledge, the first report on the susceptibility of P. falciparum clinical isolates from natural infections to vaccine-induced mAbs to PfRH5.