Investigation of the Plasmodium falciparum RH5-Interacting Protein (RIPR) as a blood-stage malaria vaccine target

The most severe form of human malaria is caused by the Plasmodium falciparum parasite. Despite recent and encouraging advances in malaria control measures, current estimates suggest that in 2015 there were still over 200 million clinical cases leading to 438,000 deaths. Consequently, the development of an effective and durable vaccine remains a key strategic goal to aid the control, local elimination and eventual eradication of this disease. The mainstay approach to vaccination against the blood-stage of malaria infection is to induce antibodies against the merozoite form of the parasite that invades red blood cells (RBC). Such a vaccine would protect against disease severity and could reduce transmission.
A major recent advance has been the identification of a critical non-redundant interaction during RBC invasion - mediated between basigin (CD147) on the RBC surface and the parasite protein RH5. New data suggest RH5 is delivered to the parasite's surface in a protein complex whose components are not fully elucidated. All known components of the complex are essential and need to be investigated as vaccine targets to complement on-going approaches against RH5. RH5 Interacting Protein (RIPR) is one of the proteins that form this protein complex. Initial studies have suggested that RIPR may make an effective vaccine. However, RIPR is a large and difficult protein to manufacture. The primary aim of this project is to generate the pre-clinical clinical data which supports the development of a RIPR vaccine. This includes identifying neutralising epitopes on the RIPR protein, investigating novel methods of manufacturing RIPR and testing new vaccine technologies such as Viral Like Particles (VLPs) to boost the immune response. In parallel, a second project will be to develop monoclonal antibodies against RIPR. There are very few published anti-RIPR monoclonal antibodies (mAbs) and our group has so far been unsuccessful at generating neutralising anti-RIPR mAbs. Generating new neutralising mAbs will aid structure-based vaccine design by providing powerful tools for studying neutralising epitopes and the interactions between proteins in the complex. In addition, mAbs may be engineered to be powerful therapeutics in their own right, such therapeutics may be important for future malaria treatment strategies.
This DPhil project will have two overriding aims: 1. To thoroughly investigate RIPR as a candidate malaria vaccine. 2. To develop monoclonal antibodies (mAbs) against RIPR. These will be screened for functional anti-parasitic activity and combined with leading mAbs against RH5 to identify a highly inhibitory mAb cocktail.