Last Updated: 17/11/2025
Assessing the functional contribution of genetic diversity in Plasmodium falciparum RH5 vaccine candidate complex in immune evasion
Objectives
This project proposes to assess the functional contribution of genetic diversity in PfRH5 and its complex members (CyRPA, and Ripr) on P. falciparum immune evasion of both vaccine-induced and naturally acquired human antibody responses.
This objective will be achieved through the following specific aims:
- To investigate the natural genetic diversity present in the PfRH5 complex in disease-endemic settings.
- Evaluate the degree of resistance to monoclonal antibodies targeting PfRH5 or receptor Basigin in ex vivo assays in diverse malaria-endemic regions, spanning the endemicity spectra in Senegal
- Assess the breadth of natural genetic diversity in the PfRH5 complex using targeted, deep amplicon sequencing in Senegalese P. falciparum clinical isolates
- Employ structure-based approaches to model the impact of genetic diversity in the PfRH5 complex, identifying sites likely to impact receptor binding or complex formation
- To evaluate the functional impact of genetic diversity on the inhibitory potential of human antibodies to PfRH5 complex
- Engineer transgenic P. falciparum lines harbouring naturally occurring polymorphisms in the PfRH5 complex
- Isolate human monoclonal antibodies through single-cell sequencing of PfRH5, P113, CyRPA, and Ripr-specific B-cells from malaria-exposed individuals across the transmission spectra, using LIBRA-SEQ
- Evaluate the neutralizing potential of naturally derived total IgG human and monoclonal antibodies to the PfRH5 complex in comparison to vaccine-induced total IgG and human monoclonal antibodies using P. falciparum transgenic lines expressing prioritized polymorphisms and ex vivo clinical isolates.
One of the major challenges that has limited the progress of an effective, deployable malaria vaccine is the breadth of parasite genetic diversity, which often results in the development of strain-specific immunity. This problem has diminished enthusiasm for several invasion-blocking candidates after costly Phase IIb trials. The WHO approval of the first malaria vaccine (RTS,S) is a major achievement and it represents a useful first-generation tool that can be used together with other interventions, but designing a highly-effective, strain-transcendent second-generation malaria vaccine remains the “holy grail” of malaria vaccinology. An ideal malaria vaccine is the one that not only combines safety and efficacy, but also can overcome natural genetic diversity – yielding high efficacy against all circulating strains. Such a vaccine will require a rigorous evaluation of the effect of genetic diversity in the earliest stages of vaccine development, clinical trials, and implementation. Over the last decade, the P. falciparum reticulocyte-binding-like protein homolog 5 (PfRH5) has gained special interest as a promising malaria vaccine candidate, as it is shown to be conserved, immunogenic and essential for parasite survival. PfRH5 binds to other parasite antigens, namely the RH5 interacting protein (Ripr) and the cysteine-rich protective antigen (CyRPA), which together, form an essential complex for merozoite invasion of human erythrocytes.
Jun 2022 — May 2027
$463,660
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